Abstract
Leishmania is the causative protozoan parasite of leishmaniasis. Distinct species provoke localized/diffuse cutaneous leishmaniasis or visceral leishmaniasis. Leishmania parasites have developed diverse strategies to evade the host immune response expressed through various cells, especially macrophages, NK cells, and dendritic cells. Participating in some of these strategies are Leishmania surface molecules, such as lipophosphoglycan (LPG) and protease gp63, which are thus considered virulence factors. LPG has been shown to modulate proinflammatory responses. For example, L. major LPG activates NK cells through toll-like receptor-2 (TLR2), while L. mexicana LPG elicits a differential production of cytokines in human dendritic cells and monocytes. Moreover, L. mexicana LPG activates MAP kinases in macrophages, which in turn enhance proinflammatory cytokine production through TLRs. Additionally, Leishmania exosomes have been found to strongly affect macrophage signaling and functions. Furthermore, proteins secreted by Leishmania promastigotes and amastigotes modulate the production of proinflammatory cytokines in human macrophages. Since Leishmania is an obligate intracellular parasite, its promastigotes utilize several mechanisms to survive and duplicate inside host cells, including the inhibition of apoptosis. It is now clear that MAPK p38, JNK, ERK 1/2, and PI3K/Akt participate in the inhibition of both natural and induced apoptosis of macrophages, neutrophils, and dendritic cells.
Keywords
- Leishmania
- cytokines
- TLR
- inflammasome
- apoptosis
- NO
1. Introduction
Leishmaniasis is a complex of neglected tropical diseases (NTDs) caused by protozoan parasites of the genus
The outcome of a
Whether
2. Parasite molecules that regulate host cell signaling pathways
Two of the most studied molecules of
Other important molecules for
The term “secretome” was introduced for the first time in the global study of the genome of proteins secreted by
Regarding trypanosomatids, the term secretome was introduced by Silverman in a proteomics approach used to identify a large number of extracellular proteins in a culture media conditioned by
The authors found various proteins with several possible functions. For instance, some proteins take part in the vesicular transport process, essential for the survival of the parasite, and may thus be virulence factors. Among the proteins participating in signal transduction are those encoded by the gene LmjF 25.0750 of
Since the flagellum of
2.1. Exosomes secreted by Leishmania
Exosomes are organelles (30–100 nm) released by numerous mammalian cells, including reticulocytes, B cells, T cells, dendritic cells, and macrophages [18]. Bioactive exosomes are released by cells infected with viruses and bacteria as well as some tumor cells [19, 20]. The release of exosomes also constitutes a mechanism for the secretion of proteins by
Other studies confirm a nonclassical route of secretion for
In
Diverse
3. Leishmania modulates proinflammatory cytokines, inflammasomes, and TLR expression
To detect
There is a subset of NLRs that assembles large multiprotein complexes known as inflammasomes. The latter trigger inflammatory caspase 1, which in turn promotes the conversion of pro–IL-1β and pro–IL-18 into their bioactive forms. For instance, NLRP3 (the best-characterized inflammasome) consists of the NLRP3 protein, the bipartite adaptor protein ASC, and caspase 1 (in its minimum form). It has been demonstrated that this inflammasome, activated by bacterial toxins, bacterial RNA, ATP, nigericin, uric acid, and silica crystals, is an essential component of the host immune response against bacterial and viral pathogens [25].
After infecting the THP1 human cell line with
Interestingly, other authors analyzed the expression of some components related to the inflammasome pathway in murine macrophages infected with
It has been documented, based on
In the case of
Regarding
4. Leishmania modulates L-arginine metabolism via NOS2 and arginase-1
Among other strategies developed by
Proinflammatory cytokines (e.g., TNF-α and IFN-γ) induce the classical activation of macrophages, upregulating NOS2 expression. This enzyme catalyzes the conversion of L-arginine into L-citrulline and NO, the latter molecule being considered the most potent leishmanicidal agent for the elimination of intracellular
To establish infection and avoid host surveillance,
The parasite-induced upregulation of arginase-1 can affect the production of NO through substrate (L-arginine) competition [41]. Additionally, the generation of some polyamines resulting from L-arginine metabolism via arginase-1 (e.g., spermine, spermidine and putrescine) inhibit NOS2 function [38, 39, 43]. The modulation of L-arginine metabolism is relevant not only during the onset of the infection but throughout the course the disease. The success of host immunity or the pathology of leishmaniasis depends mainly on the balance of the immune response. Since the formation of either NOS2 or arginase leads to the inhibition of the other, these two metabolic states are competitive and tightly regulated [44], determining the levels of NO and therefore the outcome of
Besides the production of polyamines and the resulting enhancement of
5. Inhibition of apoptosis
Although the inhibition of the phagosome-lysosome fusion comprises one such strategy, one of the most intriguing is the inhibition of apoptosis. The latter process is a type of programmed cell death characterized by a very orderly and immunologically silent dismantling of a cell [47, 48]. The activation or inhibition of several signaling pathways is required for apoptosis to occur [49, 50, 51, 52, 53]. Whereas the initiation of apoptosis involves gene activation and transduction pathways, the executioner phase requires the activation of the cellular machinery necessary for the dismantling of the cell.
Apoptosis is a crucial defense mechanism against intracellular pathogens [54]. However, many pathogenic microorganisms such as virus [55], bacteria [56], and protozoan parasites [57, 58] have developed mechanisms to persist within host cells without inducing apoptosis. It has been widely documented that
Recently, it has been demonstrated that
In particular, infection with
5.1. Signaling pathways involved in Leishmania -induced inhibition of host cell apoptosis
Although
Diverse signaling pathways have been implicated in the inhibition of apoptosis by
6. Conclusion
Apoptosis is a type of programmed cell death involving a precisely orchestrated series of steps that culminate in the orderly dismantling of the cell. This process encompasses the activation and silencing of a wide variety of signaling pathways, among which a leading role is played by MAPK, PI3K/Akt and proapoptotic/antiapoptotic proteins of the Bcl-2 family.
Acknowledgments
The authors are especially grateful to Bruce Allan Larsen for proofreading the manuscript.
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