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Mycobacterium leprae causes leprosy. M. leprae enters the body through the upper respiratory tract where it interacts with host’s cells. Interferon (IFN) is a class of cytokines in human body that are released in case of viral and intracellular pathogen infection and they activate the immune cells to eradicate those pathogens. IFN-γ (Type-II IFN) confers immunity against bacterial, viral, and protozoan diseases. Loss of function mutations in IFN-γ results in poor immunity towards mildly virulent mycobacterium. Upon M. leprae invasion, monocytes enter the site of infection and differentiates into macrophages. IFN-γ induces endothelial cells (EC) of the pathogenic micro-environment to cause monocyte differentiation into pro-inflammatory M1 macrophages for immediate antimicrobial activity. This differentiation is ceased in the absence of endothelial cells. M1 macrophages are clinically more active than anti-inflammatory M2 macrophages induced by resting EC. The former produced higher amounts of pro-inflammatory cytokines in response to the TLR2/1 ligand of M. leprae. The former also showed elevation of vitamin D-associated antimicrobial pathway genes, which are required to counter M. leprae. In addition, the former accumulates less oxidised LDL to prevent growth of M. leprae. Thus, advancement of IFN-γ research would help in the design of next-generation anti- leprosy therapeutics.
Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India
Prama Ghosh
Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India
Soumyadeep Ghosh
Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India
Anwesha Behera
Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India
Oyendrilla Mitra
Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India
Ishanee Das Sharma
Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India
Diya Adhikary
Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India
Asesh Banerjee*
Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India
Prabuddha Gupta*
Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India
*Address all correspondence to: abanerjee1@kol.amity.edu and pgupta@kol.amity.edu
1. Introduction
Leprosy (Hansen’s disease) is a complex, chronic, granulomatous dermato-neurological disease caused by Mycobacterium leprae. Leprosy is characterised by acute immunological reactions which lead to neural damage and disabilities with a myriad of clinical as well as serological manifestations. It includes the eyes, the mucosa of the upper respiratory tract, muscle, bone, and testes [1]. The infection by Mycobacterium leprae causes loss of sensation or numbness loss of feeling and lumps and bumps in the hands of the infected person along with disFig.d skin and muscle weakness; nose, eyes, and other internal organs, such as kidneys are also affected (Figure 1), thus characterised as broad-spectrum chronic infectious disease.
Figure 1.
Mycobacterium leprae causes leprosy. In this disease, the skin and peripheral nerves are mainly affected. It also affects the nose, eyes, kidneys, etc.
The pathogen is transmitted from an infected person to healthy individuals via aerosols harbouring the bacteria, especially infection by multibacillary patients supporting respiratory transmission [2]. The initial and common route for the pathogen is the upper respiratory tract, indicating that the interaction between the host and the bacteria initiates in the nasal passage [2]. The protective mucosal innate immune mechanism in the respiratory tract contributes to the low infectivity of the pathogen to some extent [3]. A detailed study of the nasal swab samples of patients by asymptomatic qPCR also indicates that the air route is a common entry canal for the bacteria. Thus, intimating that such contacts have a high chance of developing leprosy. The hypothesis of respiratory transmission is further validated by the adherence of M. leprae to alveolar and nasal epithelial cells [4].
Leprosy is not a single clinical entity but rather classified as a polymorphic infectious disease. The manifestation of this mycobacterial disease is determined by the host’s immune system. Proper classification of the disease is of fundamental priority to determine accurate diagnosis followed by unerring treatments and management of the patients. Amidst several classifications of leprosy, the most widely accepted classification has been the one which was reported by Ridley and Jopling in the year 1966. As per their report, the classification was based mainly on immunological, whistopathological, and microbiological parameters and the immune status of the host [5]. There are six stages of leprosy with varying clinical symptoms (Table 1).
Stage
Description
Intermediate leprosy (IL)
It is the first stage of leprosy with few visible flat lesions
Tuberculoid leprosy (TT)
It is mainly characterised by fewer solitary skin lesions which are typically hypopigmented or erythematous macules
Borderline tuberculoid leprosy (BT)
Different grades of skin lesions with varied nerve involvements are found here
Borderline leprosy (BB)
Cutaneous lesions are characteristically reddish annular plaques with moderate numbness, swollen lymph glands having sharp interior and exterior borders
Borderline lepromatous leprosy (BL)
It is basically the skin condition characterised by numerous dimorphic flat lesions with raised bumps, nodules, and sometimes numb
Lepromatous leprosy (LL)
This type of leprosy is the most unfavourable clinical variant characterised by pale macules in the skin with no epithelioid cells in the lesions
As many of the public health facilities might not have the technical setup to follow the above classifications, a comparatively simpler flowchart of classification is being followed. Using Ridley’s bacterial index (BI) as a primary criterion, WHO in 1982 classified leprosy as multibacillary (infectious) and paucibacillary (non-infectious). Patients (BB, BL, LL) with BI ≥ 2 are classified as multibacillary. Besides, patients (TT and BT) with BI < 2 at all sites are classified under paucibacillary. Patients with TT and LL elicit different types of immune responses in the body (Figure 2a). Considering clinical and operational needs to avoid treatment inconveniences, smear-positive cases were grouped under multibacillary whereas smear-negative cases were considered paucibacillary [5]. There is an increase in the response of IFN-γ at the tuberculoid pole than at the lepromatous pole (Figure 2b) [7].
Figure 2.
(a) Effect on tuberculoid pole and lepromatous pole upon exposure to M. leprae by the human immune system. (b) Response of human immune system at the tuberculoid pole and lepromatous pole under Erythema nodosum leprosum (ENL).
In tropical countries, leprosy is found to be endemic although there are still many cases in Southeast Asia, America, Africa, Eastern Pacific, and Western Mediterranean [8]. As many as 171,948 new cases of leprosy were recorded in early 2012 with a prevalence of 0.23 cases per 10,000 inhabitants [9].
From the 15 million people treated with multidrug (rifampicin, clofazimine, and dapsone) therapy against leprosy, around 2 million people have been prevented from developing disabilities [10]. Prevalence of leprosy fell from 620,638 cases in 2002 to 213,036 in 2009 [11]. In the year 2020, 127,558 new cases of leprosy were detected worldwide from 139 countries. Out of these, 8629 cases were found in children below 15 years.
India records the highest number of leprosy cases in the world. A study conducted in the state of Maharashtra in India showed three to nine cases of leprosy per 10,000 population and 30% of these newly detected cases were found in children [12].
Leprosy cases in Brazil are a major health problem. Brazil ranks second in the number of leprosy cases with a prevalence rate of 1.54 cases per 10,000 inhabitants. In 2011, there were 33,955 new cases out of which 61% were multibacillary (MB).
In 2003, 4181 cases were detected in children under the age of 15 years in Brazil which resulted in the detection coefficient of 7.98 per 100,000 inhabitants. The number of cases fell in 2011 with 2420 new cases resulting in a detection coefficient of 5.22 per 100,000 inhabitants (Table 2) [13].
Year
Place
No. of cases
2002
Worldwide
6,20,638
2003
Brazil
4181 (detected in children under the age of 15 years)
2009
Worldwide
2,13,036
2011
Brazil
2420 (detected in children under the age of 15 years)
2011
Brazil
33,955 (cumulative)
2012
Southeast Asia, America, Africa, Eastern Pacific and Western Mediterranean
171,948
2022
Worldwide
1,27,558
Table 2.
Epidemiology of leprosy.
WHO suggests that close disease surveillance for leprosy is necessary to eliminate the sources of infection and prevent the further spread of the disease. Tools are required for accurate, comparable grading practices. Although various instruments are available for measuring disabilities [14], their application in leprosy needs to be validated.
Histopathological analysis of LL skin, nasal swabs, and other tissues demonstrates that the majority of mycobacterial colonies are present inside macrophages. M. leprae was also noticed inside Schwann cells, pseudostratified epithelium, secretory glands, and ducts [15]. Analysis of skin lesions depicted that foamy macrophage is generally found in multibacillary (BB, BL, and LL) patients and epithelioid cells are usually present in paucibacillary (TT and BT) patients. During early and active infection, macrophages remain filled with granular eosinophilic cytoplasm colonised by a large number of bacilli. But in latent lesions, vacuolated cells are present with a foamy appearance [16]. In both paucibacillary and multibacillary leprosy, nerves are gradually destroyed and replaced by fibrous tissues [17].
Cell-mediated immunity (CMI) plays a major role in eradicating tuberculoid form or paucibacillary leprosy. CMI forms granulomas, destroying most of the mycobacteria, with traces of few remaining in the tissues. Skin and peripheral nerves face severe damage, but TT or the tuberculoid form progress slowly and the patient usually survives. Whereas there is a hike in humoral immunity for lepromatous form or multibacillary leprosy and the cell-mediated response is depressed, sometimes resulting in hypergammaglobulinemia. The mycobacteria are widely disseminated in macrophages with the number reaching as high as 1010 per gram of tissue. LL causes disseminated infection of bones and cartilages with extensive nerve damage. Recent studies explained the fact that the macrophages present in lepromatous skin tissues are positive for adipose differentiation-related protein (ADRP). This further demonstrates that their foamy appearance is due to lipid bodies accumulation by M. leprae [18, 19].
Two types of leprosy reactions are noted in the patients. One is the reversal reaction. It is an acute inflammatory episode that occurs in skin and nerves in response to immediate activation of cellular immunity against the pathogen [20]. It affects dermis and Schwann cells in peripheral nerves causing demyelination, apoptosis, and ischaemia (Figure 3). Activated epithelioid macrophages are found in the reversal reaction lesions. Another is Erythema nodosum leprosum (ENL). It is clinically reported in approximately 50% of patients from lepromatous poles. It occurs primarily due to complex interaction between innate and CMI [21, 22]. ENL is marked by the infiltrate of neutrophils in the dermis and hypodermis, often accompanied by macrophages [23, 24].
6. Interferon-gamma (IFN-γ) in mycobacterial infection: a preamble
IFNs are a smaller subdivision of a larger class of proteins called cytokines, which are molecules used to establish communication between immune cells and non-immune cells to trigger the action of the immune system that helps in the eradication of pathogens [25, 26]. IFNs get their name because they have the capacity to “interfere” with viral replication and put a stop to further viral infections [26]. These not only help in the activation of immune cells but they also help to escalate host defences by increasing MHC (Major Histocompatibility Complex antigens) expression by causing an up-regulation in antigen expression markers. There exist more than 20 distinct IFN genes in animals and they are divided into three main classes: Type I, II, and III category. Out of these, IFN-γ is the sole member of the Type II IFN, mainly secreted by M1 effector macrophages, T-cells, and NK cells which are activated by interleukin-12. It is also referred to as the immune IFN [26].
IL-18 along with IL-1 is the key player in inducing IFN-γ production. IL-18 and IL-12 synergize with each other during the production of IFN-γ [27]. These IFNs block the proliferation of type-2 T helper cells; they are essentially released by type-1 T helper cells, cytotoxic T cells, macrophages, mucosal epithelial cells, and NK cells [28]. IFN-γ blocks the Th2 immune response system but furthers the Th1 immune response system (Figure 4) [29]. The released IFN-γ binds to the IFN-γ receptor protein complex (IFN-γ R) which is a heterodimer of two chains, IFNγR1 and IFNγR2 [26].
Figure 4.
Pathway of IFN-γ in the immune system in response to pathogen.
IFN-γ confers adaptive and innate immunity against bacterial, viral, and many protozoan diseases. It is a key stimulator of macrophages where it augments lysosome activity for effective management of bacterial burden. It helps to initiate binding and adhesion required for proper leukocyte migration. Not only does it help in priming alveolar macrophages against secondary bacterial infection, but it also increases the expression of class I MHC as well as class II MHC molecules through induction of antigen processing genes [30, 31].
IFN-γ interacts with the specific heterodimeric IFN-γ receptors (IFN-γR) located on target cells, such as macrophages, dendritic cells, and many other cell types. Similar to the other IFNs, IFN-γ also signals via the classical Janus kinase/signal transducers and activators of the transcription (JAK-STAT) signalling pathway (Figure 5).
Figure 5.
Interferon-γ is mainly secreted by T-cell and NK cell signals via the classical Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signalling pathway.
Functional IFN-γR is made up of two ligand-binding α subunits, IFN-γR1 (drawn in black (Figure 5)), and two signal transducing β subunits, IFN-γR2 (drawn in red (Figure 5)). Both the receptor chains are classified under the class II cytokine receptor family. IFN-γ stimulates the heterodimerization of these two types of receptor chains, prior to its binding to IFN-γR1. However, such stimulation and binding happen only when the two mature IFN-γ monomers associate to form a biologically active homo-dimer [32]. The IFN-γR1 and IFN-γR2 subunits are associated with Janus Tyrosine Kinases, JAK1, and JAK2 [33, 34]. Followed by IFN-γ binding, the two receptor subunits undergo cross-linking and auto-phosphorylation, and subsequent activation of JAK1 and JAK2 occurs [35]. The intracellular domains of IFN-γR1 contain binding motifs for JAK 1 and the Signal Transducer and Activator of Transcription protein called STAT-1, a latent cytoplasmic transcription factor [28]. Phosphorylation of the STAT1 binding motif at tyrosine (Y) 440 residues promotes the recruitment of STAT1in the nucleus. Activated JAK2 is the major player in phosphorylation of mostly latent STAT-1 close to its C terminal region at Y701 [19, 36, 37]. Phosphorylated STAT-1 forms homo-dimers and subsequently detaches from the receptor and translocates into the nucleus to interact with the γ-activation site (GAS) elements at sequences like TTCN(2-4) GAA, within the promoter regions, to either stimulate or repress IFN-γ-regulated genes [38]. Therefore, IFN-γ-IFN-γR signalling induces or triggers several transcription factors like the IRF1, which plays key roles in regulating adaptive or innate immune responses, stimulating further transcription processes, and activating other transcription factors simultaneously.
Studies on IFN-γ or IFN-γR1 or IFN-γR2 deficient animals revealed that these animals are highly susceptible to a wide range of microbial and some viral pathogens [26]. Similar observations have been seen in humans presenting loss of function mutations in either the IFN-γR1 or IFN-γR2 chains. Such patients express poor immunity towards mildly virulent mycobacterium, early onset of its infection, and often death at a young age [28]. IFN-γ exercises significant roles in inflammatory responses and immune regulation. Infants having complaints of deficient IFN-γ production show inhibited neutrophil mobility and NK cell functioning [39].
Neutrophils from LL patients with or without ENL release TNF and IL-8 when they are stimulated with M. leprae [40]. The apoptotic rate of ENL neutrophils is found to be greater when compared to LL patients and healthy people [40]. E-selectin and its ligands are the key molecules that mediate neutrophil recruitment to inflammatory sites. It is observed in the microarray analyses comparing skin lesions of LL patients and patients with ENL that an up-regulation of these cell movement genes happens in ENL [41]. Circulating neutrophils express CD64 on the cell surface during ENL. This phenomenon is absent in reversal reaction (RR). Non-reactional leprosy or healthy people have lower levels of CD64 expression on the cell surface [42]. Neutrophil function and adhesion to the endothelium increase with increased CD64 expression in cells in vivo [43, 44, 45, 46].
LL is characterised by the presence of massive granulomas containing severely infected macrophages. This is due to the impairment of both RNI and ROS pathways in monocytes of LL patients. This deficiency is rectified by injecting recombinant human IFN-γ intradermally into lepromatous lesions, which resulted in measurable bacilli clearance from the lesions [47].
As a direct means of assessing the killing potential of infected macrophages against intracellular M. leprae is not available, Toxoplasma gondii death was utilised as an indicator of such microbicidal activity [48, 49]. Using the footpad model, Sibley and Krahenbuhl demonstrated that IFN-γ treatment does not activate M. leprae-burdened-footpad-granuloma-macrophages to inhibit Toxoplasma gondii [48]. This deficiency in activity is linked to an excess of intracellular Lipoarabinomannan (LAM) in macrophages [49], a significant ingredient of the mycobacterial cell wall and the primary carbohydrate-containing component identified by antibodies in TB and leprosy patients' sera [50].
8. Antimicrobial effects of IFN-γ against M. tuberculosis and M. leprae
The activation of cellular immunity and inflammation by IFN-γ is a characteristic of tuberculosis infection. Animals lacking either IFN-γ or IFNγ-R gene are vulnerable to mycobacterial infections, and this deficiency promotes fulminant mycobacterial growth and develops disseminated tuberculosis [51].
In IFN-γ treated macrophages, M. tb and M. leprae suppress MHC class II expression and antigen processing, dampening the pro-inflammatory and protective effects of IFN-γ. This effect is thought to be owing to inhibitory effects imposed on the chromatin remodelling of class II transactivator (CIITA) via the TLR2 and MAPK pathways, as well as restricted expression of CIITA in a TLR-dependent manner [52, 53]. M. tb inhibits downstream transcriptional responses caused by IFN-γ, though the proximal stages in IFNγ-R signalling, including STAT1 phosphorylation and dimerization, are unaffected. Diminished interaction of STAT1 dimers with related co-activators, such as cAMP response element-binding protein (CREB) and p300 in M. tb infected macrophages is ascribed to reduced IFN-γ induced responses [54]. Whereas M. leprae is found to negatively regulate macrophage-driven immune response by inducing high levels of MCP1 [55]. A high level of MCP1 expression is observed as a marker of nerve damage in leprosy [56]. On the other hand, TLR signalling has been connected to the generation of inhibitory responses to IFN-γ in mycobacterium-infected macrophages. TLR2 activation has been shown to suppress IFN-γ responsive effects by stabilising and expressing a dominant-negative version of STAT1β. Higher level or stabilisation of STAT1β is found to be associated with a lowering of IFN-γ gene expression [53]. In cases of M. avium infection, higher amounts of STAT1β are produced, which lowers the gene expression of IFN-γ [53]. The pathogenicity by M. leprae triggers the host immune system to prepare for the defence against the same. The circulating monocytes identify and enter the site of the disease, where the local microenvironment activates the tissue macrophages to differentiate.
The disease lesions in TT are associated with well-organised granulomas with M1 macrophages. It expresses macrophage marker CD209 armed with antimicrobial effector function [57]. In LL patients the lesions are distinguished by disorganised granulomas containing macrophages. It is CD209/163++ but does not have antimicrobial activity. These macrophages accumulate host-derived lipids which favours the M. leprae growth and are identified as M2 macrophages [58].
The study of the pathogenicity of leprosy reported predominancy of M1 and M2 type macrophages in the self-limited form of lesions and the progressive form of lesions, respectively. In normal situations unstimulated endothelial cells (EC) trigger monocytes to differentiate into M2 macrophages which are phagocytic in nature [59, 60]. Further biochemical screening analysis depicted that when IFN-γ acts upon EC, it differentiates monocytes into M1 macrophages. It has been hypothesised that in a stable micro-environment if the infection is below a detectable level, then EC signals monocytes to differentiate into M2 macrophages. But in the pathogenic micro-environment, IFN-γ provokes EC to instruct monocyte differentiation into M1 macrophages for immediate antimicrobial activity (Figure 6) [61]. IFN-γ primed T cells induce antimicrobial peptide gene expression in monocytes and macrophages in response to mycobacteria [62].
Figure 6.
Interferon-gamma in leprosy. (A) Human monocytes and macrophages when treated with IFN-γ induce autophagy of M. leprae with the assistance of vitamin D. (B) IFN-γ up-regulates TLR2/1 Ligand inducing antimicrobial peptide expression by activating CYP27BI. (C) In the pathogenic micro-environment of M. leprae, IFN-γ provokes EC to facilitate monocyte differentiation to CD209 + CD163 M1 macrophages which is associated with host defence for immediate antimicrobial activity. (D) IFN-γ induces cathelicidin in M. leprae-infected monocytes in the presence of vitamin D enriched serum which is strongly correlated during multidrug therapy of leprosy.
Many research groups studied various immune response combinations of cytokines, EC, and macrophages in leprosy. Most of the cytokines used in the pre-treatment, cumulatively triggered EC to signal monocyte differentiation to M2 macrophages. Only IFN-γ-treated EC facilitated monocyte differentiation to CD209 +/CD163 M1 macrophages which is associated with host defence [56]. But monocyte differentiation to M1 macrophages ceases when IFN-γ acts directly upon the monocyte in absence of EC. The M1 macrophages induced by IFN-γ-treated EC were clinically more active than M2 macrophages induced by resting EC. The former was reported to (i) accumulate less oxidised LDL, to prevent the nourishment of M. leprae. (ii) Initiates mass production of pro-inflammatory cytokines in response to mycobacterial TLR2/1 ligand [56] (iii) the level of vitamin D antimicrobial pathway genes, for instance: Cyp27b1, VDR, and cathelicidin are all elevated greatly against the pathogen [1, 53, 63, 64]. This emphasises that IFN-γ contributes to an active defence mechanism against M. leprae and is a potent inflammatory mediator which stimulates an extensive gene program in EC as it fails to directly trigger monocytes differentiation to respective macrophages expressing CD209 phenotype and antimicrobial function [65, 66].
Thereafter, IFN-γ induces CYP27B1-hydroxylase in monocytes and macrophages which converts 25-hydroxyvitamin D (25D) to bioactive 1,25-dihydroxy vitamin D (1,25D) [66]. IFN-γ up-regulates TLR2/1 ligand inducing antimicrobial peptide expression by activating CYP27BI (Figure 6) [67]. Antagonistically IFN-γ down-regulates the CYP24 gene which instigates the production of antimicrobial peptides. M. leprae evades the macrophage antimicrobial response successfully by obstructing phagosome maturation and phagolysosomal fusion [68, 69, 70]. An efficient host defence mechanism to overcome this barrier is autophagy which creates autophagosomes and their corresponding fusion with lysosomes [71, 72, 73, 74]. IFN-γ plays an active role in this autophagy (Figure 6). IFN alone or in a combination with vitamin D induces autophagy in human monocytes and macrophages [75]. IFN-γ induces the secretion of cathelicidin in M. leprae-infected monocytes in the presence of vitamin D enriched serum. Vitamin D and cathelicidin levels can both be strongly correlated during multidrug therapy of leprosy. This combination strengthens the immune system of the host against leprosy suggesting the concerted antileprosy function of vitamin D and IFN-γ (Figure 6) [76].
In another study, it is reported that IFN-γ-mediated autophagy in macrophages leads to control in M. leprae counts in TT leprosy. Whereas in LL leprosy, BCL2 mediated block in autophagy results in augmented IFN-γ, reversal reactions, and tissue damage [77]. Therefore, the use of IFN-γ as a part of leprosy therapy could be a challenging endeavour as it could do more harm than curing the disease. To date, only one noteworthy effort has been made to this effect where intradermal injection of IFN-γ reduced BI of leprosy in some cases but patients are four-fold more prone to develop ENL/Type II reactions, offsetting the usefulness of IFN-γ therapy [78].
Leprosy still affects a large number of people worldwide causing several forms of disabilities in them. IFN-γ, a type II IFN, possesses antimicrobial and antiviral activities. This activates endothelial cells to facilitate the differentiation of monocytes into M1 macrophages which are phagocytic in nature in a pathogenic microenvironment. IFN-γ activates T cells to induce antimicrobial gene expression in response to M. leprae. IFN primed endothelial cells trigger the differentiation of macrophages which prevented the growth of M. leprae. It is also seen that IFN-γ played an important role in escalating antimicrobial and anti-inflammatory pathways in conjunction with vitamin D to eliminate M. leprae. IFN-γ also plays an active role in autophagy to eliminate the pathogen suggesting that IFN-γ contributes to the host defence against leprosy. But, as a therapeutic agent, it has not been successfully used so far. A better understanding of leprosy immunology might help us to overcome this limitation for the application of IFN-γ in leprosy therapy.
PG and AB thank Amity University Kolkata for organisational support.
Funding
None.
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Pragya Santra, Prama Ghosh, Soumyadeep Ghosh, Anwesha Behera, Oyendrilla Mitra, Ishanee Das Sharma, Diya Adhikary, Asesh Banerjee and Prabuddha Gupta
Submitted: 25 February 2022Reviewed: 06 April 2022Published: 30 May 2022
Open access peer-reviewed chapter
