Open access peer-reviewed chapter

Protective and Pathogenic Immune Responses to Cutaneous Leishmaniasis

Written By

Elina Panahi, Danielle I. Stanisic, Christopher S. Peacock and Lara J. Herrero

Submitted: September 8th, 2021 Reviewed: October 11th, 2021 Published: December 16th, 2021

DOI: 10.5772/intechopen.101160

Chapter metrics overview

76 Chapter Downloads

View Full Metrics

Abstract

Leishmania (Kinetoplastida: Trypanosomatidae) parasites are known to cause a broad spectrum of clinical diseases in humans, collectively known as the leishmaniases. Cutaneous leishmaniasis is the most common clinical presentation with varying degrees of severity largely driven by host immune responses, specifically the interplay between innate and adaptive immune response. The establishment of a T lymphocyte driven cell-mediated immune response, leading to activated phagocytic cells, leading to Leishmania parasite killing and control of infection. Alternatively, the Leishmania parasite manipulates the host immune system, enabling parasite proliferation and clinical disease. Here we review how the cumulative interactions of different aspects of the host immune response determines disease outcome, severity, and immunity to re-infection.

Keywords

  • Leishmania
  • innate immunity
  • adaptive immunity
  • cytokine
  • T-cell response
  • immunopathology

1. Introduction

The leishmaniases are a diverse group of vector-borne diseases resulting from infection with parasites of the genus Leishmania(L.) (Kinetoplastida: Trypanosomatidae). More than 20 species of Leishmaniaparasites are considered public health threats with the Leishmania(Leishmania) and Leishmania(Viannia) subgenera encompassing the medically important human pathogenic Leishmaniaparasites (reviewed in [1]). Leishmaniasis is acquired through the bite of an infected phlebotomine sandfly, with the genera Phlebotomus(Old World; OW) and Lutzomyia(New World; NW) responsible for human transmission. The Leishmanialife-cycle (Figure 1) is complex as the parasites alternate between a flagellated promastigote form within the insect vector (reviewed in [2]) and an intracellular amastigote form that resides within phagolysosomes of mammalian phagocytic cells (reviewed in [3]). Clinical manifestations of infection with L. (Leishmania) and L. (Viannia) species vary from spontaneous self-healing localized lesions (cutaneous leishmaniasis; CL) to life-threatening systemic multi-organ disease (visceral leishmaniasis; VL, also known as kala-azar). Nearly all Leishmaniaparasites can cause CL of varying severity ranging from sub-clinical (also referred to as asymptomatic; reviewed in [4]) and self-resolving lesions to persistent chronic infections that result in severe tissue destruction and disfigurement (Table 1) [1].

Figure 1.

The development ofLeishmaniaparasites and their interaction with cells of the immune system. (A) During blood feeding, promastigotes are injected into the skin. (B) Neutrophils are the first phagocytic cells to arrive at the site of inoculation and play several roles. They arrive rapidly and release interleukin-1β (IL-1β), which is triggered by sandfly gut microbiota and promotes phagocytosis. (C) Neutrophils release neutrophil extracellular traps (NETs) and kill promastigotes through NETosis. (D) Neutrophils phagocytose promastigotes and (E) infected neutrophils interact with dendritic cells (DCs) inducing IL-10 which favors parasite survival. (F) DCs also phagocytose promastigotes and (G) interact with natural killer cells, resulting in the production of IFNγ. (H)Leishmaniacan escape apoptotic neutrophils. (I) Neutrophils degranulate and release mediators, such as macrophage inflammatory protein (MIP-1β), which recruits monocytes and macrophages. (J) Macrophages phagocytose promastigotes and neutrophils can then activate infected macrophages to induce intracellular parasite killing by releasing reactive oxygen species (ROS). (K) Apoptotic infected-neutrophils are engulfed by macrophages providing a silent entry for the parasite by downregulating ROS and nitric oxide (NO). (L) Within the macrophage, the promastigotes undergo significant biochemical and metabolic changes by transforming into their intracellular amastigote form to proliferate and infect more cells and/or (M) persist indefinitely. The life cycle is continued when (N) a female phlebotomine sandfly ingests a blood meal containingLeishmaniainfected phagocytes. (O) Within the vector, the amastigotes develop into the promastigote stage, (P) replicate and undergo further development (not shown here) (Q) concluding in a migration to the stomodeal valve to enable transmission to a mammalian host. Created withBioRender.com

Clinical formLeishmaniaparasiteClinical manifestations in humansReferences
Old world cutaneous leishmaniasis
LCLSubgenusLeishmaniaCharacterized by a single localized skin lesion that develops over a period of weeks to months at the site of the phlebotomine sandfly bite. Erythema first appears before developing into a papule. This further advances into a nodule, which progressively becomes ulcerated with a well-demarcated, raised border. Depending on the infective parasite, LCL may present in various forms (see below). Following resolution of disease, permanent scarring is common[1, 5, 6, 7, 8, 9]
Leishmania aethiopicaRather than having a classic ulcer, patients present with crusty lesions with a patchy distribution, local oedema, and color changes often persisting for several years
Leishmania majorMultiple ulcero-crusted nodules and wet sores; necrosis and severe inflammation
Leishmania infantum
Leishmania donovani
Manifests as papules and nodules with minimal ulceration that recovers slowly. More commonly causes systemic infection
Leishmania tropicaDry ulcerating lesions, frequently presenting in multiple sites which may persist for several years
MCLLeishmania aethiopicaMucosal lesions present simultaneously with lesions on the skin; primarily on the skin with spread to mucosa afterwards
DCLLeishmania aethiopicaChronic and progressive condition affecting large areas of the skin with multiple nodules across the skin that often lack ulceration. Parasites grow uncontrollably in lesions and lesion growth can persist for decades
New world cutaneous leishmaniasis, collectively grouped as American tegumentary leishmaniasis (ATL)
LCLSubgenusViannia
Leishmania braziliensis
Leishmania guyanensis
Leishmania panamensis
SubgenusLeishmania
Leishmania mexicana Leishmania amazonensis
Presents with severe, ulcerating lesions that may later manifest as MCL (see below). Characterized by single or multiple ulcerated lesions with elevated borders. The self-healing time of lesions can range from a few months (L. mexicana) to several years (e.g., L. braziliensis).[1, 10]
MCLLeishmania braziliensis
Leishmania guyanensis
Leishmania panamensis
Healed LCL can progress to destruction of the mucosa affecting predominately the nasopharyngeal mucosa (90% have had a previous history of CL). Characterized by the destruction of tissues of the nasal septum, lips, and palate. The excessive immune response seen with MCL has been attributed to the presence of Leishmaniadouble-stranded RNA (dsRNA) virus (LVR), which is unique to the NW L. (Viannia) subgenus [11]
DCLSubgenusLeishmania
Leishmania amazonensis
Leishmania mexicana
Multiple non-healing cutaneous lesions, erythematous nodules and papules with various types of eruptions. DCL manifests as multiple widespread papules and non-ulcerating nodules with large numbers of viable parasites
DsCLLeishmania braziliensisCharacterized by multiple pleomorphic lesions in two or more non-contiguous areas of the body. Lymphatic spread is common for L. braziliensis
DsCL is characterized by various lesions located on the body with few detectable parasites

Table 1.

Clinical manifestations of cutaneous leishmaniasis caused by medically important Old World and New World Leishmania parasites.*

Abbreviations: NW, New World; OW, Old World; LCL, localized cutaneous leishmaniasis; MCL, mucocutaneous leishmaniasis; DCL, diffuse cutaneous leishmaniasis; DsCL, disseminated cutaneous leishmaniasis.


The interaction between the parasite and the host immune response is complex and varied leading to a range of possible different disease outcomes. While the species of Leishmaniaparasite plays a large role in determining disease manifestations, host immunity and genetics largely influence the severity of infection. The classic T helper 1/T helper 2 (TH1/TH2) model has been applied for many years to explain the disease severity and outcome, with CD4+ TH1 cells mediating resistance to Leishmaniaand CD4+ TH2 cells promoting host susceptibility [12]. However, this assumption is based primarily on an experimental Leishmania(L.) majormodel of infection in congenic mouse strains, which are not entirely relevant to human infections. The model fails to explain the different immune responses and clinical presentations observed in the range of CL phenotypes caused by the various Leishmaniaspecies. Similar to the immunological spectrum observed in humans, the combination of mouse strain (reviewed in [13]), mode of challenge [14], infectious dose [15] and infecting parasite species or strain (reviewed in [16]), influences clinical presentation. With a focus on innate and adaptive immunity and subsequent immunopathology, here we describe the key immune responses induced by cutaneous Leishmaniainfection. We further discuss the coordination between innate and adaptive immune responses in parasite control and how persistent parasites play an important role in protective immunity.

Advertisement

2. The innate immune system in Leishmaniainfection and disease

The innate immune response is the host’s first line of defense against invading pathogens and consists of physical (e.g., skin), chemical (e.g., nitric oxide and reactive oxygen species), soluble factors (e.g., complement, chemokines and cytokines) and cellular defenses (e.g., neutrophils and macrophages), all of which play a vital role in determining the course of infection.

2.1 Complement activation

Inoculated Leishmaniapromastigotes rapidly interact with the host’s complement system. All three complement pathways (alternative, classical and lectin) are involved to varying degrees in Leishmaniaparasite killing and result in the activation of complement (C) protein C3 convertase cleaving C3 to generate C3b (Figure 2; reviewed in [17]). C3b facilitates the deposition of the C5b-C9 membrane attack complex (MAC) onto the surface of culture-derived stationary phase Leishmaniapromastigotes (a stage predominately found in the sandfly midgut), resulting in lysis of the parasite and subsequent uptake by phagocytic cells [17, 18]. C3b also acts as an opsonin, promoting direct phagocytosis and destruction by immune cells. In vitroexperiments demonstrated killing of up to 90% of culture-derived procyclics Leishmaniapromastigotes (including L. donovani, L. amazonensis, L. infantumand L. majorspecies) via complement-mediated lysis within the first few minutes of serum contact [19]. The remaining resistant parasites used the surface bound C3b to enter immune cells and cause infection. Contrary to culture-derived procyclics promastigotes, metacyclic promastigotes (the infective stage that is deposited into the skin by blood-feeding phlebotomine sandflies) are able to subvert phagocytosis to promote their survival and mediate host pathogenesis [17, 18, 19]. The glycocalyx component, known as lipophosphoglycan (LPG), and metalloproteinase glycoprotein 63 (GP63), is distinct to the surface of the infective metacyclic promastigotes, preventing the formation of MAC and complement lysis by cleaving the C3b into an inactive form of C3b (iC3b) [18, 20, 21], thereby subverting the complement system. The MAC can also be physically inhibited by elongated LPG on the surface of metacyclic promastigotes [17]. Moreover, iC3b serves as an opsonin that facilitates the parasite’s uptake by binding to complement receptor 1 (CR1) and CR3 on macrophages and neutrophils. Binding via CR3 inhibits the production of interleukin 12 (IL-12) and oxidative burst, which provides safe parasite entry into macrophages [22].

Figure 2.

Activation of complement byLeishmaniaparasites. (A) All three complement pathways are activated by theLeishmaniaparasite. (B) The alternative pathway is activated directly by theLeishmaniaparasite and is considered to be the main complement pathway involved inLeishmaniaclearance. The classical pathway is antibody-driven, while the lectin pathway is activated by the binding of mannose-binding lectin and ficolin on the parasite [16]. (C) Following activation of all pathways, the complement protein C3 convertase cleaves C3 to generate C3b. C3b facilitates the deposition of the C5b-C9 membrane attack complex (MAC) onto the surface of theLeishmaniaparasite, (D) ultimately resulting in uptake by neutrophils and macrophages following lysis of the parasite. (E) However, the lipophosphoglycan (LPG) metalloproteinase glycoprotein (GP63) on the parasite’s surface inhibits MAC formation through its virulence factor, such as activating protein kinase and inducing interleukin-12 (IL-12) [16]. LPG and GP63 resist complement lysis by cleaving the C3b into inactive C3b (iC3b) to inhibit MAC convertase leading to safe entry into host cells and protection from complement-mediated attack. Created with Biorender.

2.2 Pattern recognition receptors on innate immune cells

Pathogen recognition receptors (PRRs) expressed on innate immune cells are critical for recognizing invading pathogens via pathogen-associated molecular patterns (PAMPs) and initiating the host immune response (Figure 3). Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are the most studied PRRs in leishmaniasis and play a dual role in promoting protection or resistance depending on the infecting Leishmaniaspecies, which receptor the parasite interacts with first and the model used [23, 24, 25].

Figure 3.

Macrophage recognition ofLeishmaniaparasites. Toll-like receptors (TLR) are categorized as extracellular receptors (TLR2 and TLR 4) and intracellular receptors (TLR3, TLR7, TLR8 and TLR9). TLRs are activated and use the adaptor proteins (myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF)) for signal transduction, which is important forLeishmaniaclearance. TLR2, TLR4, TLR7, TLR8 and TLR9 use MyD88, TLR3 uses TRIF and TLR4 uses both MyD88 and TRIF. (A) On the macrophage surface, TLR2 and TLR4 recognize lipophosphoglycan (LPG) molecules found on the surface ofLeishmaniapromastigotes and amastigotes (L. major). (B) Upon recognition ofLeishmania, macrophages release cytokines and nitric oxide (NO) that promote either parasite death or survival. (C) TLR2 activation by LPG can also induce the release of suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3, which inhibits TLR4 signaling. (D) Complement receptors 1 (CR1) and CR3 are also categorized as extracellular receptors and can recognize LPG and metalloproteinase glycoprotein 63 (GP63) both expressed on the promastigote surface. (E) Fc receptors, located on the extracellular surface of macrophages, can also recognize immunoglobulin G (IgG) on the surface of amastigotes. (F) Intracellular TLRs recognizeLeishmaniaRNA (TLR3, TLR7 and TLR8) and DNA (TLR 9). In the cytoplasm, (G) the NLRP3 inflammasome activates caspase-1, which cleaves pro-interleukin-1β (IL-1β) and pro-IL-18 to generate mature IL-1β and IL-18. Created withBiorender.com.

Both TLR2 and TLR4 (extracellular receptors) are found on the surface of host macrophages and neutrophils and recognize Leishmaniapromastigote LPG and GP63 [23, 24, 25] and Leishmaniaamastigote LPG (L. majorspecific) and proteophosphoglycan (PPG), which are expressed on the amastigote and promastigote surface [26, 27].

TLRs are activated and use the adaptor protein myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF) for signal transduction. The MyD88 adapter was shown to be required for the clearance of L. majorinfection in C57BL/6 mice, with MyD88-null C57BL/6 mice showing a greater susceptibility to infection than WT mice [23]. Furthermore knocking out TLR2 in C57BL/6 mice [TLR2−/−] resulted in mice displaying higher resistance to Leishmania(V.) braziliensisinfection compared to WT and this resistance was associated with increased enhanced IFN-γ production [24]. Similarly, C57BL/6 TLR2−/− mice infected with Leishmania(L.) amazonensisshowed a reduced parasite burden compared to infected WT C57BL/6 mice [25]. It has been proposed that LPG on the surface of Leishmaniapromastigotes may explain why TLRs promote both protection and resistance, as the density and diversity of surface polysaccharide extensions to the LPG molecules varies between Leishmaniaspecies and between their morphological stages [24]. Similarly, TLR4 has a dual role that depends on the time of stimulation [28]. When TLR4 on mouse macrophages is primed in vitrowith interferon-γ (IFNγ) prior to L. majorinfection, host protective TNF-α and NO are induced, promoting parasite killing. However, when IFNγ is added at the time of infection without sufficient priming time, macrophages increase IL-10 production, favoring parasite persistence [28, 29]. Interestingly, ex vivostudies using human monocytes from CL patients revealed that infection with L. braziliensisup-regulated TLR2 and TLR4 expression on inflammatory monocytes subsets [30, 31]. Moreover, a correlation with detrimental outcomes of CL was linked to the TLR up-regulation and production of TNF-α and IL-10 in infected monocytes [31]. These results using monocytes from human CL patients infected with L. braziliensissuggest that TLR2 and TLR4 expression triggers an inflammatory response and pathology.

TLR3, TLR7 and TLR9 are intracellular receptors recognizing Leishmaniaparasites in the endosomes of macrophages and are activated by Leishmanianucleic acids [17]. TLR9 is the most studied intracellular receptor and is associated with disease outcome having an important role in the early events of lesion development and parasite burden. A direct correlation was seen between TLR9 expression and lesion size in mice infected with L. braziliensis[32, 33]. Similarly ex vivohuman monocytes from CL patients presenting with larger lesion size, were found to express higher levels of TLR9 [33]. Little is still known about the role of TLR3 in CL. TLR3 promotes immune protection against L. (Leishmania) donovani(visceral Leishmaniaspecies) through the production of TNF-α and NO [34]. Recent studies identified TLR7 as having an essential role in early L. majorinfection control by neutrophils. In TLR7/ C57BL/6 mice infection with L. majorleads to long-term exacerbation of CL [35].

In contrast to TLRs, NLRs are cytoplasmic pattern recognition receptors. The NLRP3 inflammasome is a major regulator of IL-1β and IL-18 in Leishmaniainfection [36]. Similar to TLRs, the involvement and role of NLRs is dependent on the infecting Leishmaniaspecies. In murine models, activation of the inflammasome and IL-1β production have been shown to be associated with a protective role in parasite control during infection with L. amazonensisand L. braziliensis[37, 38, 39]. In contrast, they have no involvement in resistance to L. majorinfection. Moreover, the NLRP3 inflammasome promotes the development of TH2 cells resulting in non-healing lesions during L. majorinfection in BALB/c mice [40].

2.3 Innate cellular immunity

The recruitment and activation of innate immune cells are critical for the killing of invading pathogens by phagocytosis. However, these cells can also facilitate the survival of Leishmaniaparasites (Figure 1). Leishmaniahas evolved mechanisms to subvert host killing by modulating the response of specific immune cells. Macrophages and monocytes are the primary host cell for Leishmaniaparasites; however, a variety of immune cells are recruited to the inoculation site and play critical roles in determining the course of infection and disease outcome.

2.3.1 Neutrophils

Neutrophils are the first phagocytic cells to arrive at the site of the phlebotomine sandfly bite [41]. These cells are capable of clearing Leishmaniaparasites early in infection through phagocytosis and via the production of an array of microbicidal factors that target Leishmaniaparasites (recently reviewed in [42]). Neutrophils release neutrophil extracellular traps (NETs) to capture and kill Leishmaniapromastigotes through a cell death mechanism (NETosis) [43]. Infected neutrophils degranulate and secrete inflammatory mediators, such as the chemokine macrophage inflammatory protein 1β (MIP-1β) and CC-chemokine ligend-3 (CCL3), aiding in the migration of macrophages, and recruitment of monocytes and dendritic cells [44, 45]. Under normal circumstances, compromised neutrophils undergo spontaneous apoptosis, however prevention of neutrophil apoptosis is an important mechanism that Leishmaniauses to subvert death [41, 44]. For example, infected apoptotic neutrophils can act as silent vectors by providing a safe entry for Leishmaniapromastigotes into macrophages without triggering mechanisms to kill Leishmania[44, 46]. This silent entry into macrophages has been likened to the Trojan horse scenario [41, 47], as the promastigotes suppress neutrophil apoptosis until macrophages arrive at the site of infection and then downregulate the microbicidal responses (ROS and NO) [44, 48]. Infected neutrophils are engulfed by macrophages allowing promastigotes to transform into amastigotes and proliferate. L. majoris able to delay neutrophil apoptosis for up to two days by inducing the secretion of the anti-apoptotic cytokines IL-8 and granulocyte macrophage colony-stimulating factor (GM-CSF) [48]. Infected neutrophils undergoing apoptosis have also been reported to release higher levels of MIP-1β to attract macrophages to the site of infection thereby ensuring a safe entry for the parasite [44].

The ability of neutrophils to promote parasite killing or parasite survival [3549] appears to be Leishmaniaspecies-specific, impacted by the route of infection [3550], and influenced by the genetic background of the host [41, 44, 49, 51, 52, 53]. Studies investigating the role of neutrophils in the development of CL utilized two mouse models namely the susceptible (BALB/c) and resistant (C57BL/6) mice and found differences in the number of neutrophils recruited at the site of L. majorinoculation. Interestingly, only lesions of susceptible mice demonstrated a sustained presence of neutrophils and this was associated with early IL-4 activation and the development of aTH2 response [51]. These observations suggest that in susceptible BALB/c mice the early events of the immune response are important in initiating a subsequent TH differentiation following infection with L. major.

In vitrostudies with human neutrophils suggest that they play either protective or pathogenic roles depending on the infecting Leishmaniaspecies. A study comparing neutrophils from CL and healthy subjects, which were then infected with L. braziliensis ex vivo, observed that neutrophils from CL patients produced more ROS and higher levels of the chemokines CXCL8 and CXCL9 which are both associated with the recruitment of neutrophils and TH1-type cells [54]. Neutrophils from both groups were equally competent to phagocytose L. braziliensis, however the cells from CL patients exhibited a pro-inflammatory profile necessary for parasite clearance [54]. The protective role of neutrophils depends on the infecting Leishmaniaspecies. In vitroinfection of human neutrophils with L. amazonensisresulted in neutrophil production of ROS and leukotriene B4 (an inflammatory mediator) leading to neutrophil degranulation and the killing of L. amazonensis[55, 56]. In contrast, human neutrophils infected with L. majorhave been shown to contribute to pathogenesis through the secretion of high levels of MIP-1β, which attracts macrophages to the site of infection. These macrophages then engulf apoptotic infected-neutrophils, thereby providing a silent and safe parasite transmission into macrophages [44].

2.3.2 Macrophages and monocytes

Macrophages and monocytes are recruited to the inoculation site by degranulating, infected neutrophils releasing inflammatory mediators, such as MIP-1β and CCL2 [44, 57]. These cells become infected either by phagocytosing apoptotic Leishmania-infected neutrophils, by free Leishmaniapromastigotes that have escaped neutrophils, or by amastigotes that have previously ruptured their host cell [41]. Cells of the monocyte lineage are the main host cells of Leishmaniaparasites and once inside, Leishmaniapromastigotes differentiate into amastigotes, where they survive and replicate.

Both macrophages and monocytes are efficient in controlling Leishmaniain the early stages of infection (reviewed in [3]). During phagocytosis, these cells release ROS, through a mechanism known as the respiratory burst, which kills Leishmaniarapidly leading to early parasite control [30]. These cells also produce NO, which is generated by inducible NO synthase (iNOS) [58]. NO diffuses across cell membranes to initiate parasite killing within both the NO-producing cells and bystander cells [58]. For macrophages to release ROS that is sufficient in parasite killing, the cells need to first be activated by IFNγ and TNF-α, which enhance the respiratory burst [59]. Though non-activated macrophages will still release ROS through the respiratory burst following infection, it is insufficient to kill Leishmania. In a mouse model, the respiratory burst and subsequent release of ROS that occurs in Leishmania-infected macrophages were found to be insufficient to kill the parasites if the host cell was not previously activated by IFNγ [59]. During infection, the main producers of IFNγ are CD4+ TH1 cells. Prior to the differentiation and activation of CD4+ TH1 cells, natural killer (NK) cells are the primary producers of IFNγ [60]. In contrast, in vitro studieswith human and mouse monocytes infected with Leishmaniaspecies showed competence in parasite killing through the secretion of ROS and without the need for prior activation [30, 47, 59].

The majority of studies investigating the role of NO have used rodent models, where NO is considered necessary to control Leishmania[58, 61, 62], however it is not yet clear if NO is required for Leishmaniacontrol in humans as activated human macrophages have not been shown to produce NO upon Leishmaniainfection [59, 63], It has been suggested that inhibiting NO promotes Leishmaniainfection in phagocytes [63]. Similar, the exact role of ROS in human Leishmaniainfection is yet to be elucidated, although it is believed that the production of ROS is an important mechanism in eradicating Leishmaniaparasites throughout the course of disease [59].

2.3.3 Dendritic cells

DCs play an important role as a bridge between the innate and adaptive immune systems (reviewed in [64]). In addition to phagocytosing Leishmaniaparasites and infected apoptotic neutrophils [45], DCs are important in the maintenance of immunity and in rapid stimulation of the adaptive immune response during the early stage of infection. DCs present Leishmania-specific antigen to naïve T cells and promoting their differentiation. The migration of DCs to the lymph node (where they activate T cells) is vital to establish an efficient adaptive immune response. Leishmaniahas evolved strategies to inhibit interaction between DCs and T cells by reducing DC migration [64, 65]. It was demonstrated that Leishmaniawas capable of blocking CCR2 (expressed on DC surface) thereby impairing the cells’ ability to migrate, however the mechanisms used by the parasite remain elusive [65].

Advertisement

3. Adaptive immune system in Leishmaniainfection and disease

Following the involvement of innate immune cells in targeting Leishmaniaparasites and antigen presentation, immune cells of the adaptive immune system are activated to induce a Leishmania-specific response. The adaptive immune system plays a pivotal role in Leishmaniainfection through the interplay between T cell-mediated and antibody-mediated immune responses and the induction of immune memory. The complexity of these immune responses, which facilitate the resolution of CL is also reflected by the various phenotypes of clinical CL presentations observed in individuals [66]. On one end of the immune spectrum, a strong T cell response is observed. Although the high levels of IFNγ lead to parasite control, an exacerbated T helper (TH) type-1 response and increased number of CD8+ cytotoxic T cells may also lead to the development of MCL. In contrast, the other end of the immune spectrum is characterized by a high level of Leishmania-specific antibodies and a limited T cell-mediated response. Individuals have an uncontrolled parasite load (as parasites are not neutralized by antibodies), which is a consequence of low levels of TH1 cytokines and this results in DCL manifestations [16, 67, 68]. An intermediate level of both T cell and antibody responses will lead to a form of CL that will normally self-heal over time.

3.1 CD4+ T cells

The generation of Leishmania-specific CD4+ T cells is required for protective immunity, and they play a major role in shaping the adaptive immune response. CD4+ TH cells are essential in determining disease outcome by driving the differentiation and activation of different CD4+ TH cell subsets through the production of cytokines, which either mediate host protection or promote disease pathogenesis (Figure 4).

Figure 4.

Interaction between immune cells andLeishmaniaparasites. (A) Infected macrophages produce pro-inflammatory cytokines such as interleukin-12 (IL-12), IL-18 and tumor necrosis factor-α (TNF-α). These cytokines (B) recruit natural killer (NK) cells to the infection site and (C) promote CD4+ TH cell differentiation into CD4+ TH1. (B) NK cells and (C) CD4+ TH1 cells activate infected macrophages by producing interferon-γ (IFNγ). (D) Activated infected macrophages then release reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS), which results in parasite killing. (E) Infected monocytes killLeishmaniaparasites through the release of ROS and migrate to the lymph node. Here they promote CD4+ TH1 differentiation by producing IL-12. CD4+ TH1 migrates to the skin where they (D) activate infected macrophages. In contrast (F) CD4+ TH cells produce IL-4 (an anti-inflammatory cytokine) which drives the differentiation of CD4+ TH2 cells. (G) Secretion of anti-inflammatory cytokines (such as transforming growth factor-β; TGFβ) by CD4+ TH2 suppresses the production of iNOS and NO by macrophages leading to parasite survival. (H) TGFβ drives the differentiation into CD4+ TH9 cells, which downregulates the release of IFNγ and TNF-α from infected macrophages, thereby promoting disease. (I) TGFβ and IL-6 drives differentiation into CD4+ TH17 cells that stimulates the secretion of IL-1β and infiltration of neutrophils that are believed to aggravate the disease. Adapted from [69]. Created withBiorender.com

Previously, it was widely believed that the induction of either a CD4+ TH1 or TH2 response determined the outcome of infection i.e., induction of protection versus pathology. Subsequent studies have shown that there are a multitude of factors that contribute to the outcome of Leishmaniainfection, thus the TH1/TH2 model oversimplifies a complex interaction between host and parasite. Factors such as the genetic background of the model (or host) and the Leishmaniaparasite (species and strain) studied, contribute to differential disease outcomes. It is acknowledged that several CD4+ T cell subsets are implicated in disease outcome, such as CD4+ regulatory T (Treg) cells, CD4+ T helper populations (TH1, TH2, TH9 and TH17 effector) and T follicular helper (TFH) cells [58, 70, 71, 72].

Cytokines produced by CD4+ T cell subsets and other infected immune cells are generally classified as pro-inflammatory or anti-inflammatory and have been shown to be differentially associated with disease protection or progression, respectively (Table 2). Their role in activating and recruiting immune cells to the infection site shapes the adaptive immune response.

Immune mediatorsCell association/expressed byGeneral functionRole in cutaneous leishmaniasis
IL-1
  • Secreted by epithelial cells, endothelial cells, activated macrophages, DCs, neutrophils and lymphocytes

  • Pro-inflammatory cytokine

  • Critical regulator for early differentiation of TH17 cells

  • Supports the generation of IFNγ secreting T cells (similar to IL-12)

  • Prolonged high levels of IL-1α induces TH2 differentiation and increases pathology severity

  • IL-1β promotes (with IL-23) development of TH17 cells

  • Maintains cytokine secretions in TH17 effector cells (together with IL-6 and IL-23)

  • Can be both protective by secretion of IL-1α and promotion of TNF-α production, and pathogenic during Leishmaniainfection

  • Secretion of IL-1α mediates disease resolution, reduction in parasite burden and enhancement of TH1 response (via higher secretion of IFNγ and lower production of IL-4)

  • Continuous treatment with IL-1α in L. majorinfected C57BL/6 mice induced TH2 responses and promoted disease susceptibility [69]

  • IL-1β treatment during early phases in L. majorinfected C57BL/6 mice mediates protection by promoting TH1 responses [69]

  • Conversely, during the chronic phase, IL-1β can contribute to pathogenesis and worsen clinical symptoms of CL in L. majorinfected C57BL/6 mice through development of TH17 cells and regulation of IL-17 levels [69]

  • IL-1β and IL-1α drive pathogenesis in L. majorinfected BALB/c mice. It was shown that IL-1α deficient and IL-1β deficient mice were resistant to infection and presented delayed nodule development and death [73]

IL-2
  • CD4+ TH1 cells secrete IL-2 which promotes proliferation of T cells

  • Secreted in smaller amounts by CD8+ T cells, NK cells and NKT cells [74]

  • Pro-inflammatory and growth factor cytokine

  • Plays a dual role that may promote susceptibility to infection (by limiting secretion of IL-12 via TH cells) and can also mediate resistance

  • Promotes immune responses by increasing proliferation and cytokine secretion (IFNγ by TH1 cells), cytolytic activity (CD4+, CD8+ and NK cells; binding via IL-2 receptors on lymphocytes)

  • Can stimulate proliferation of TH2 cells through generation of IL-4

  • Involved in the protective immune response against CL and facilitates (along with IFNγ), macrophage activation and a TH1 response and for parasite killing

  • Reduced IL-2 production has been associated with aggravated human CL [75]

IL-4
  • Secreted by activated T cells, TH2 cells and TFH cells

  • A signature anti-inflammatory cytokine of the TH2-type immune response

  • Activates TH2 cell differentiation from naïve CD4+ T cells and production of TH2-associated cytokines (IL-5, IL-10 and IL-13)

  • Powerful inhibitor of IFNγ-producing CD4+ T cells and suppressor of TH1 cells and pro-inflammatory cytokines

  • Associated with non-healing forms of CL in mice (similar to IL-13) [76]

  • Induces TH2 responses in L. majorinfected mice [77]

  • High levels of IL-4 in early stage of infection lead to the secretion of IL-12 by DCs and subsequent TH1 proliferation [76]

  • Functions as a powerful inhibitor of IFNγ-producing CD4+ T cells and suppressor of protective TH1 immune responses

IL-6
  • Secreted by TH2 cells, macrophages, fibroblasts and endothelial cells

  • Can act as a pro-inflammatory and anti-inflammatory cytokine

  • Together with TGFβ, IL-6 can stimulate production of TH17 cells to secrete IL-17 and IL-10

  • IL-6 deficient (−/−) BALB/c mice showed no difference in pathology (parasite burden, lesion burden) when infected with L. majorin comparison to BALB/c wild type (WT) mice. However, IL-6−/− mice did produce lower levels of TH1 and TH2 cytokines [78]

IL-8
  • Secreted by tissue-resident macrophages in response to Leishmaniainfection

  • Monocyte-derived neutrophil chemotactic factor; an activating cytokine

  • Plays a role in the initial recruitment and activation of neutrophils

  • L. majorinfected neutrophils secrete high levels of IL-8 that leads to increased infiltration of neutrophils for parasite phagocytosis [79]

IL-10
  • Secreted by Regulatory T (Treg) cells, TH2 and TH9 cells, DCs, activated macrophages, NK cells and neutrophils

  • Anti-inflammatory cytokine

  • Suppresses activity of TH1 cells, NK cells and macrophages

  • Down-regulates expression of IFNγ, IL-2, IL-3 and TNF-α

  • Important regulator of immunity in CL

  • Associated with CL susceptibility. High levels of IL-10 are strongly associated with non-healing forms of disease [16]

  • The absence of IL-10 in murine models is associated with the control of parasite replication and resolution of cutaneous infection. IL-10−/− mice express higher levels of IFNγ and produce more nitric oxide (NO) than IL-10 +/+ mice [80]

IL-12
  • Secreted by monocytes, macrophages, dendritic cells (DCs) and B lymphocytes

  • Pro-inflammatory cytokine

  • Activates T helper type 1 (TH1) differentiation; stimulates differentiation of naïve T cells into TH1 effectors; inhibits T cell apoptosis

  • Together with IL-15, this cytokine facilitates IFNγ and TNF-α secretion by natural killer (NK) and T cells

  • The absence of the IL-12, IL-23, and IL-27 promotes the development of a TH2 response and increases susceptibility to Leishmaniainfection [81]

IL-13
  • Secreted by TH2 cells and NK cells

  • Anti-inflammatory cytokine

  • Activates the differentiation of naïve TH0 cells into TH2 cells

  • High levels are associated with chronic CL

  • BALB/c IL-13−/− mice were able to control L. majorinfection (production of TH1 responses and effectively control parasite growth), whereas C57BL/6 mice became susceptible to disease pathology due to the increased TH2 responses [82].

IL-17
  • Secreted by TH17 cells, DCs

  • Pro-inflammatory cytokine and mediates tissue inflammation

  • IL-17 can both mediate protection and susceptibility

  • Stimulates secretion of cytokines and chemokines (e.g., TNF-α, IL-1β, CXCL1 and CXCL10)

  • Increased levels of IL-17 (together with IL-23) and rapid neutrophil infiltration are associated with aggravated CL and ML diseases [83]

  • Increased IL-17-dependent neutrophil recruitment into lesions has been shown to significantly promote disease outcome (L. majorinfected BALB/c mice) [84]

  • BALB/c mice infected with L. major shows high levels of IL-17 in contrast to IL-17−/− BALB/c mice despite typical TH2 development (reduction in recruitment of neutrophils in lesional tissue and CXCL2 levels in infected skin) [84]

IL-18
  • Secreted by activated macrophages and DCs, CD8+ memory T cells, neutrophils

  • Pro-inflammatory cytokine

  • An IFNγ inducing factor (induces TH1 responses via IFNγ production with IL-12)

  • Plays a role in early control of CL caused by L. major, but not critical for the development of protective TH1 responses or resolution of infection

  • IL-18−/− C57BL/6 mice had increased susceptibility to L. majorinfection in the early phase of infection but were able to resolve the infection similar to IL-18+/+ mice due to an increased level of IL-12 and IFNγ secretion [85]

IL-22
  • Secreted by TH17, TH1 cells and NKT cells

  • Critical role in tissue repair during CL

  • Strengthens epithelial barrier functions; involved in tissue homeostasis, tissue repair and wound healing

  • Induces keratinocyte proliferation and hyperplasia resulting in thickening of the epidermis

  • L. majorinfected IL-22−/− C57BL/6 mice developed increased pathology in contrast to WT mice due to deficient wound healing of keratinocytes in the absence of IL-22 [86]

  • IL-22 is associated with pathogenesis when secreted with cytokines such as IL-17 [70]

IL-27
  • Secreted by macrophages and DCs

  • Anti-inflammatory cytokine and pro-inflammatory

  • TH17 cell suppressor

  • Promotes differentiation and production of IL-10 producing Treg cells

  • Promotes the differentiation and expansion of Treg cells (main producers of IL-10) and suppresses TH17 cells

  • IL-27−/− WSX-1 mice developed severe L. majorinfection, which correlated with the increased levels of IL-17 CD4+ TH17 cells, reduced levels of IL-10 and increased in IL-4 [87]

IFNγ
  • Secreted by CD4+ TH1 cells; CD8+ TH1 cells, NK cells, and NKT cells

  • Pro-inflammatory cytokine (involved in protection and pathology of CL) [88]

  • Stimulates iNOS expression and activity in infected cells, which promotes parasite killing

  • Stimulates NO secretion in activated macrophages and inhibits amastigote growth

  • Promotes differentiation of naïve CD4+ TH cells into TH1 cells and inhibits the development of TH2 and TH16 cells

  • Compared to WT mice, C57BL/6, IFNγ −/− mice were more susceptible to L. amazonensisinfection with large lesions, increased parasite burden and development of TH2-type responses associated with increased IL-4 [89]

  • High levels of IFNγ can be detrimental and found in patients with MCL [7]

TNF-α
  • Mostly produced by macrophages

  • Secreted by TH1 cells, TFH cells

  • Pro-inflammatory cytokine (involved in protection and pathology of CL)

  • Plays a vital role in Leishmaniaclearance through increasing macrophage activity and NO synthesis

  • Promotes TH1/IFNγ responses against L. majorinfection

  • TNF-α −/− C57BL/6 mice infected with L. majormanifested as fatal disease, a strong protective TH1 response [90]

  • High levels of TNFα can promote disease pathogenesis leading to lesion chronicity [91]

Table 2.

Selection of cytokines and their role in cutaneous leishmaniasis.

−/−, deficient; DCs, dendritic cells; IL, interleukin; IFN, Interferon; MIP, macrophage inflammatory protein; NK, natural killer; NKT, natural killer T cells; NO, nitric oxide; TFH, T follicular helper cells; TGF, transforming growth factor; TH, T helper cell; TNF, tumor necrosis factor; Treg, T regulatory cell; WT, wild type.

It is recognized that the development of CD4+ TH1 immune responses promotes host protection against CL and is associated with the production of pro-inflammatory cytokines (such as IFNγ and IL-12). CD4+ TH1 cells are key producers of IFNγ, which has been shown in resistant and susceptible mouse models to be vital in controlling L. majorparasites [92, 93]. In human and mice, the production of IFNγ activates infected macrophages to enhance the respiratory burst (as discussed above), which eliminates parasites residing and replicating within the phagolysosome, as explained earlier [59].

In contrast to the protective role of CD4+ TH1 cells, susceptibility to Leishmaniainfection and CL progression is influenced by the induction of an IL-4-driven TH2-type immune response as well as the production of the anti-inflammatory cytokines, IL-10, IL-13 and TGFβ [94]. Rodent studies have shown that IL-4-secreting CD4+ TH2 cells and IL-10 secreting Treg cells promote parasite growth and disease susceptibility [95]. For example, the CD4+ TH2-secreting cytokines, IL-4 [96] and IL-10 [97], was identified as having important roles in BALB/c mice’ susceptibility to infection. In the absence of IL-4 or IL-10, BALB/c mice, were able to control parasite growth and resolve lesions resulting in a protective CD4+ TH1 response. Likewise, IL-10 likewise plays a role in disease self-healing C57BL/6 mice. When lacking IL-10, C57BL/6 mice exhibited a faster lesion healing time compared to WT [98]. The roles of IL-4 and IL-10 in promoting susceptibility in human patients with CL are less clear, although elevated IL-10 has been linked to uncontrolled parasite growth in VL [99].

Some cytokines are also considered to have a dual role in relation to disease outcome [100]. The production of the CD4+ TH1 cytokines IFNγ and TNF-α is critical in controlling Leishmaniainfection, however an aggravated production of these two cytokines have been affiliated with severe disease with lesion chronicity [91].

3.2 CD8+ T cells

The role of CD8+ T cells in Leishmaniainfection is still poorly understood. They have both a protective and a pathological role depending on whether the cells are producers of cytokines or are acting as cytolytic T cells, respectively (reviewed in [101]). The contribution and effectiveness of CD8+ T cells in relation to parasite control is determined by the Leishmaniaspecies and experimental model (infective dose and host genetics).

RAG knockout (KO) mice (deficient in both B and T cells) developed lesions at a slower rate (L. majorinfection) compared to WT mice or not at all (L. braziliensisand L. amazonensisinfection) [102, 103, 104]. When reconstituted with CD8+ T cells, RAG KO mice developed severe pathology with lesions [102, 103]. In BALB/c mice infected with L. braziliensis, depletion of CD8+ T cells resulted in reduced lesion size despite having a similar level of parasites in the skin compared with control mice [103].

Mimicking a natural low-dose infection with L. major, studies revealed that CD8+ T cells play a role in protection, associated with high production of IFNγ, which activates macrophages leading to parasite control [102, 105]. Furthermore, IFNγ stimulates DCs to produce IL-12 which promote the development and differentiation of CD4+ TH1 cells. This suggests that CD8+ T cells are important in skewing towards TH1 response through the production of IFNγ and in eliminating the majority of parasites before lesion development. The role that CD8+ T cells play in infection may be associated with their location in the host [106]. When located in the draining lymph node, CD8+ T cells produce IFNγ and are protective [107]. In contrast, when migrating to the lesion site during infection, CD8+ T cells produce lower levels of IFNγ and exhibit cytolytic activity, leading to cell death and an exaggerated inflammatory response that further promotes tissue damage [108]. This is supported by findings from a mouse model showing CD8+ T cells that had migrated to the skin, produced lower levels of IFNγ and instead exhibited cytolytic activity promoting disease progression [103]. There is substantial evidence for a pathogenic role of CD8+ T cells in patients infected with L. braziliensis[109, 110, 111]. As the disease progresses from small nodules to larger skin lesions, an increase in CD8+ T cells and a decrease in CD4+ T cells was observed in the histopathological analysis of human skin lesions [112]. In CL patients a link between CD8+ T cell mediated cytotoxicity and IL-1β inflammasome activation was observed [111]. This activation of NLRP3 inflammasome pathway and its promotion of disease inflammation is currently targeted for host-directed therapy [88, 106].

3.3 Regulatory T cells

The role of Treg cells in Leishmaniainfection is still being elucidated, although though they have been shown in rodent models to be involved in disease pathology and parasite persistence depending on the experimental model used. CD4+ CD25+ Treg cells have been shown to suppress CD4+ T cell activity in L. major-infected C57BL/6 mice, thereby favoring parasite persistence [98, 113, 114]. Treg cells influence both primary and secondary infections with L. major, as they render otherwise non-susceptible mice susceptible to infection [115]. However, their activity may also be dependent on the infecting Leishmaniaspecies. For example, Treg cells play a protective role during infection with New World Leishmaniaspecies, such as L. amazonensis[95, 116]. Transferring Treg cells from an L. amazonensis-infected mouse to a naïve mouse prior to infection with L. amazonensisreduced the development of lesions suggesting that they may also contribute to the control of immunopathogenic responses [116]. Understanding how Treg cells are involved in human Leishmania-infections is still being explored, with evidence so far suggesting that these cells play a role at the infection site and contributing directly to parasite persistent as the main source of IL-10 production [95, 98].

3.4 B cells and antibodies

The function of B cells in CL has not conclusively been shown. During the initial Leishmaniainfection, antibody production by B cells themselves are not believed to play a role, in controlling parasites as Leishmaniaare intracellular. However, some studies indicate that B cells may regulate both protective and pathogenic immune responses during Leishmaniainfection, depending on the infecting species and model used. Production of L. majorantibodies was shown to be important for DCs to phagocytose parasites, as the absence of antibodies by B cells resulted in larger lesions in B cell−/− mice, higher parasite load, low production of IFNγ and a decreased cell-mediated immune response [117]. Moreover, IgG−/− BALB/c mice infected with L. majorresulted in larger lesions and higher parasite load compared to IgG+ BALB/c mice [118]. In contrast, a study using a BALB/c mice deficient in IgM transmembrane domain (μMT), thereby lacking mature B cells, observed that these mice were resistant to L. majorinfection [119]. Other studies using BALB/c mice lacking IL-4Rα expression specifically on B cells, mbicreIL-4Rα−/lox BALB/c mice, resulted in a protective host immunity [29, 119, 120].

There is still a lot of knowledge to gain on B cells’ function and whether they play a part in protection or pathology during infection with Leishmaniaparasites.

Advertisement

4. Persistent Leishmaniainfection and emulating concomitant immunity

Naturally and experimental infection with cutaneous Leishmaniaspecies is controlled following the development of an adaptive TH1 immune response. After induction of this response, parasite numbers decline in infected tissues, lesions heal and lifelong immunity against the infecting Leishmaniaspecies is gained [121]. Though recovery from cutaneous disease has been reached, a small number of Leishmaniaparasites normally remain indefinitely in the host at the initial site of infection; known as persistent parasites [122, 123]. These parasites play an important role in maintaining protective immunity in the event of reinfection by providing a constant source of Leishmaniaantigen for immune stimulation [121, 124]. Both mice and humans who recover from CL maintain chronic subclinical infection at the lesion site and have been shown to be highly resistant to second challenge through sandfly transmitted infections [125]. Though, the immune response is unable to clear the primary infection, the immune system can facilitate concomitant immunity by IFNγ secreting CD4+ TH1 cells [126]. However, reactivation of disease causing infection has been documented for leishmaniasis when the immune system is no longer able to control this low level chronic parasite infection [127, 128]. This is frequently observed when persistently infected individuals become immunosuppressed, such as during infection with the human immunodeficiency virus (HIV) [127, 129].

Currently, vaccine programs have been unsuccessful to emulate the protective responses mediated by concomitant immunity as observed during subclinical infections with persistent parasites (reviewed in [130]). Similar, a sterile cure whereby the parasites are completely eliminated has not been achieved without consequently the loss of long-term immunity [131].

In the past the leishmanization live vaccine practice was employed by inoculating virulent Leishmaniaparasites into individuals, however this has since fallen out of practice due to safety concerns regarding development of non-healing lesions [132]. Since then, vaccine-candidates have failed to provide protection against natural exposure even though they demonstrate protective cell-mediated immunity in rodent models. It is thought that this is due to differences in experimental delivery versus the natural route of infection via the bite of a sandfly. Other challenges are observed when using whole killed parasites or subunit protein vaccine candidates only short-term protection in rodent models has been observed [123, 131].

The difference in protective immunity induced following natural infection and inoculation of whole killed parasites is not fully understood but it has been hypothesized that there is a difference in the immunologic memory responses, which is influenced by the presence of live versus killed parasites. Moreover, the adjuvant dose-quantity tested to date may not be sufficient to generate a memory T cell population [123, 128]. It is possible that vaccines utilizing live-attenuated parasites will most closely mimic natural infection, potentially providing long-term protection against infection and disease [131].

Recently, vector-associated factors have been identified to have an important impact on challenge models in vaccine-mediated immunity [130]. Following needle versus infected sandfly challenge in mice showed that various protein/adjuvant-based vaccines provided intermediate protection against needle challenge whereas sandfly challenge failed to provide protection. Despite generating antigen-specific TH1 immune responses prior to and following challenge, vaccines failed to protect against infected sandfly challenge [125, 133]. The sandfly vector challenge model clearly emphasizes important factors induced by the sandfly, such as the impact of recruited inflammatory cells and immune-mediated host cell activation by the vector.

Advertisement

5. Concluding remarks

The leishmaniases are one of the most important groups of neglected tropical diseases estimated to affect 1 million people annually in nearly 100 countries [1]. The fact that an effective vaccine has yet to be developed reflects the gap in our understanding of host responses to Leishmaniaspecies, disease pathogenesis and what actually constitutes a protective immune response. The different Leishmaniaparasites inducing different host immune responses, which are further impacted by host genetics, have made it difficult to achieve consensus among experimental studies regarding the role of the different immune components in Leishmaniainfection. Furthermore, research to date highlights the inadequacies of small animal models in understanding human host responses to Leishmania. The increase in in vitro/ex vivocharacterization of Leishmania-specific immune responses using samples derived from human clinical studies has provided more information on human CL, however more efforts towards human clinical studies (cohort and case control-studies) including human ex vivoinfection models should be emphasized to gain a better understanding of the human immune response to Leishmaniaparasites. An interesting recent focus has been the use of humanized mice to further examine the role of specific immune cells and responses in Leishmaniainfection; this could further inform the development of novel vaccine strategies [134].

Additionally, there are other important vector and parasite-derived components affecting host immune responses, which were outside the scope of this chapter but are important to consider in terms of host-parasite interactions. Recent experimental studies are providing new insights into host immune responses by employing a sandfly challenge model using the natural route of parasite inoculation via phlebotomine sandflies [46]. Vector-derived components have been shown to contribute to early immune responses in infection [14]. For example, tissue damage caused by the phlebotomine sandfly’s proboscis and the delivery of sandfly saliva triggers the rapid recruitment of neutrophils which induce inflammation [41]. Leishmania-derived components have also been shown to play a role during inoculation and Leishmaniaexosomes have been shown to modulate immune cells and host responses through direct and indirect contact [135].

This chapter has highlighted the complexity associated with CL and how host immune cells can both be protective and pathogenic depending on the interaction with Leishmaniaspecies parasite and host genetic. Employing a human CL model that provides a better understanding and more accurately represents parasite-host interactions will be critical for the development of an effective vaccine capable of inducing long-lasting protective immunity.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1. Burza S, Croft SL, Boelaert M. Leishmaniasis. Lancet. 2018;392:951-970. DOI: 10.1016/S0140-6736(18)31204-2
  2. 2. Dostálová A, Volf P. Leishmania development in sand flies: Parasite-vector interactions overview. Parasites & Vectors. 2012;5:276. DOI: 10.1186/1756-3305-5-276
  3. 3. Martínez-López M, Soto M, Iborra S, Sancho D. Leishmania Hijacks myeloid cells for immune escape. Frontiers in Microbiology. 2018;9. DOI: 10.3389/fmicb.2018.00883
  4. 4. Andrade-Narvaez FJ, Loría-Cervera EN, Sosa-Bibiano EI, Van Wynsberghe NR. Asymptomatic infection with American cutaneous leishmaniasis: Epidemiological and immunological studies. Memórias do Instituto Oswaldo Cruz. 2016;111:599-604. DOI: 10.1590/0074-02760160138
  5. 5. van Henten S, Adriaensen W, Fikre H, Akuffo H, Diro E, Hailu A, et al. Cutaneous Leishmaniasis Due to Leishmania aethiopica. EClinicalMedicine 2018;6:69-81. DOI: 10.1016/j.eclinm.2018.12.009
  6. 6. Fikre H, Mohammed R, Atinafu S, van Griensven J, Diro E. Clinical features and treatment response of cutaneous leishmaniasis in North-West Ethiopia. Tropical Medicine & International Health. 2017;22:1293-1301. DOI: 10.1111/tmi.12928
  7. 7. Padovese V, Terranova M, Toma L, Barnabas GA, Morrone A. Cutaneous and mucocutaneous leishmaniasis in Tigray, northern Ethiopia: clinical aspects and therapeutic concerns. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2009;103:707-711. DOI: 10.1016/j.trstmh.2009.02.023
  8. 8. Masmoudi A, Hariz W, Marrekchi S, Amouri M, Turki H. Old World cutaneous leishmaniasis: diagnosis and treatment. Journal of Dermatological Case Reports. 2013;7:31-41. DOI:10.3315/jdcr.2013.1135
  9. 9. Siriwardana Y, Deepachandi B, Gunasekara C, Warnasooriya W, Karunaweera ND. Leishmania donovani Induced Cutaneous Leishmaniasis: An Insight into Atypical Clinical Variants in Sri Lanka. Journal of Tropical Medicine. 2019;2019:1-11. DOI: 10.1155/2019/4538597
  10. 10. Hashiguchi Y, Gomez EL, Kato H, Martini LR, Velez LN, Uezato H. Diffuse and disseminated cutaneous leishmaniasis: Clinical cases experienced in Ecuador and a brief review. Tropical Medicine and Health. 2016;44(1):2. Available from:http://tropmedhealth.biomedcentral.com/articles/10.1186/s41182-016-0002-0
  11. 11. Ives A, Ronet C, Prevel F, Ruzzante G, Fuertes-Marraco S, Schutz F, et al. Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis. Science. 2011;331:775-778. DOI: 10.1126/science.1199326
  12. 12. Osero BO, Aruleba RT, Brombacher F, Hurdayal R. Unravelling the unsolved paradoxes of cytokine families in host resistance and susceptibility to Leishmania infection. Cytokine X. 2020;2:100043. DOI: 10.1016/j.cytox.2020.100043
  13. 13. Loeuillet C, Bañuls A-L, Hide M. Study of Leishmania pathogenesis in mice: Experimental considerations. Parasites & Vectors. 2016;9:144. DOI: 10.1186/s13071-016-1413-9
  14. 14. Dey R, Joshi AB, Oliveira F, Pereira L, Guimarães-Costa AB, Serafim TD, et al. Gut microbes egested during bites of infected sand flies augment severity of leishmaniasis via inflammasome-derived IL-1β. Cell Host & Microbe. 2018;23:134-143.e6. DOI: 10.1016/j.chom.2017.12.002
  15. 15. Kimblin N, Peters N, Debrabant A, Secundino N, Egen J, Lawyer P, et al. Quantification of the infectious dose of Leishmania major transmitted to the skin by single sand flies. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:10125-10130. DOI: 10.1073/pnas.0802331105
  16. 16. Scott P, Novais FO. Cutaneous leishmaniasis: Immune responses in protection and pathogenesis. Nature Reviews. Immunology. 2016;16:581-592. DOI: 10.1038/nri.2016.72
  17. 17. Gurung P, Kanneganti T-D. Innate immunity against Leishmania infections. Cellular Microbiology. 2015;17:1286-1294. DOI: 10.1111/cmi.12484
  18. 18. Puentes SM, Da Silva RP, Sacks DL, Hammer CH, Joiner KA. Serum resistance of metacyclic stage Leishmania major promastigotes is due to release of C5b-9. Journal of Immunology. 1990;145:4311-4316
  19. 19. Domínguez M, Moreno I, López-Trascasa M, Toraño A. Complement interaction with trypanosomatid promastigotes in normal human serum. The Journal of Experimental Medicine. 2002;195:451-459. DOI: 10.1084/jem.20011319
  20. 20. Yao C, Gaur Dixit U, Barker JH, Teesch LM, Love-Homan L, Donelson JE, et al. Attenuation of Leishmania infantum chagasi metacyclic promastigotes by sterol depletion. Infection and Immunity. 2013;81:2507-2517. DOI: 10.1128/IAI.00214-13
  21. 21. Joshi PB, Kelly BL, Kamhawi S, Sacks DL, McMaster WR. Targeted gene deletion in Leishmania major identifies leishmanolysin (GP63) as a virulence factor. Molecular and Biochemical Parasitology. 2002;120:33-40. DOI:10.1016/s0166-6851(01)00432-7
  22. 22. Ricardo-Carter C, Favila M, Polando RE, Cotton RN, Bogard Horner K, Condon D, et al. Leishmania major inhibits IL-12 in macrophages by signalling through CR3 (CD11b/CD18) and down-regulation of ETS-mediated transcription. Parasite Immunology. 2013;35:409-420. DOI: 10.1111/pim.12049
  23. 23. de Veer MJ, Curtis JM, Baldwin TM, DiDonato JA, Sexton A, McConville MJ, Handman E, Schofield L. MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll-like receptor 2 signaling. European Journal of Immunology. 2003;33:2822-2831. DOI: 10.1002/eji.200324128
  24. 24. Vargas-Inchaustegui DA, Tai W, Xin L, Hogg AE, Corry DB, Soong L. Distinct roles for MyD88 and Toll-like receptor 2 duringLeishmania braziliensisinfection in mice. Infection and Immunity. 2009;77:2948-2956. DOI: 10.1128/IAI.00154-09
  25. 25. Guerra CS, Macedo Silva RM, Carvalho LOP, Calabrese K d S, Bozza PT, Côrte-Real S. Histopathological analysis of initial cellular response in TLR-2 deficient mice experimentally infected byLeishmania(L.)amazonensis. International Journal of Experimental Pathology. 2010;91:451-459. DOI: 10.1111/j.1365-2613.2010.00717.x
  26. 26. Franco LH, Beverley SM, Zamboni DS. Innate immune activation and subversion of mammalian functions by Leishmania lipophosphoglycan. Journal of Parasitology Research. 2012;2012:1-11. DOI: 10.1155/2012/165126
  27. 27. Rogers ME. The role of Leishmania proteophosphoglycans in sand fly transmission and infection of the mammalian host. Frontiers in Microbiology. 2012;3. DOI: 10.3389/fmicb.2012.00223
  28. 28. Filardy AA, Pires DR, Nunes MP, Takiya CM, Freire-de-Lima CG, Ribeiro-Gomes FL, et al. Proinflammatory clearance of apoptotic neutrophils induces an IL-12 low IL-10 high regulatory phenotype in macrophages. Journal of Immunology. 2010;185:2044-2050. DOI: 10.4049/jimmunol.1000017
  29. 29. Kopf M, Brombacher F, Köhler G, Kienzle G, Widmann KH, Lefrang K, et al. IL-4-deficient Balb/c mice resist infection withLeishmania major. The Journal of Experimental Medicine. 1996;184:1127-1136. DOI: 10.1084/jem.184.3.1127
  30. 30. Carneiro PP, Conceição J, Macedo M, Magalhães V, Carvalho EM, Bacellar O. The role of nitric oxide and reactive oxygen species in the killing of Leishmania braziliensis by monocytes from patients with cutaneous leishmaniasis. PLoS One. 2016;11:e0148084. DOI: 10.1371/journal.pone.0148084
  31. 31. Polari LP, Carneiro PP, Macedo M, Machado PRL, Scott P, Carvalho EM, et al. Leishmania braziliensis infection enhances toll-like receptors 2 and 4 expression and triggers TNF-α and IL-10 production in human cutaneous leishmaniasis. Frontiers in Cellular and Infection Microbiology. 2019;9:120. DOI: 10.3389/fcimb.2019.00120
  32. 32. Weinkopff T, Mariotto A, Simon G, La TYH, Auderset F, Schuster S, et al. Role of toll-like receptor 9 signaling in experimental leishmania braziliensis infection. Infection and Immunity. 2013;81:1575-1584. DOI: 10.1128/IAI.01401-12
  33. 33. Vieira ÉLM, Keesen TSL, Machado PR, Guimarães LH, Carvalho EM, Dutra WO, et al. Immunoregulatory profile of monocytes from cutaneous leishmaniasis patients and association with lesion size. Parasite Immunology. 2013;35:65-72. DOI: 10.1111/ pim.12012
  34. 34. Flandin J-F, Chano F, Descoteaux A. RNA interference reveals a role for TLR2 and TLR3 in the recognition ofLeishmania donovanipromastigotes by interferon–γ-primed macrophages. European Journal of Immunology. 2006;36:411-420. DOI: 10.1002/eji.200535079
  35. 35. Regli IB, Passelli K, Martínez-Salazar B, Amore J, Hurrell BP, Müller AJ, et al. TLR7 sensing by neutrophils is critical for the control of cutaneous Leishmaniasis. Cell Reports. 2020;31:107746. DOI: 10.1016/j.celrep.2020.107746
  36. 36. Charmoy M, Hurrell BP, Romano A, Lee SH, Ribeiro-Gomes F, Riteau N, et al. The Nlrp3 inflammasome, IL-1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice. European Journal of Immunology. 2016;46:897-911. DOI: 10.1002/eji.201546015
  37. 37. Kautz-Neu K, Kostka SL, Dinges S, Iwakura Y, Udey MC, von Stebut E. IL-1 signalling is dispensable for protective immunity in Leishmania-resistant mice. Experimental Dermatology. 2011;20:76-78. DOI: 10.1111/j.1600-0625.2010.01172.x
  38. 38. Satoskar AR, Okano M, Connaughton S, Raisanen-Sokolwski A, David JR, Labow M. Enhanced Th2-like responses in IL-1 type 1 receptor-deficient mice. European Journal of Immunology. 1998;28:2066-2074. DOI: 10.1002/(SICI)1521-4141(199807)28:07<2066::AID-IMMU2066>3.0.CO;2-X
  39. 39. Lima-Junior DS, Costa DL, Carregaro V, Cunha LD, Silva ALN, Mineo TWP, et al. Inflammasome-derived IL-1β production induces nitric oxide–mediated resistance to Leishmania. Nature Medicine. 2013;19:909-915. DOI: 10.1038/nm.3221
  40. 40. Gurung P, Karki R, Vogel P, Watanabe M, Bix M, Lamkanfi M, et al. An NLRP3 inflammasome–triggered Th2-biased adaptive immune response promotes leishmaniasis. The Journal of Clinical Investigation. 2015;125:1329-1338. DOI: 10.1172/JCI79526
  41. 41. Peters NC, Egen JG, Secundino N, Debrabant A, Kimblin N, Kamhawi S, et al. In vivo imaging reveals an essential role for neutrophils in Leishmaniasis transmitted by sand flies. Science (80-). 2008;321:970-974. DOI: 10.1126/science.1159194
  42. 42. Passelli K, Billion O, Tacchini-Cottier F. The impact of neutrophil recruitment to the skin on the pathology induced by Leishmania infection. Frontiers in Immunology. 2021;12:649348. DOI: 10.3389/fimmu.2021. 649348
  43. 43. Ribeiro-Gomes FL, Sacks D. The influence of early neutrophil-Leishmania interactions on the host immune response to infection. Frontiers in Cellular and Infection Microbiology. 2012;2:59. DOI: 10.3389/fcimb.2012.00059
  44. 44. van Zandbergen G, Klinger M, Mueller A, Dannenberg S, Gebert A, Solbach W, et al. Cutting edge: Neutrophil granulocyte serves as a vector for leishmania entry into macrophages. Journal of Immunology. 2004;173:6521-6525. DOI: 10.4049/jimmunol.173.11.6521
  45. 45. Charmoy M, Brunner-Agten S, Aebischer D, Auderset F, Launois P, Milon G, et al. Neutrophil-derived CCL3 is essential for the rapid recruitment of dendritic cells to the site of Leishmania major inoculation in resistant mice. PLoS Pathogens. 2010;6:e1000755. DOI: 10.1371/ journal.ppat.1000755
  46. 46. Chaves MM, Lee SH, Kamenyeva O, Ghosh K, Peters NC, Sacks D. The role of dermis resident macrophages and their interaction with neutrophils in the early establishment ofLeishmania majorinfection transmitted by sand fly bite. PLoS Pathogens. 2020;16:e1008674. DOI: 10.1371/journal.ppat.1008674
  47. 47. Romano A, Carneiro MBH, Doria NA, Roma EH, Ribeiro-Gomes FL, Inbar E, et al. Divergent roles for Ly6C+CCR2+CX3CR1+ inflammatory monocytes during primary or secondary infection of the skin with the intra-phagosomal pathogenLeishmania major. PLoS Pathogens. 2017;13:e1006479
  48. 48. Aga E, Katschinski DM, van Zandbergen G, Laufs H, Hansen B, Müller K, et al. Inhibition of the spontaneous apoptosis of neutrophil granulocytes by the intracellular parasiteLeishmania major. Journal of Immunology. 2002;169:898-905. DOI: 10.4049/jimmunol.169.2.898
  49. 49. Novais FO, Santiago RC, Báfica A, Khouri R, Afonso L, Borges VM, et al. Neutrophils and macrophages cooperate in host resistance againstLeishmania braziliensisinfection. Journal of Immunology. 2009;183:8088-8098. DOI: 10.4049/jimmunol.0803720
  50. 50. Ribeiro-Gomes FL, Roma EH, Carneiro MBH, Doria NA, Sacks DL, Peters NC. Site-dependent recruitment of inflammatory cells determines the effective dose ofLeishmania major. Infection and Immunity. 2014;82:2713-2727. DOI: 10.1128/IAI.01600-13
  51. 51. Tacchini-Cottier F, Zweifel C, Belkaid Y, Mukankundiye C, Vasei M, Launois P, et al. An immunomodulatory function for neutrophils during the induction of a CD4 + Th2 response in BALB/c mice infected withLeishmania major. Journal of Immunology. 2000;165:2628-2636. DOI: 10.4049/jimmunol.165.5.2628
  52. 52. Charmoy M, Megnekou R, Allenbach C, Zweifel C, Perez C, Monnat K, et al. Leishmania major induces distinct neutrophil phenotypes in mice that are resistant or susceptible to infection. Journal of Leukocyte Biology. 2007;82:288-299. DOI: 10.1189/jlb.0706440
  53. 53. Sousa LMA, Carneiro MBH, Resende ME, Martins LS, dos Santos LM, Vaz LG, et al. Neutrophils have a protective role during early stages ofLeishmania amazonensisinfection in BALB/c mice. Parasite Immunology. 2014;36:13-31. DOI: 10.1111/pim.12078
  54. 54. Conceição J, Davis R, Carneiro PP, Giudice A, Muniz AC, Wilson ME, et al. Characterization of neutrophil function in human cutaneous Leishmaniasis caused byLeishmania braziliensis. PLoS Neglected Tropical Diseases. 2016;10:e0004715. DOI: 10.1371/journal.pntd.0004715
  55. 55. Tavares NM, Araújo-Santos T, Afonso L, Nogueira PM, Lopes UG, Soares RP, et al. Understanding the mechanisms controlling leishmania amazonensis infection in vitro: The role of LTB4 derived from human neutrophils. The Journal of Infectious Diseases. 2014;210:656-666. DOI: 10.1093/infdis/jiu158
  56. 56. Tavares N, Afonso L, Suarez M, Ampuero M, Prates DB, Araújo-Santos T, et al. Degranulating neutrophils promote leukotriene B 4 production by infected macrophages to killLeishmania amazonensisparasites. Journal of Immunology. 2016;196:1865-1873. DOI: 10.4049/jimmunol.1502224
  57. 57. Goncalves R, Zhang X, Cohen H, Debrabant A, Mosser DM. Platelet activation attracts a subpopulation of effector monocytes to sites ofLeishmania majorinfection. The Journal of Experimental Medicine. 2011;208:1253-1265. DOI: 10.1084/jem.20101751
  58. 58. Olekhnovitch R, Ryffel B, Müller AJ, Bousso P. Collective nitric oxide production provides tissue-wide immunity during Leishmania infection. The Journal of Clinical Investigation. 2014;124:1711-1722. DOI: 10.1172/JCI72058
  59. 59. Novais FO, Nguyen BT, Beiting DP, Carvalho LP, Glennie ND, Passos S, et al. Human classical monocytes control the intracellular stage ofLeishmania braziliensisby reactive oxygen species. The Journal of Infectious Diseases. 2014;209:1288-1296. DOI: 10.1093/infdis/jiu013
  60. 60. Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance toLeishmania majorin mice. The Journal of Experimental Medicine. 1993;178:567-577. DOI: 10.1084/jem.178.2.567
  61. 61. Wei X, Charles IG, Smith A, Ure J, Feng G, Huang F, et al. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature. 1995;375:408-411. DOI: 10.1038/375408a0
  62. 62. Roma EH, Macedo JP, Goes GR, Gonçalves JL, De CW, Cisalpino D, et al. Impact of reactive oxygen species (ROS) on the control of parasite loads and inflammation inLeishmania amazonensisinfection. Parasites & Vectors. 2016;9:193. DOI: 10.1186/s13071-016-1472-y
  63. 63. Gantt KR, Goldman TL, McCormick ML, Miller MA, Jeronimo SMB, Nascimento ET, et al. Oxidative responses of human and murine macrophages during phagocytosis ofLeishmania chagasi. Journal of Immunology. 2001;167:893-901. DOI: 10.4049/jimmunol.167.2.893
  64. 64. Tibúrcio R, Nunes S, Nunes I, Rosa Ampuero M, Silva IB, Lima R, et al. Molecular aspects of dendritic cell activation in Leishmaniasis: An immunobiological view. Frontiers in Immunology. 2019;10:227. DOI: 10.3389/ fimmu.2019.00227
  65. 65. Sato N, Ahuja SK, Quinones M, Kostecki V, Reddick RL, Melby PC, et al. Cc chemokine receptor (Ccr)2 is required for langerhans cell migration and localization of T Helper Cell Type 1 (Th1)-inducing dendritic cells. The Journal of Experimental Medicine. 2000;192:205-218. DOI: 10.1084/jem.192.2.205
  66. 66. Carvalho AM, Guimarães LH, Costa R, Saldanha MG, Prates I, Carvalho LP, et al. Impaired Th1 response is associated with therapeutic failure in patients with cutaneous Leishmaniasis caused byLeishmania braziliensis. The Journal of Infectious Diseases. 2021;223:527-535. DOI: 10.1093/infdis/jiaa374
  67. 67. de Lima CMF, Magalhães AS, Costa R, Barreto CC, Machado PRL, Carvalho EM, et al. High anti-leishmania IgG antibody levels are associated with severity of mucosal Leishmaniasis. Frontiers in Cellular and Infection Microbiology. 2021;11:652956. DOI: 10.3389/fcimb.2021.652956
  68. 68. Christensen SM, Belew AT, El-Sayed NM, Tafuri WL, Silveira FT, Mosser DM. Host and parasite responses in human diffuse cutaneous leishmaniasis caused byL. amazonensis. PLoS Neglected Tropical Diseases. 2019;13:e0007152. DOI: 10.1371/journal.pntd.0007152
  69. 69. Kostka SL, Knop J, Konur A, Udey MC, von Stebut E. Distinct roles for IL-1 receptor type I signaling in early versus establishedLeishmania majorinfections. Journal of Investigative Dermatology. 2006;126(7):1582-1589. Available from:https://linkinghub.elsevier.com/retrieve/pii/S0022202X15329900
  70. 70. Rutz S, Eidenschenk C, Ouyang W. IL-22, not simply a Th17 cytokine. Immunological Reviews. 2013;252:116-1132. DOI: 10.1111/imr.12027
  71. 71. Araujo Flores GV, Sandoval Pacheco CM, Sosa Ochoa WH, Gomes CMC, Zúniga C, Corbett CP, et al. Th17 lymphocytes in atypical cutaneous leishmaniasis caused byLeishmania(L.)infantumchagasi in Central America. Parasite Immunology. 2020;42:e12772. DOI: 10.1111/pim.12772
  72. 72. Alexander J, Brombacher F. T Helper1/T Helper2 cells and resistance/susceptibility to Leishmania infection: Is this paradigm still relevant? Frontiers in Immunology. 2012;3:80. DOI: 10.3389/fimmu.2012.00080
  73. 73. Voronov E, Dotan S, Gayvoronsky L, White RM, Cohen I, Krelin Y, et al. IL-1-induced inflammation promotes development of leishmaniasis in susceptible BALB/c mice. International Immunology. 2010;22(4):245-257
  74. 74. Malek TR. The main function of IL-2 is to promote the development of T regulatory cells. Journal of Leukocyte Biology. 2003;74:961-965. DOI: 10.1189/jlb.0603272
  75. 75. Oliveira PRS, Dessein H, Romano A, Cabantous S, de Brito MEF, Santoro F, et al. IL2RA genetic variants reduce IL-2–dependent responses and aggravate human cutaneous Leishmaniasis. Journal of Immunology. 2015;194:2664-2672. DOI: 10.4049/jimmunol.1402047
  76. 76. Biedermann T, Zimmermann S, Himmelrich H, Gumy A, Egeter O, Sakrauski AK, et al. IL-4 instructs TH1 responses and resistance toLeishmania majorin susceptible BALB/c mice. Nature Immunology [Internet]. 2001;2(11):1054-1060. Available from:http://www.nature.com/articles/ni725
  77. 77. Poudel B, Yorek MS, Mazgaeen L, Brown SA, Kanneganti T-D, Gurung P. Acute IL-4 governs pathogenic T cell responses duringLeishmania majorinfection. ImmunoHorizons. 2020;4:546-560. DOI: 10.4049/immunohorizons.2000076
  78. 78. Titus RG, Dekrey GK, Morris RV, Soares MBP. Interleukin-6 deficiency influences cytokine expression in susceptible BALB mice infected with Leishmania major but does not alter the outcome of disease. Infection and Immunity. 2001;69:5189-5192. DOI: 10.1128/IAI.69.8.5189-5192.2001
  79. 79. Laufs H, Müller K, Fleischer J, Reiling N, Jahnke N, Jensenius JC, et al. Intracellular survival ofLeishmania majorin neutrophil granulocytes after uptake in the absence of heat-labile serum factors. Infection and Immunity. 2002;70:826-835. DOI: 10.1128/IAI.70.2.826-835.2002
  80. 80. Buxbaum LU, Scott P. Interleukin 10- and Fcγ receptor-deficient mice resolveLeishmania mexicanalesions. Infection and Immunity. 2005;73:2101-8. DOI: 10.1128/IAI.73.4.2101-2108.2005
  81. 81. Park AY, Hondowicz BD, Scott P. IL-12 is required to maintain a Th1 response duringLeishmania majorinfection. Journal of Immunology [Internet]. 2000;165(2):896-902. Available from:http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.165.2.896
  82. 82. Matthews DJ, Emson CL, McKenzie GJ, Jolin HE, Blackwell JM, McKenzie ANJ. IL-13 is a susceptibility factor forLeishmania majorinfection. Journal of Immunology [Internet]. 2000;164(3):1458-1462. Available from:http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.164.3.1458
  83. 83. Banerjee A, Bhattacharya P, Joshi AB, Ismail N, Dey R, Nakhasi HL. Role of pro-inflammatory cytokine IL-17 in Leishmania pathogenesis and in protective immunity by Leishmania vaccines. Cellular Immunology [Internet]. 2016;309:37-41. Available from:https://linkinghub.elsevier.com/retrieve/pii/S0008874916300533
  84. 84. Lopez Kostka S, Dinges S, Griewank K, Iwakura Y, Udey MC, von Stebut E. IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice. Journal of Immunology [Internet]. 2009;182(5):3039-3046. Available from:http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.0713598
  85. 85. Monteforte GM, Takeda K, Rodriguez-Sosa M, Akira S, David JR, Satoskar AR. Genetically resistant mice lacking IL-18 gene develop Th1 response and control cutaneousLeishmania majorinfection. Journal of Immunology [Internet]. 2000;164(11):5890-5893. Available from:http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.164.11.5890
  86. 86. Gimblet C, Loesche MA, Carvalho L, Carvalho EM, Grice EA, Artis D, et al. IL-22 protects against tissue damage during cutaneous leishmaniasis. PLoS One. 2015
  87. 87. Anderson CF, Stumhofer JS, Hunter CA, Sacks D. IL-27 regulates IL-10 and IL-17 from CD4 + cells in nonhealingLeishmania majorinfection. Journal of Immunology[Internet]. 2009;183(7):4619-4627. Available from:http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.0804024
  88. 88. Farias Amorim CO, Novais F, Nguyen BT, Nascimento MT, Lago J, Lago AS, et al. Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature. PLoS Neglected Tropical Diseases. 2021;15:e000932110.1371/journal.pntd.0009321
  89. 89. Pinheiro RO, Rossi-Bergmann B. Interferon-gamma is required for the late but not early control ofLeishmania amazonensisinfection in C57Bl/6 mice. Memórias do Instituto Oswaldo Cruz [Internet]. 2007;102(1):79-82. Available from:http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762007000100013&lng=en&tlng=en
  90. 90. Fromm PD, Kling JC, Remke A, Bogdan C, Körner H. Fatal leishmaniasis in the absence of TNF despite a strong Th1 response. Frontiers in Microbiology. 2016;6:1520. DOI: 10.3389/fmicb.2015.01520
  91. 91. Melby PC, Andrade-Narvaez FJ, Darnell BJ, Valencia-Pacheco G, Tryon VV, Palomo-Cetina A. Increased expression of proinflammatory cytokines in chronic lesions of human cutaneous leishmaniasis. Infection and Immunity. 1994;62:837-842. DOI: 10.1128/IAI.62.3.837-842.1994
  92. 92. Heinzel FP, Schoenhaut DS, Rerko RM, Rosser LE, Gately MK. Recombinant interleukin 12 cures mice infected withLeishmania major. The Journal of Experimental Medicine. 1993;177:1505-1509. DOI: 10.1084/jem.177.5.1505
  93. 93. Sypek JP, Chung CL, Mayor SEH, Subramanyam JM, Goldman SJ, Sieburth DS, et al. Resolution of cutaneous leishmaniasis: Interleukin 12 initiates a protective T helper type 1 immune response. The Journal of Experimental Medicine. 1993;177:1797-1802. DOI: 10.1084/jem.177.6.1797
  94. 94. Carneiro MB, Lopes ME, Hohman LS, Romano A, David BA, Kratofil R, et al. Th1-Th2 cross-regulation controls early leishmania infection in the skin by modulating the size of the permissive monocytic host cell reservoir. Cell Host & Microbe. 2020;27:752-768.e7. DOI: 10.1016/j.chom.2020.03.011
  95. 95. Mendez S, Reckling SK, Piccirillo CA, Sacks D, Belkaid Y. Role for CD4+ CD25+ regulatory T cells in reactivation of persistent Leishmaniasis and control of concomitant immunity. The Journal of Experimental Medicine. 2004;200:201-210. DOI: 10.1084/jem.20040298
  96. 96. Sadick MD, Heinzel FP, Holaday BJ, Pu RT, Dawkins RS, Locksley RM. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. The Journal of Experimental Medicine. 1990;171:115-127. DOI: 10.1084/jem.171.1.115
  97. 97. Kane MM, Mosser DM. The role of IL-10 in promoting disease progression in Leishmaniasis. Journal of Immunology. 2001;166:1141-1147. DOI: 10.4049/jimmunol.166.2.1141
  98. 98. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL. CD4+CD25+ regulatory T cells controlLeishmania majorpersistence and immunity. Nature. 2002;420:502-507. DOI: 10.1038/nature01152
  99. 99. Nylén S, Sacks D. Interleukin-10 and the pathogenesis of human visceral leishmaniasis. Trends in Immunology. 2007;28:378-384. DOI: 10.1016/j.it.2007.07.004
  100. 100. Carneiro MBH, Lopes MEDM, Vaz LG, Sousa LMA, Dos Santos LM, De Souza CC, et al. IFN-γ-dependent recruitment of CD4+ T cells and macrophages contributes to pathogenesis during leishmania amazonensis infection. Journal of Interferon & Cytokine Research. 2015;35:935-947. DOI: 10.1089/jir.2015.0043
  101. 101. Novais FO, Scott P. CD8+ T cells in cutaneous leishmaniasis: The good, the bad, and the ugly. Seminars in Immunopathology. 2015;37:251-259. DOI: 10.1007/s00281-015-0475-7
  102. 102. Belkaid Y, Von Stebut E, Mendez S, Lira R, Caler E, Bertholet S, et al. CD8 + T cells are required for primary immunity in C57BL/6 mice following low-dose, intradermal challenge withLeishmania major. Journal of Immunology. 2002;168:3992-4000. DOI: 10.4049/jimmunol.168.8.3992
  103. 103. Novais FO, Carvalho LP, Graff JW, Beiting DP, Ruthel G, Roos DS, et al. Cytotoxic T cells mediate pathology and metastasis in cutaneous Leishmaniasis. PLoS Pathogens. 2013;9:e1003504. DOI: 10.1371/ journal.ppat.1003504
  104. 104. Soong L, Chang CH, Sun J, Longley BJ, Ruddle NH, Flavell RA, et al. Role of CD4+ T cells in pathogenesis associated withLeishmania amazonensisinfection. Journal of Immunology. 1997;158:5374-5383. PMID: 9164958
  105. 105. Uzonna JE, Joyce KL, Scott P. Low doseLeishmania majorpromotes a transient T helper cell type 2 response that is down-regulated by interferon γ–producing CD8+ T cells. The Journal of Experimental Medicine. 2004;199:1559-1566. DOI: 10.1084/jem.20040172
  106. 106. Novais FO, Nguyen BT, Scott P. Granzyme B inhibition by tofacitinib blocks the pathology induced by CD8 T cells in cutaneous Leishmaniasis. The Journal of Investigative Dermatology. 2021;141:575-585. DOI: 10.1016/j.jid.2020.07.011
  107. 107. Bertholet S, Debrabant A, Afrin F, Caler E, Mendez S, Tabbara KS, et al. Antigen requirements for efficient priming of CD8+ T cells byLeishmania major-infected dendritic cells. Infection and Immunity. 2005;73:6620-6628. DOI: 10.1128/ IAI.73.10.6620-6628.2005
  108. 108. Da-Cruz AM, Oliveira-Neto MP, Bertho ÁL, Mendes-Aguiar CO, Coutinho SG. T cells specific to Leishmania and other nonrelated microbial antigens can migrate to human Leishmaniasis skin lesions. The Journal of Investigative Dermatology. 2010;130:1329-1336. DOI: 10.1038/jid.2009.428
  109. 109. Cardoso TM, Machado Á, Costa DL, Carvalho LP, Queiroz A, Machado P, et al. Protective and pathological functions of CD8 + T Cells inLeishmania braziliensisinfection. Infection and Immunity. 2015;83:898-906. DOI: 10.1128/IAI.02404-14
  110. 110. Santos CDS, Boaventura V, Ribeiro Cardoso C, Tavares N, Lordelo MJ, Noronha A, et al. CD8+ granzyme B+–mediated tissue injury vs. CD4+IFNγ+−mediated parasite killing in human cutaneous Leishmaniasis. The Journal of Investigative Dermatology. 2013;133:1533-1540. DOI: 10.1038/jid.2013.4
  111. 111. Novais FO, Carvalho AM, Clark ML, Carvalho LP, Beiting DP, Brodsky IE, et al. CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1β production. PLoS Pathogens. 2017;13:e1006196. DOI: 10.1371/journal.ppat.1006196
  112. 112. Faria DR, Souza PEA, Durães FV, Carvalho EM, Gollob KJ, Machado PR, et al. Recruitment of CD8(+) T cells expressing granzyme A is associated with lesion progression in human cutaneous leishmaniasis. Parasite Immunology. 2009;31:432-439. DOI: 10.1111/j.1365-3024.2009.01125.x
  113. 113. Yurchenko E, Tritt M, Hay V, Shevach EM, Belkaid Y, Piccirillo CA. CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites ofLeishmania majorinfection favors pathogen persistence. The Journal of Experimental Medicine. 2006;203:2451-2460. DOI: 10.1084/jem.20060956
  114. 114. Suffia IJ, Reckling SK, Piccirillo CA, Goldszmid RS, Belkaid Y. Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. The Journal of Experimental Medicine. 2006;203:777-788. DOI: 10.1084/jem.20052056
  115. 115. Okwor I, Liu D, Beverley SM, Uzonna JE. Inoculation of killedLeishmania majorinto immune mice rapidly disrupts immunity to a secondary challenge via IL-10-mediated process. Proceedings of the National Academy of Sciences. 2009;106:13951-13956. DOI: 10.1073/pnas.0905184106
  116. 116. Ji J, Masterson J, Sun J, Soong L. CD4 + CD25 + regulatory T cells restrain pathogenic responses duringLeishmania amazonensisinfection. Journal of Immunology. 2005;174:7147-7153. DOI: 10.4049/jimmunol.174.11.7147
  117. 117. Woelbing F, Kostka SL, Moelle K, Belkaid Y, Sunderkoetter C, Verbeek S, et al. Uptake of Leishmania major by dendritic cells is mediated by Fcγ receptors and facilitates acquisition of protective immunity. The Journal of Experimental Medicine. 2006;203:177-188. DOI: 10.1084/jem.20052288
  118. 118. Miles SA, Conrad SM, Alves RG, Jeronimo SMB, Mosser DM. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. The Journal of Experimental Medicine. 2005;201:747-754. DOI: 10.1084/jem.20041470
  119. 119. Hurdayal R, Ndlovu HH, Revaz-Breton M, Parihar SP, Nono JK, Govender M, et al. IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases. Proceedings of the National Academy of Sciences of the United States of America. 2017;114:E8430-E8439. DOI: 10.1073/pnas.1708125114
  120. 120. Radwanska M, Cutler AJ, Hoving JC, Magez S, Holscher C, Bohms A, et al. Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant toLeishmania majorinfection. PLoS Pathogens. 2007;3:e68. DOI: 10.1371/ journal.ppat.0030068
  121. 121. Mandell MA, Beverley SM. Continual renewal and replication of persistentLeishmania majorParasites in concomitantly immune hosts. Proceedings of the National Academy of Sciences of the United States of America. 2017;114:E801-E810. DOI: 10.1073/ pnas.1619265114
  122. 122. Mendonça MG, de Brito MEF, Rodrigues EHG, Bandeira V, Jardim ML, Abath FGC. Persistence of Leishmania parasites in scars after clinical cure of American cutaneous leishmaniasis: Is there a sterile cure? The Journal of Infectious Diseases. 2004;189:1018-1023. DOI: 10.1086/382135
  123. 123. Okwor I, Uzonna J. Persistent parasites and immunologic memory in cutaneous leishmaniasis: Implications for vaccine designs and vaccination strategies. Immunologic Research. 2008;41:123-136. DOI: 10.1007/s12026-008-8016-2
  124. 124. Pagán AJ, Peters NC, Debrabant A, Ribeiro-Gomes F, Pepper M, Karp CL, et al. Tracking antigen—specific CD4 + T cells throughout the course of chronicLeishmania majorinfection in resistant mice. European Journal of Immunology. 2013;43:427-438. DOI: 10.1002/eji.201242715
  125. 125. Peters NC, Kimblin N, Secundino N, Kamhawi S, Lawyer P, Sacks DL. Vector transmission of Leishmania abrogates vaccine-induced protective immunity. PLoS Pathogens. 2009;5:e1000484. DOI: 10.1371/ journal.ppat.1000484
  126. 126. Peters NC, Pagán AJ, Lawyer PG, Hand TW, Henrique Roma E, Stamper LW, et al. Chronic parasitic infection maintains high frequencies of short-lived Ly6C+CD4+ effector T Cells that are required for protection against re-infection. PLoS Pathogens. 2014;10:e1004538. DOI: 10.1371/journal.ppat.1004538
  127. 127. Alvar J, Aparicio P, Aseffa A, Den Boer M, Cañavate C, Dedet J-P, et al. The relationship between Leishmaniasis and AIDS: The second 10 years. Clinical Microbiology Reviews. 2008;21:334-359. DOI: 10.1128/CMR.00061-07
  128. 128. Bogdan C. Mechanisms and consequences of persistence of intracellular pathogens: Leishmaniasis as an example. Cellular Microbiology. 2008;10:1221-1234. DOI: 10.1111/j.1462-5822.2008.01146.x
  129. 129. Parmentier L, Cusini A, Müller N, Zangger H, Hartley M-A, Desponds C, et al. Severe cutaneous leishmaniasis in a human immunodeficiency virus patient coinfected withLeishmania braziliensisand its endosymbiotic virus. The American Journal of Tropical Medicine and Hygiene. 2016;94:840-843. DOI: 10.4269/ajtmh.15-0803
  130. 130. Hohman LS, Peters NC. CD4+ T cell-mediated immunity against the phagosomal pathogen Leishmania: Implications for vaccination. Trends in Parasitology. 2019;35:423-435. DOI: 10.1016/j.pt.2019.04.002
  131. 131. Nylén S, Gautam S. Immunological perspectives of leishmaniasis. Journal of Global Infectious Diseases. 2010;2:135. DOI: 10.4103/0974-777X.62876
  132. 132. Okwor I, Mou Z, Liu D, Uzonna J. Protective immunity and vaccination against cutaneous leishmaniasis. Frontiers in Immunology. 2012;3:128. DOI: 10.3389/fimmu.2012.00128
  133. 133. Peters NC, Bertholet S, Lawyer PG, Charmoy M, Romano A, Ribeiro-Gomes FL, et al. Evaluation of recombinant leishmania polyprotein plus glucopyranosyl lipid A stable emulsion vaccines against sand fly-transmittedLeishmania majorin C57BL/6 mice. Journal of Immunology. 2012;189:4832-484110.4049/jimmunol.1201676
  134. 134. Fischer MR, Schermann AI, Twelkmeyer T, Lorenz B, Wegner J, Jonuleit H, et al. Humanized mice in cutaneous leishmaniasis—Suitability analysis of human PBMC transfer into immunodeficient mice. Experimental Dermatology. 2019;28:1087-1090. DOI: 10.1111/exd.13999
  135. 135. Atayde VD, Aslan H, Townsend S, Hassani K, Kamhawi S, Olivier M. Exosome secretion by the parasitic protozoan Leishmania within the sand fly midgut. Cell Reports. 2015;13:957-967. DOI: 10.1016/j.celrep.2015.09.058

Written By

Elina Panahi, Danielle I. Stanisic, Christopher S. Peacock and Lara J. Herrero

Submitted: September 8th, 2021 Reviewed: October 11th, 2021 Published: December 16th, 2021