Impact Factor 2021: 3.041 (@Clarivate Analytics)
5-Year Impact Factor: 2.776 (@Clarivate Analytics)
Impact Factor Rank: 10/24, Q2 (Tropical Medicine)
  • Users Online: 466
  • Print this page
  • Email this page

Table of Contents
Year : 2021  |  Volume : 14  |  Issue : 5  |  Page : 195-208

Leishmania donovani: Immune response and immune evasion with emphasis on PD-1/PDL-1 pathway and role of autophagy

1 Department of Medical Parasitology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Human Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission04-Jan-2021
Date of Decision06-May-2021
Date of Acceptance08-May-2021
Date of Web Publication25-May-2021

Correspondence Address:
Samar Habib
Department of Medical Parasitology, Faculty of Medicine, Mansoura University, Mansoura
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1995-7645.315895

Rights and Permissions

Leishmania donovani is one of the causative agents of visceral leishmaniasis. The immune response against Leishmania depends on CD4+ T helper type 1 cells. The immune system is unable to combat Leishmania because the parasite can exert several immune suppressive mechanisms that facilitate escaping the immune responses. One of these mechanisms is the up-regulation of programmed death-1/programmed death ligand-1 pathway which causes T cells to undergo exhaustion. Autophagy is strongly linked to the immune response, with some research indicating that activating autophagy reduces the immune response to some intracellular pathogens, while others indicate that activating autophagy limits the growth of intracellular pathogens. Leishmania was found to subvert the host defense mechanisms for its own persistence, such as Leishmania-induced autophagy modulation. Leishmania was reported to activate autophagy in different studies, thus getting a dual benefit by evading the immune system and simultaneously utilizing the autophagy byproducts as nutrients. In this review, we introduced different immune evasion/suppressive mechanisms used by Leishmania, and different immunotherapies which were developed accordingly. We focused on the programmed death-1/programmed death ligand-1 pathway as well as autophagy with the potential interplay of both mechanisms.

Keywords: Leishmania donovani; PD-1/PDL-1; Autophagy; Immune response; Immunity

How to cite this article:
Habib S, Azab M, Elmasry K, Handoussa A. Leishmania donovani: Immune response and immune evasion with emphasis on PD-1/PDL-1 pathway and role of autophagy. Asian Pac J Trop Med 2021;14:195-208

How to cite this URL:
Habib S, Azab M, Elmasry K, Handoussa A. Leishmania donovani: Immune response and immune evasion with emphasis on PD-1/PDL-1 pathway and role of autophagy. Asian Pac J Trop Med [serial online] 2021 [cited 2023 Mar 23];14:195-208. Available from:

  1. Introduction Top

Visceral leishmaniasis (VL) is the disease caused by Leishmania (L.) donovani and is transmitted by the female sand fly. It is considered as one of the most overlooked infectious diseases owing to the large number of affected patients, poor prognosis, and problems concerning the current available therapy. It is necessary to find out new therapies because the available ones are expensive, cause side effects, and the parasite has developed resistance against them[1]. Successful immune response against leishmaniasis requires fine-tuned coordination between both the innate and the adaptive immune responses. The fate of the infection, whether recovery or progression to chronicity, depends, in part, on the ability of the protozoan to escape the immune response[2]. Leishmania inhibits T cell priming via decreasing the toll-like receptor (TLR)-2, TLR-4 mediated tumor necrosis factor (TNF)-a, interleukin (IL)- 12 expression[3] and decreasing antigen presentation by antigen presenting cells (APCs)[4]. It also endorses T helper type (Th) 2 and T regulatory cells (Tregs) which preclude the intracellular parasite clearance with enhanced secretion of transforming growth factor (TGF)-β, IL-4, and IL-10[5].

The liver and spleen constitute the principal organs hosting L. donovani, however, the immune response of each organ to the infection is different. The liver displays successful immune response that leads to granuloma formation around the infected cells which protects them from reinfection. In contrast, the spleen develops immune pathological response that helps parasite persistence[6].

Programmed death (PD) 1 is expressed on T cells, while its ligand (PDL-1) is expressed on APCs. Their binding is essential for keeping the immune balance and preventing host tissue damage[7]. Interestingly, several pathogens exploit this pathway to weaken the immune response and support their persistence[8]. Leishmania was reported to upregulate the PD-1/PDL-1 pathway in different models, allowing the possibility of the immune system restoration to be achieved through blocking of either PD-1 or PDL-1[9],[10],[11].

Autophagy is the recycling process which allows the cells to degrade unwanted materials in lysosomes. It is crucial for clearance of microorganisms, regulation of inflammation, and adaptive immune response[12]. Autophagy activation attenuates T cell responses, thus, several Leishmania species stimulate autophagy to evade the immune system[13],[14],[15],[16]. Autophagy induction helps the parasite persistence and replication through supplying nutrients. It also interferes with lysosomal acidification causing less parasite degradation[17]. Recently, studies have pointed out a salient contribution of the autophagy process in the host defense against Leishmania[18],[19].

  2. The immune response against Leishmania Top

2.1. Innate immunity

Neutrophils are recruited to the site of the sand fly bite and engulf the inoculated promastigotes. They have been shown to produce various microbicidal substances such as nitric oxide (NO) and neutrophil elastase[20]. Natural killer (NK) cells participate as well, as it is the main source of interferon gamma (IFN-γ) supporting CD4+ T cells differentiation into Th1 phenotype[21]. It also helps direct lysis of the parasite, as well as cytotoxic mediated lysis of infected macrophages[22]. Natural killer T (NKT) cells were reported to help the clearance of the parasites in the liver of mice during the initial stages of infection via inducing IFN-γ production[23].

The complement system is concerned with destruction of promastigotes in the blood stream. Interestingly, L. donovani promastigotes, more specifically the metacyclic stages, are more resistant to complement-mediated destruction than other Leishmania species[24].

2.2. Adaptive immunity

T lymphocytes are the cornerstone factor in shaping the susceptibility or the resistance to L. donovani. The differentiation of T lymphocytes into either Th1 or Th2 will determine the immune response against Leishmania. Th1 cells provide help to macrophages by activating the intracellular killing mechanisms like inducible nitric oxide synthetase. Moreover, Th1 cells help CD8+ T cells in the conversion into cytotoxic T cells, causing lysis of the infected cells via granzyme B, perforin, and granulysin[25]. On the other hand, Tregs secrete immune-regulatory mediators such as IL-10, which is exploited by L. donovani to attenuate the effector functions of CD4+ T cells[26]. Bankoti et al.[27] stressed the detrimental role played by B lymphocyte in the persistence of L. donovani infection as they were revealed to decrease both IFN-γ expression on CD4+ T cells and the cytotoxic activity of Leishmania-specific CD8+ T cells. Additionally, Babiker et al.[28] remarked that effector cytokines such as Il-12, TNF-α, and IFN-γ versus regulatory cytokines such as IL-4, IL-10, and TGF-β also determine the infection outcome towards parasite clearance or persistence.

  3. Immune evasion mechanisms used by L. donovani Top

The success of L. donovani to establish chronic infection is largely dependent on its ability to exploit and evade the host immune mechanisms. These evasion mechanisms affect various elements of the immune system including T and B lymphocytes, the complement system, macrophages, and fibroblasts.

3.1. The complement system

Sacks et al.[29] demonstrated that the infective metacyclic promastigotes develop lipophosphoglycan (LPG) elongation on its surface, which hinders the engagement of C5-C9 membrane attack complex, thus hindering the complement-mediated lysis. In addition, this infective stage of promastigotes contains higher protein kinases than other non-infective stages which phosphorylate different complement compounds, leading to inactivation of both complement pathways[30]. Moreover, Leishmania glycoprotein 63 (GP63) is highly expressed on the surface of the matacyclic promastigotes, which cleaves C3b to an inactive form, allowing Leishmania to join the complement receptor (CR) 3 on macrophages rather than CR1 leading to inhibition of IL-12 production, thus facilitating silent entry into the host cells[31].

3.2. The macrophages

3.2.1. TLRs

TLR-2 is critical for recognition of various antigens on the surface of Leishmania, particularly LPG. In optimal conditions, TLR-2 binding promotes TNF-α, IL-12, and reactive oxygen species (ROS) formation in macrophages. In order to escape this mechanism, L. donovani activates host ubiquitin-editing enzyme A20, leading to impairment of TLR-2-mediated induction of TNF-α and IL-12[32]. TLR-4-mediated macrophage stimulation is also subverted by both Src homology 2 domain phosphotyrosine phosphatase 1 (SHP-1) and A20, both are enhanced by over expression of TGF-β[33].

3.2.2. Survival inside phagosomal compartments

Promastigotes are phagocytized by the macrophages either directly or after phagocytosis of neutrophils recruited to the sand fly bite, they are enclosed by the phagosomes where they differentiate into amastigotes. To protect itself from the harsh conditions of the phagolysosome, Leishmania initially inhibits the fusion between the phagosome and the lysosome[34]. Leishmania not only inhibits the acidification of lysosomes through interfering with the V-ATPase pump[17], but also regulates the lysosomal trafficking proteins[35] with subsequent formation of large Parasitophorous vacuole (PV). It is essential for Leishmania containing phagosome to move along macrophage microtubule tracks towards the endolysosomal pathway, which is critical for maturation of PV, thus helping Leishmania survival and proliferation[36],[37].

3.2.3. Antigen presentation

Leishmania targets antigen presentation to inhibit co-stimulation of T cells. To achieve this, the parasite sequesters antigens and interferes with loading of these antigens on the major histocompatibility complex (MHC)[38]. Interestingly, Leishmania increases the fluidity of the macrophage membrane lipid rafts where the MHC class II should exist as microdomains, thus interfering with antigen presentation[4]. Of note, megasomes are MHC II containing organelles which exist in the PV of parasitized macrophages. L. donovani amastigotes were reported to endocytose these organelles and degrade them[39]. Consequently, the parasite is able to evade recognition by T cell receptors.

3.2.4. Macrophages signaling

L. donovani LPG, GP63[40], and enhanced IL-10 production[41] were reported to impair protein kinase C complex, leading to the inhibition of phosphorylation of various subunits of nicotinamide adenine dinucleotide phosphate oxidase complex, an essential compound in the protective mechanisms against Leishmania. Additionally, several studies have described the role of Leishmania in interrupting various signaling pathways, resulting in promoted parasite survival. For example, inhibition of JAK/STAT pathway with resulting decrease in NO production and inhibition of MAPK signaling pathway, with resultant reduction of pro-inflammatory cytokines, both will dampen the macrophage microbicidal functions[42].

3.2.5. Cytokines

In macrophages, pro-inflammatory cytokines including IL-12, TNF-α, and IFN-γ tend to decrease while anti-inflammatory cytokines including IL-13, IL-4, and IL-10 tend to increase, which support chronic infection and renders the disease difficult to control[43]. The anti-inflammatory milieu is attributed to macrophages polarization towards M2 phenotype, which was demonstrated as increase in blood arginase levels[44], decrease in NO levels[45], decrease in oxidative burst in monocytes and macrophages, and increase in levels of IL-10, CD163, and CXCL14[46].

3.3. Fibroblasts and epithelial cells

Although macrophages represent the most important host cell for Leishmania, studies have shown involvement of fibroblasts[47] and epithelial cells[48] in hosting this parasite. Bodgan et al.[49] described that following healing of a cutaneous lesion of L. major, 40% of persisting amastigotes were accumulating in fibroblasts of the draining lymph nodes. They also reported that cytokine-activated fibroblasts cannot kill L. major because of the basic inability to produce NO, therefore, these cells represent important shelter for the parasite during chronic infection. Interestingly, they found that these amastigotes inside fibroblasts are susceptible to NO produced by neighboring macrophages, creating a balance between parasite elimination and evasion in chronically infected lymph nodes.

Fibroblasts are the main source of collagen type I, which is the major component of extracellular matrix[50]. Although fibroblasts can limit Leishmania propagation in the dermis through enhancement of fibrosis, Petropolis et al.[51] described that L. amazonensis promastigotes can use collagen I scaffolds to help its movement. They also remarked degradation of 20% of collagen I upon invasion by Leishmania promastigotes, possibly due to metallo- and cysteine proteinases, which render the skin matrix softer, thus enabling Leishmania migration before internalization into the host macrophages. Interestingly, they noticed faster migration of Leishmania promastigotes when macrophages are present, indicating the possibility of the parasite chemotaxis by the secreted cytokines. Of note, promastigote secretory gel was stated to enhance proliferation and migration of fibroblasts in a scratch wound model[52].

3.4. T cell response

Th1 cells are critical for anti-leishmanial immune response. It provides assistance not only for the macrophages to activate NO-mediated intracellular killing but also for the CD8+ T cells to kill the parasites either directly or through killing of infected cells[53]. Osorio et al.[54] showed that Leishmania favors switch of CD4+ T cells towards Th2 with subsequent anti-inflammatory cytokines production rather than the protective subset, Th1. On the other hand, Tregs are promoted by L. donovani infection, leading to the production of TGF-β and IL-10, which in turn inhibits the macrophages and Th1 responses[26]. A recent study by Kumar et al.[55] concluded that Leishmania infection induces differential microRNA expression in CD4+ T cells producing mixed Th1/Th2 response.

Importantly, L. donovani was reported to activate immune check points including cytotoxic T-lymphocyte-associated protein (CTLA)-4 and PD-1. CTLA-4 is a co-inhibitory molecule located on T cells and engages to B7-1 (CD80) and B7-2 (CD86) on the APC surface with greater affinity than the co-stimulatory molecule CD28[56], while PD-1 is also located on T cell surface and engages to PDL-1 and PDL-2 on the surface of the APC[57]. As elucidated in [Figure 1], over-expression by certain types of pathogens, including L. donovani, causes T cells to undergo limited clonal expansion, defective cytokine production, and enhanced apoptosis[58].
Figure 1: Immune checkpoints are upregulated during Leishmania donovani infection. For keeping self-tolerance, controlling the immune response, and reducing tissue damage, binding of Leishmania antigen-MHC II complex which is located on antigen presenting cell (APC) to T cell receptor (TCR) that is present on T cells promotes expression of the immune check points; PD-1 and CTLA-4 on the surface of T cells. PD-1 binds to PDL-1 and PDL-2, while CTLA-4 binds to B7-1 and B7-2, with greater affinity than the co-stimulatory molecule CD28. The net result is reduction of T cell proliferation and decreased pro-inflammatory cytokines production.

Click here to view

3.5. B cell response

Regarding the humoral response, Rodrigues et al.[59] reported that hypergammaglobulinemia starts to appear in L. infantum-infected macaques during the early stages of infection and persists during the chronic phase, however, the anti-Leishmania IgG is transitory and decreases during the chronic phase suggesting that most antibodies are not Leishmania-specific. They also reported that B cells gain atypical phenotype (CD21-CD27-) which is responsible for the nonspecific hypergammaglobulinemia.

  4. Immunosuppressive strategies used by L. donovani Top

Leishmania infection has been found to induce several immunosuppressive mechanisms to attenuate the effector functions of T cell and to establish the infection. Several human and animal studies have identified different immune checkpoints, such as CTLA-4, IL-27, and PD-1 on anergic T cells during chronic infection.

4.1. IL-10

Studies showed that IL-10 limits T cells functions. It was found to be co-expressed with IFN-γ by the effector T cells, which are termed as type 1 regulatory cells, which aim to protect the tissues from inflammation, however, they were found to support the infection through decreasing the effector functions of T cells[60]. VL in humans is associated with increased circulating plasma IL-10 levels. Also, IL-10 mRNA levels increased in spleen, bone marrow, and lymph nodes. Additionally, following parasite antigen stimulation, whole blood cells from VL patients exhibited more IL-10 production. IL- 10 suppresses the dendritic cells (DCs) and renders the macrophages unresponsive to stimulation through reduction of MHC II expression, decreasing NO and TNF-α release which leads to decreased activation of Th1 cells and reduced parasite clearance[5],[61],[62]. IL-10 endorses T cell exhaustion[63]. Notably, mice lacking IL-10 can resist leishmaniasis[64]. In addition, Gautam et al.[65] have demonstrated that targeting IL-10 in splenic aspirate cultures obtained from VL patients could control the parasite number and increase Th1 cell cytokines.

4.2. CTLA-4

CTLA-4 on T cells is an important immune check-point as a vital controller of self-reactivity. It is up-regulated on primed T cells, particularly Tregs[66],[67]. Mice lacking CTLA-4 showed a fatal over- activated phenotype resulting in intense autoimmunity. This finding confirms the salient contribution of CTLA-4 in keeping immune tolerance[68],[69]. The main function of CTLA-4 is to directly control the activation of the stimulatory CD28 pathway via its ligands, B7-1 (CD80) and B7-2 (CD86), where CTLA-4 binds to the shared CD28- ligands expressed by APCs[70]. Of note, CTLA-4 binding to B7-2, not B7-1, is linked to Th2 phenotype observed in both helminthic and L. major infections[71]. Blockade of CTLA-4 decreased the parasite load, increased frequencies of IFN-γ producing cells, accelerated the hepatic granulomatous response[72], and increased the drug efficacy in animal models of L. donovani[73].

4.3. IL-27

IL-27 is implicated in VL as a regulatory cytokine. Patients with active VL show increased IL-27 levels, which is important, along with IL-21, for promoting T cells to produce IL-10[74]. IFN-γ enhances the production of IL-27 from macrophages which stimulates IL-10 release, decreases IL-17, and IL-22 as a feedback mechanism to decrease the tissue damage[75]. Notably, Rosas et al.[76] reported that following L. donovani infection, mice lacking IL-27 receptors showed increased Th1 response with consequent marked hepatic pathology.

4.4. Tregs

Tregs limit autoimmunity via inhibition of possibly self-reactive T cells[77]. Several studies have reported that Tregs accumulate in VL models where they produce IL-10, TGF-β, IL-35, and CTLA- 4[78],[79].

4.5. Dendritic cells

DCs contribute to the early T cell response against Leishmania as they help their switch to memory T cells. Intriguingly, DC-specific ICAM-3-grabbing non-integrin receptor, was reported to support the parasite survival[80]. DCs-based immunotherapy combined with antimonial compounds has been successful in animal models[81].

4.6. PD-1/PDL-1 pathway

The immune system maintains critically balanced mechanisms to eliminate pathogens and at the same time minimize self-reactivity and tissue damage. PD-1 (CD279) belongs to the CD28 family that works as a T cell inhibitory receptor. PD-1 accounts for T cell dysfunction observed in chronic infections and malignancies. It is detected on both activated and anergic T cells following TCR binding[82].

PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) are the solely recognized ligands for PD-1. They belong to B7 family[83]. PD-1/PDL-1/2 pathway is essential for regulating T cell response in different animal models of infections, malignancies, and autoimmunity. Of note, mice deficient in PD-1 have evolved autoimmune diseases such as glomerulonephritis, arthritis, and cardiomyopathy[84].

4.6.1. Regulation and expression of PD-1/PDL-1 pathway

PD-1 is a 288 amino acid expressed on thymocytes changing from double negative (CD4- CD8-) to double positive (CD4+ CD8+) phase, on T and B lymphocytes post-activation, and on macrophages[85]. PDL-1 and PDL-2 are differentially expressed in multiple tissues suggesting the possibility of post-transcriptional modification. Activated macrophages, DCs, T, and B lymphocytes express PDL-1, while PDL-2 is expressed on inflammatory macrophages and activated DCs[86].

PD-1 is enhanced on T cells following TCR activation. Cytokines signaling through the common gamma chain were reported to have a role in PD-1 up-regulation[87]. T-bet is a transcription factor which inhibits PD-1 expression directly. With prolonged exposure to antigen, T-bet is down-regulated, resulting in PD-1 up-regulation[88]. IL-6 and IL-12 can also control PD-1 via interaction of distal regulatory molecules with PD-1 promoter[89].

Similarly, PDL-1 is regulated by B cell receptor and TCR signaling. Several gamma chain signaling cytokines, IL-4, and granulocyte macrophage colony stimulating factor have significant role in PDL-1 and PDL-2 expression on macrophages[90]. IFN-γ up-regulates PDL-1 in non-lymphoid tissues where PDL-1 promoter was found to have several IFN-γ responsive elements[91].

PDL-1 expression was detected in several kinds of human tumors[92]. Moreover, some human cancer cell lines were also found to up-regulate PDL-1 upon IFN-γ stimulation, suggesting that tumors may evade the immune response via PD-1/PDL-1 interaction[93]. Additionally, loss of phosphate and tensin homolog can lead to increased expression of PDL-1[94].

4.6.2. Signaling pathways of PD-1/PDL-1 pathway

PD-1 binding inhibits the expression of transcription factors involved in effector T cell response [Figure 2]. It exerts its negative effect when cross-linked with TCR hindering glucose utilization, cytokine release, proliferation, and persistence of T cells[95].
Figure 2: PD-1/PDL-1 ligation negatively regulates T cell functions. Once PD1 on T cell binds to PDL-1 on the APC, immunoreceptor tyrosine-based inhibitory motif and immunoreceptor tyrosine-based switch motif, which are located on the cytoplasmic end of PD-1 become phosphorylated. This results in recruitment of Src homology 2 domain phosphotyrosine phosphatase 1 and 2 (SHP-1 and SHP-2) which dephosphorylate early molecules of the TCR and CD28 signaling pathway leading to decreased clonal expansion of T cells, decreased effector and memory functions, and increased Tregs and exhausted T (TEX) phenotype.

Click here to view

Once TCR is activated, PD-1 engages, accumulates and localizes to the TCR complex. This results in phosphorylation of the immune-receptor tyrosine-based inhibitory motif and immune- receptor tyrosine-based switch motif which are present on the cytoplasmic end of PD-1, causing recruitment of SHP-1 and SHP-2 that dephosphorylate early signaling elements of TCR and CD28, specifically, the RAS/MEK/ERK and PI3K/AKT pathways leading to their inhibition[96]. It also promotes TGF-β-mediated signaling with enhanced differentiation of naïve T cells into inducible regulatory T cells[97].

Different metabolic processes are crucial to determine T cell fate. Chang et al.[98] found that glycolysis accompanies effector T cells differentiation, while fatty acid oxidation helps the conversion of the effector T cells to a memory cells or Tregs. PD-1 ligation was found to inhibit glycolysis and glutaminolysis, but increased the oxidation of fatty acids[99].

4.6.3. PD-1/PDL-1 pathway and anti-tumor immunity

PD-1 ligation dampens the anti-tumor immune response. Various studies have confirmed that different types of cancers express PDL-1 with associating poor prognoses[100],[101]. Besides cancer cells, PDL-1 and PDL-2 were found to be expressed on various cells in the tumor microenvironment (TME) such as macrophages, mainly M2. Interestingly, high expression of PDL-1 in the TME indicates better response to PD-1/PDL-1 blockade therapy[102].

PD-1/PDL-1 interaction in the TME down-regulates signaling pathways essential for tumor antigen recognition by T cells. It inhibits their differentiation into effector and memory phenotypes and promotes exhausted T (TEX) and Treg phenotypes. Moreover, it endorses persistence of cancer cells through PDL-1 mediated anti- apoptotic signals[103],[104]. Blockade of the pathway decreases the survival of the cancer cells and enhances anti-tumor T cell functions resulting in tumor regression[105]. For instance, Nivolumab was the first anti-PD-1 antibody showing efficacy in different types of malignancies, including melanoma, renal cell carcinoma, and non- small cell lung cancer[106].

Anti-PDL-1 antibodies interfere with binding of PD-1 to PDL-1 but it causes less toxicity since it allows PD-1 to interact with PDL-2, which contributes to the peripheral tolerance[107]. Different anti-PDL-1 antibodies are used in clinical trials for patients with refractory malignancies. The lack of toxicity suggests the role of PDL-2 in achieving a good level of peripheral tolerance which is lacking in anti-PD-1 therapies[100].

4.6.4. PD-1/PDL-1 pathway and infectious diseases

PD-1 has a major regulatory function controlling both viral and parasitic infections. In acute viral infections, antigen specific CD8+ T cells get activated, expand and convert into effector cytotoxic T cells which defeat the invading pathogens efficiently, then a small number converts to memory cells and the rest of these effector cells undergo apoptosis. In contrast, during chronic viral infections, prolonged antigen exposure causes loss of effector T cell functions with inability to differentiate into memory cells and the cells become in an unresponsive and exhausted state with failure to clear the infection[82]. TEX showed increased expression of PD-1 as well as other inhibitory receptors, however, PD-1 blockade was enough to reinvigorate a considerable number of those exhausted cells. Additionally, the use of anti-PD-1 in patients with human immune deficiency virus[108] and hepatitis C virus[109] caused significant increase in the antigen-specific T cells and decreased the viral burden. Simultaneous blocking of PD-1 and the inhibitory receptor lymphocyte-activation gene (LAG)-3 reinvigorated the exhausted cells and cleared the virus in mice infected with chronic lymphocytic choriomeningitis virus[110].

Regarding parasitic infections, PD-1 blockade was used in several studies. In toxoplasmosis, it restored exhausted CD8+ T cell functions, and resulted in decreased reactivation of the parasite and enhanced survival of chronically infected mice[111]. In malaria infection, in vivo blockade of PDL-1 and LAG-3 improved CD4+ T cell response, enhanced anti-malaria antibodies, and rapidly eliminated malaria stages from the blood[112].

4.6.5. PD-1/PDL-1 role in Leishmania infection

PD-1/PDL-1 interaction was reported to enhance the apoptosis of T cells, increase the anti-inflammatory cytokines by leukocytes from peripheral blood and spleen, and increase the magnitude of infection in L. infantum-infected dogs[58]. In a similar animal model, Esch et al.[10] confirmed that ex vivo blockade of PDL-1 promoted return of CD4+ T cells functions, CD8+ T cells proliferation, but not IFN-γ production, dramatically increased ROS production in co-cultured monocyte-derived phagocytes, and led to decreased parasite load.

Joshi et al.[9] used transgenic L. donovani parasites to track Leishmania-specific CD8+ T cell response. The cells expressed limited expansion, functional exhaustion and apoptosis. They blocked PD-1 in vivo and were able to increase the life span of CD8+ T cells, however, the cytokine levels were not recovered. On the other hand, we have shown that in vivo blockade of PDL-1 in L. donovani-infected mice could rescue CD4+ and CD8+ T cells and promoted their cytokine profile, enhanced macrophages functions and antigen presentation capabilities, and increased the effector memory CD4+ and CD8+ T cells. Altogether, the parasitic load decreased dramatically[11].

Besides, Filippis et al.[113] elucidated that anti PD-1 enhances T cell expansion and pro-inflammatory cytokine release during the co-culture of L. major infected human cells with PD-1+ lymphocytes. Another study conducted by da Fonseca-Martins et al. targeted PD-1 and PDL-1 in a mouse model of non-healing L. amazonensis infection. They found that anti PD-1 and anti PDL-1 promoted IFN-γ expression by CD4+ and CD8+ T cells, respectively. It caused significant decrease in IL-4 and TGF-β with consequent decrease in the parasitic burden. Noteworthy, neither anti-Leishmania antibodies nor IL-10 levels were affected[114].

  5. Autophagy Top

Autophagy is the process which deals with degradation of unwanted cellular components through the lysosomes. There are 3 main kinds of autophagy: macroautophagy, microautophagy, and chaperone- mediated autophagy.

Macroautophagy includes the sequestration of the cellular components into the double membrane autophagosome, which unites with the lysosomes where the components get digested and the cell can use them again for its function. It is dependent on the autophagy related proteins (ATGs)[115]. Microautophagy is a ATGs-independent process which involves the small proteins of the cytoplasm and is characterized by invaginations of the lysosomal membrane into the lysosomal lumen. Chaperone-mediated autophagy depends on direct transfer across the lysosomal membrane[116].

There are other forms of autophagy which involve particular components such as lipophagy where the lipids are targeted; mitophagy where damaged or dysfunctional mitochondria are targeted; aggrephagy where the protein aggregates are targeted; and xenophagy where intracellular microorganisms are degraded by the macroautophagic pathway[117].

5.1. The autophagy pathway

Starvation stimulates the autophagy process. It deactivates the mammalian target of rapamycin (mTOR), with resulting autophagy stimulation. As illustrated in [Figure 3], the autophagy process contains several steps: initiation, elongation, fusion, and degradation[118]. It starts with assembly of some ATGs to form the elongation membrane known as the phagophore, which appears as a double layered crescent in the cytoplasm. Several ATGs are involved in the initiation step such as Beclin 1 and ULK1. During the elongation step, the phagophore elongates and surrounds the cargo to form a closed double layered autophagosome with the cargo inside. In this step, the micro tubule associated protein light chain 3 (LC3) I is lipidated to form LC3 II. Then the autophagosome unites with the lysosome, forming the phagolysosome and the lysosomal enzymes start to digest the components[119].
Figure 3: The autophagy steps. The autophagy process contains several steps: Initiation, elongation, fusion, and degradation. It starts with formation of the isolation membrane, the phagophore, which extends and surrounds the cargo, forming the autophagosome with the cargo inside. Autophagosome unites with the lysosome leading to formation of the phagolysosome and the lysosomal enzymes start to digest the components.

Click here to view

5.2. Autophagy functions in infections and immunity

Autophagy is responsible for maintaining the cellular integrity through clearing the cellular debris and regenerating the metabolic precursors, thus achieving cellular and tissue homeostasis and suppressing oncogenesis. It also recycles damaged organelles[120]. Moreover, it regulates lipid metabolism, and prevents the accumulation of poly-ubiquinated protein aggregates which accumulate during aging, stress and diseases, and affect the protein structure and folding[121].

From an immunological perspective, autophagy plays a dual role. It may favor an inflammatory or immune-regulatory response, according to the antigens presented, thus, switch of T cells towards the inflammatory Th1 or the anti-inflammatory Th2 may be affected. The balance between both types is crucial for leishmaniasis outcome[122].

Autophagy has important role in infections as it affects the immune response through degradation of the invading organisms within the autophagic compartments (xenophagy), like Mycobacterium tuberculosis, Herpes simplex virus type 1, and Toxoplasma gondii[117]. It also suppresses the inflammatory response by down-regulating the protective cytokines and inhibiting the inflammasome-dependent maturation and secretion of the inflammatory cytokines[123]. Additionally, autophagy can affect the adaptive immune response via affecting the antigen presentation and the lymphocyte development[124].

5.3. Autophagy and Leishmania

Leishmania invades the macrophages and escapes the microbicidal mechanisms of the macrophages by inhibiting the formation of the phagolysosomes. L. major surface metalloprotease GP63 was reported to prevent the formation of mTOR complex 1 (mTORc1) and inhibits the recruitment of LC3 to the phagosomes[125]. Of note, the LC3-associated phagocytosis plays a crucial role in the phagocytosis of dead cells and organisms such as Leishmania, promotes tolerogenic pathways by induction of TGF-β and IL-10 and dampening IL-1β and IL-6[126].

A study conducted by Crauwels et al.[16] has shown that L. major inoculum contains apoptotic-like Leishmania which are up-taken by LC3-associated phagocytosis and triggers autophagy activation, induces TGF-β and IL-10, and dampens IL-6, IL-1β, and TNF-α production. In the same study, autophagy inhibition by means of Spautin-1 increased T cells proliferation, however, the parasite load was not affected significantly.

Autophagy was found to increase the replication of L. amazonensis inside macrophages and its inhibition using 3 methyl adenine decreased the parasite index in infected mice[127]. Autophagy stimulation may enhance the parasite survival through increased presentation of self-antigens[128], provoking immune-silencing mechanisms with dampened adaptive immunity, decreased T cell proliferation, and provision of the parasite with the nutritive support[16]. Interestingly, it was found that L. donovani uses another pathway other than mTOR to activate the host autophgy, which is inositol monophosphatase, meanwhile, Leishmania disables mTOR pathway to achieve perfect control on the autophagy process thus optimizing its persistance[129].

Autophagy was found to play opposite roles during leishmaniasis. Although host autophagy can be subverted by Leishmania to provide nutrient support, it can significantly restrict the intracellular growth of amastigotes[130]. Frank et al.[18] proved that bone marrow-derived macrophages could destroy L. major by the aid of autophagosomes, vacuoles, and myelin-like structures. The autophagic clearance of L. major was attributed to cathepsin E and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3, however, the expression of these 2 proteins was inhibited early during the differentiation into amastigotes. In this study, the authors described that amastigotes not surrounded by autophagosomes are rather penetrated by myelin-like structures which wrap the parasite components. The parasite cell membrane separates the digestion process from the cytoplasm of the infected cell, thus preventing antigen presentation. Of note, autophagy induction in the previous model was mTOR independent. On the other hand, activation of mTOR was observed post infection. Knocking-down of p-mTOR resulted in decreased infection burden, which is consistent with another study[131], supporting the idea that early inhibition of autophagy may protect Leishmania to secure a complete differentiation.

Contrary to the mechanisms of Leishmania entry into the macrophages, L. amazonensis was recently reported to actively invade mouse embryonic firboblasts (MEFs) via endocytosis and then gain the lysosmal markers, lysosme-associated membrane protein (LAMP1 and LAMP2)[132]. An interesting study was conducted by Halder et al.[19], who were able to find the co-localization of LAMP1 within 50%-70% of Leishmania containing vacuoles (LCVs), and LAMP2 within 35%-55% of LCVs using fluorescence microscopy, after infection of wild type MEFs and human epithelial cell line A549 with L. donovani at different time points. Intriguingly, they found that LAMP-decorated LCVs were non-permissive to parasite survival and replication owing to the observation of only a few amastigotes in such vacuoles, in contrast to other vacuoles that are devoid of LAMP, which showed multiple amastigotes inside. Further, they defined a new cellular self-directed immune pathway which renders non-phagocytic cells hostile for intracellular Leishmania via IFN-γ-inducible guanylate binding proteins.

Noteworthy, guanylate binding proteins were reported to boost the autophagy machinery contributing to the antimicrobial function of LCVs[133]. Halder et al.[19] confirmed that these proteins enhance the delivery of amastigotes to the autolysosmes as they noticed reduction in LC3 staining of LCVs in GBP1-/- A549 cells and Gbpchr3-/- MEFs. In this study, MEFs lacking ATG3 contained higher numbers of amastigotes, concluding that, unlike phagocytes, guanylate binding proteins-mediated autophagy plays principal role in defense against Leishmania in fibroblasts.

mTOR inhibitors (rapamycin and GSK-2126458) were tested in mice after intra-footpad inoculation of L. major and were found to decrease the local inflammation and the parasite load in the draining lymph nodes. Additionally, splenocytes derived from the treated animals exhibited less IL-4 expression, accordingly IFN-γ/IL-4 ratio increased, signifying Th1 biased response[134].

5.4. Interplay between autophagy and PD-1/PDL-1 pathway

Although numerous studies have pointed out the relationship between PD-1/PDL-1 pathway and autophagy in tumors, few studies have emphasized this relationship in infection. We have previously shown that anti PDL-1 immunotherapy works via dampening autophagy in a mouse model of VL[11]. In addition, Mycobacterium tuberculosis infected PD-1-/- macrophages exhibited decreased LC3B expression in macrophages[135].

Understanding the interplay between autophagy and PD-1/PDL-1 pathway in cancer may be helpful in the context of chronic parasitic infections. Jiang et al.[136] reported that immunologic tolerance proteins such as CTLA-4, PD-1, and indoleamine 2, 3 dioxygenase, can use the autophagy process to regulate immune tolerance to tumors. Sigma 1 inhibitor promoted autophagic degradation of PDL-1 when tumor cells were co-cultured with T cells[137].

A negative correlation between autophagy and PD-1/PDL-1 pathway was reported in some studies. Autophagy deactivation was found to promote PDL-1 expression in stomach cancer[138], and vice versa, ligation of PD-1 on T cells to PDL-1 on tumor cells suppresses autophagy by triggering mTORC1 and limiting mTORC2 signaling[136]. Reduction of PD-1 by treatment increases autophagy[7]. In contrast, a positive correlation was reported in other studies. Binding of PD-1 on T cells was observed to decrease glucose uptake, resulting in enhanced autophagy through mTORC1 and AMP-activated protein kinase signaling[139]. Wen et al.[140] reported that the levels of LC3B+ extracellular vesicles correlate with upregulation of PDL-1 on matched monocytes from cancer patients. Additionally, they demonstrated that tumor cell-released autophagosomes induce M2 polarization which promotes tumor growth mainly through PD-1/PDL-1 signaling.

Therefore, more researches are essential to understand the interplay between autophagy and PD-1/PDL-1 pathway in leishmaniasis, to determine which pathway is downstream of the other and to define more effective therapeutic targets for this devastating disease.

  6. Conclusions Top

The ability of Leishmania to subvert the host immune mechanisms and to exploit it for its own survival helps the establishment of chronic infection. The induction of immunosuppressive mechanisms, especially the activation of PD-1/PDL-1 signaling in addition to the autophagy induction should be considered as targets for the future anti-leishmanial therapies. The relation between anti PDL-1 mechanism of action and autophagy inhibition should undergo further investigations to justify the use of chemical autophagy modulators to treat Leishmania. This will cut the cost of the expensive immunotherapy and will help better control of the disease in the developing countries.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Authors' contributions

SH: research idea, collected and analyzed the data, theoretical formatting. MA: final revision of the manuscript. KE: theoretical formatting and final revision. AH: supervision of the project.

  References Top

van Griensven J, Diro E. Visceral leishmaniasis. Infect Dis Clin North Am 2012; 26(2): 309-322.  Back to cited text no. 1
Martinez-Lopez M, Soto M, Iborra S, Sancho D. Leishmania hijacks myeloid cells for immune escape. Front Microbiol 2018; 9: 883.  Back to cited text no. 2
Srivastav S, Kar S, Chande AG, Mukhopadhyaya R, Das PK. Leishmania donovani exploits host deubiquitinating enzyme A20, a negative regulator of TLR signaling, to subvert host immune response. J Immunol 2012; 189(2): 924-934.  Back to cited text no. 3
Chakraborty D, Banerjee S, Sen A, Banerjee KK, Das P, Roy S. Leishmania donovani affects antigen presentation of macrophage by disrupting lipid rafts. J Immunol 2005; 175(5): 3214-3224.  Back to cited text no. 4
Nylen S, Sacks D. Interleukin-10 and the pathogenesis of human visceral leishmaniasis. Trends Immunol 2007; 28(9): 378-384.  Back to cited text no. 5
Stanley AC, Engwerda CR. Balancing immunity and pathology in visceral leishmaniasis. Immunol Cell Biol 2007; 85(2): 138-147.  Back to cited text no. 6
Robainas M, Otano R, Bueno S, Ait-Oudhia S. Understanding the role of PD-L1/PD1 pathway blockade and autophagy in cancer therapy. Onco Targets Ther 2017; 10: 1803-1807.  Back to cited text no. 7
Klenerman P, Hill A. T cells and viral persistence: Lessons from diverse infections. Nat Immunol 2005; 6(9): 873-879.  Back to cited text no. 8
Joshi T, Rodriguez S, Perovic V, Cockburn IA, Stager S. B7-H1 blockade increases survival of dysfunctional CD8+ T cells and confers protection against Leishmania donovani infections. PLoS Pathog 2009; 5(5): e1000431. doi: 10.1371/journal.ppat.1000431.  Back to cited text no. 9
Esch KJ, Juelsgaard R, Martinez PA, Jones DE, Petersen CA. Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function. J Immunol 2013; 191(11): 5542-5550.  Back to cited text no. 10
Habib S, El Andaloussi A, Elmasry K, Handoussa A, Azab M, Elsawey A, et al. PDL-1 blockade prevents T cell exhaustion, inhibits autophagy, and promotes clearance of Leishmania donovani. Infect Immun 2018; 86(6): e00019-18. doi:  Back to cited text no. 11
Varberg JM, LaFavers KA, Arrizabalaga G, Sullivan WJ Jr. Characterization of Plasmodium Atg3-Atg8 interaction inhibitors identifies novel alternative mechanisms of action in Toxoplasma gondii. Antimicrob Agents Chemother 2018; 62(2): e01489-17. doi: 10.1128/ AAC.01489-17.  Back to cited text no. 12
Mitroulis I, Kourtzelis I, Papadopoulos VP, Mimidis K, Speletas M, Ritis K. In vivo induction of the autophagic machinery in human bone marrow cells during Leishmania donovani complex infection. Parasitol Int 2009; 58(4): 475-477.  Back to cited text no. 13
Cyrino LT, Araujo AP, Joazeiro PP, Vicente CP, Giorgio S. In vivo and in vitro Leishmania amazonensis infection induces autophagy in macrophages. Tissue Cell 2012; 44(6): 401-408.  Back to cited text no. 14
Esch KJ, Schaut RG, Lamb IM, Clay G, Morais Lima AL, do Nascimento PR, et al. Activation of autophagy and nucleotide-binding domain leucine-rich repeat-containing-like receptor family, pyrin domain-containing 3 inflammasome during Leishmania infantum- associated glomerulonephritis. Am J Pathol 2015; 185(8): 2105-2117.  Back to cited text no. 15
Crauwels P, Bohn R, Thomas M, Gottwalt S, Jackel F, Kramer S, et al. Apoptotic-like Leishmania exploit the host's autophagy machinery to reduce T-cell-mediated parasite elimination. Autophagy 2015; 11(2): 285-297.  Back to cited text no. 16
Vinet AF, Fukuda M, Turco SJ, Descoteaux A. The Leishmania donovani lipophosphoglycan excludes the vesicular proton-ATPase from phagosomes by impairing the recruitment of synaptotagmin V. PLoS Pathog 2009; 5(10): e1000628. doi: journal.ppat.1000628.  Back to cited text no. 17
Frank B, Marcu A, de Oliveira Almeida Petersen AL, Weber H, Stigloher C, Mottram JC, et al. Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR-210. Parasit Vectors 2015; 8: 404.  Back to cited text no. 18
Haldar AK, Nigam U, Yamamoto M, Coers J, Goyal N. Guanylate binding proteins restrict Leishmania donovani growth in nonphagocytic cells independent of parasitophorous vacuolar targeting. mBio 2020; 11(4): e01464-20. doi:  Back to cited text no. 19
Ribeiro-Gomes FL, Sacks D. The influence of early neutrophil- Leishmania interactions on the host immune response to infection. Front Cell Infect Microbiol 2012; 2: 59.  Back to cited text no. 20
Messlinger H, Sebald H, Heger L, Dudziak D, Bogdan C, Schleicher U. Monocyte-derived signals activate human natural killer cells in response to Leishmania parasites. Front Immunol 2018; 9: 24.  Back to cited text no. 21
Prajeeth CK, Haeberlein S, Sebald H, Schleicher U, Bogdan C. Leishmania-infected macrophages are targets of NK cell-derived cytokines but not of NK cell cytotoxicity. Infect Immun 2011; 79(7): 2699-2708.  Back to cited text no. 22
Amprey JL, Im JS, Turco SJ, Murray HW, Illarionov PA, Besra GS, et al. A subset of liver NK T cells is activated during Leishmania donovani infection by CD1d-bound lipophosphoglycan. J Exp Med 2004; 200(7): 895-904.  Back to cited text no. 23
Moreno I, Molina R, Torano A, Laurin E, Garcia E, Dominguez M. Comparative real-time kinetic analysis of human complement killing of Leishmania infantum promastigotes derived from axenic culture or from Phlebotomus perniciosus. Microbes Infect 2007; 9(14-15): 1574-1580.  Back to cited text no. 24
Mukherjee S, Sengupta R, Mukhopadhyay D, Braun C, Mitra S, Roy S, et al. Impaired activation of lesional CD8+ T-cells is associated with enhanced expression of Programmed Death-1 in Indian Post Kala-azar Dermal Leishmaniasis. Sci Rep 2019; 9(1): 762.  Back to cited text no. 25
Chowdhury BP, Das S, Majumder S, Halder K, Ghosh S, Biswas S, et al. Immunomodulation of host-protective immune response by regulating Foxp3 expression and Treg function in Leishmania-infected BALB/c mice: Critical role of IRF1. Pathog Dis 2015; 73(8): ftv063. doi:  Back to cited text no. 26
Bankoti R, Gupta K, Levchenko A, Stager S. Marginal zone B cells regulate antigen-specific T cell responses during infection. J Immunol 2012; 188(8): 3961-3971.  Back to cited text no. 27
Babiker DT, Bakhiet SM, Mukhtar MM. Leishmania donovani influenced cytokines and toll-like receptors expression among Sudanese visceral leishmaniasis patients. Parasite Immunol 2015; 37(8): 417-425.  Back to cited text no. 28
Sacks DL, Pimenta PF, McConville MJ, Schneider P, Turco SJ. Stage- specific binding of Leishmania donovani to the sand fly vector midgut is regulated by conformational changes in the abundant surface lipophosphoglycan. J Exp Med 1995; 181(2): 685-697.  Back to cited text no. 29
Hermoso T, Fishelson Z, Becker SI, Hirschberg K, Jaffe CL. Leishmanial protein kinases phosphorylate components of the complement system. EMBO J 1991; 10(13): 4061-4067.  Back to cited text no. 30
Marth T, Kelsall BL. Regulation of interleukin-12 by complement receptor 3 signaling. J Exp Med 1997; 185(11): 1987-1995.  Back to cited text no. 31
Ronet C, Passelli K, Charmoy M, Scarpellino L, Myburgh E, Hauyon La Torre Y, et al. TLR2 signaling in skin nonhematopoietic cells induces early neutrophil recruitment in response to Leishmania major infection. J Invest Dermatol 2019; 139(6): 1318-1328.  Back to cited text no. 32
Das S, Pandey K, Kumar A, Sardar AH, Purkait B, Kumar M, et al. TGF-beta1 re-programs TLR4 signaling in L. donovani infection: Enhancement of SHP-1 and ubiquitin-editing enzyme A20. Immunol Cell Biol 2012; 90(6): 640-654.  Back to cited text no. 33
Olivier M, Gregory DJ, Forget G. Subversion mechanisms by which Leishmania parasites can escape the host immune response: A signaling point of view. Clin Microbiol Rev 2005; 18(2): 293-305.  Back to cited text no. 34
Batista MF, Najera CA, Meneghelli I, Bahia D. The parasitic intracellular lifestyle of Trypanosomatids: Parasitophorous vacuole development and survival. Front Cell Dev Biol 2020; 8: 396.  Back to cited text no. 35
Cojean S, Nicolas V, Lievin-Le Moal V. The macrophage microtubule network acts as a key cellular controller of the intracellular fate of Leishmania infantum. PLoS Negl Trop Dis 2020; 14(7): e0008396. doi:  Back to cited text no. 36
Young J, Kima PE. The Leishmania Parasitophorous vacuole membrane at the parasite-host interface. Yale J Biol Med 2019; 92(3): 511-521.  Back to cited text no. 37
Kima PE, Soong L, Chicharro C, Ruddle NH, McMahon-Pratt D. Leishmania-infected macrophages sequester endogenously synthesized parasite antigens from presentation to CD4+ T cells. Eur J Immunol 1996; 26(12): 3163-3169.  Back to cited text no. 38
De Souza Leao S, Lang T, Prina E, Hellio R, Antoine JC. Intracellular Leishmania amazonensis amastigotes internalize and degrade MHC class II molecules of their host cells. J Cell Sci 1995; 108(Pt 10): 3219-3231.  Back to cited text no. 39
Bhattacharyya S, Ghosh S, Sen P, Roy S, Majumdar S. Selective impairment of protein kinase C isotypes in murine macrophage by Leishmania donovani. Mol Cell Biochem 2001; 216(1-2): 47-57.  Back to cited text no. 40
Olivier M, Atayde VD, Isnard A, Hassani K, Shio MT. Leishmania virulence factors: Focus on the metalloprotease GP63. Microbes Infect 2012; 14(15): 1377-1389.  Back to cited text no. 41
Pessenda G, da Silva JS. Arginase and its mechanisms in Leishmania persistence. Parasite Immunol 2020; 42(7): e12722. doi: 10.1111/ pim.12722.  Back to cited text no. 42
Gupta G, Oghumu S, Satoskar AR. Mechanisms of immune evasion in leishmaniasis. Adv Appl Microbiol 2013; 82: 155-184.  Back to cited text no. 43
Tomiotto-Pellissier F, Bortoleti B, Assolini JP, Goncalves MD, Carloto ACM, Miranda-Sapla MM, et al. Macrophage polarization in leishmaniasis: Broadening horizons. Front Immunol 2018; 9: 2529.  Back to cited text no. 44
Sarkar A, Saha P, Mandal G, Mukhopadhyay D, Roy S, Singh SK, et al. Monitoring of intracellular nitric oxide in leishmaniasis: Its applicability in patients with visceral leishmaniasis. Cytometry A 2011; 79(1): 35-45.  Back to cited text no. 45
Roy S, Mukhopadhyay D, Mukherjee S, Moulik S, Chatterji S, Brahme N, et al. An IL-10 dominant polarization of monocytes is a feature of Indian visceral leishmaniasis. Parasite Immunol 2018; 40(7): e12535. doi: 10.1111/pim.12535.  Back to cited text no. 46
Schwartzman JD, Pearson RD. The interaction of Leishmania donovani promastigotes and human fibroblasts in vitro. Am J Trop Med Hyg 1985; 34(5): 850-855.  Back to cited text no. 47
Belle EA. Cultivation of Leishmania donovani in human amnion epithelial cell tissue cultures: A preliminary report. Can Med Assoc J 1958; 79(9): 726-728.  Back to cited text no. 48
Bogdan C, Donhauser N, Doring R, Rollinghoff M, Diefenbach A, Rittig MG. Fibroblasts as host cells in latent leishmaniosis. J Exp Med 2000; 191(12): 2121-2130.  Back to cited text no. 49
Wells A, Nuschke A, Yates CC. Skin tissue repair: Matrix microenvironmental influences. Matrix Biol 2016; 49: 25-36.  Back to cited text no. 50
Petropolis DB, Rodrigues JC, Viana NB, Pontes B, Pereira CF, Silva- Filho FC. Leishmania amazonensis promastigotes in 3D collagen I culture: An in vitro physiological environment for the study of extracellular matrix and host cell interactions. Peer J 2014; 2: e317.  Back to cited text no. 51
Giraud E, Lestinova T, Derrick T, Martin O, Dillon RJ, Volf P, et al. Leishmania proteophosphoglycans regurgitated from infected sand flies accelerate dermal wound repair and exacerbate leishmaniasis via insulin-like growth factor 1-dependent signalling. PLoS Pathog 2018; 14(1): e1006794. doi: 10.1371/journal.ppat.1006794.  Back to cited text no. 52
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(5): 752-768.e7. doi: 10.1016/ j.chom.2020.03.011.  Back to cited text no. 53
Osorio EY, Travi BL, da Cruz AM, Saldarriaga OA, Medina AA, Melby PC. Growth factor and Th2 cytokine signaling pathways converge at STAT6 to promote arginase expression in progressive experimental visceral leishmaniasis. PLoS Pathog 2014; 10(6): e1004165. doi: 10.1371/journal.ppat.1004165.  Back to cited text no. 54
Kumar V, Das S, Kumar A, Tiwari N, Kumar A, Abhishek K, et al. Leishmania donovani infection induce differential miRNA expression in CD4+ T cells. Sci Rep 2020; 10(1): 3523.  Back to cited text no. 55
Zubairi S, Sanos SL, Hill S, Kaye PM. Immunotherapy with OX40L-Fc or anti-CTLA-4 enhances local tissue responses and killing of Leishmania donovani. Eur J Immunol 2004; 34(5): 1433-1440.  Back to cited text no. 56
de Freitas ESR, von Stebut E. Unraveling the role of immune checkpoints in leishmaniasis. Front Immunol 2021; 12: 620144.  Back to cited text no. 57
Chiku VM, Silva KL, de Almeida BF, Venturin GL, Leal AA, de Martini CC, et al. PD-1 function in apoptosis of T lymphocytes in canine visceral leishmaniasis. Immunobiology 2016; 221(8): 879-888.  Back to cited text no. 58
Rodrigues FM, Coelho Neto GT, Menezes JG, Gama ME, Goncalves EG, Silva AR, et al. Expression of Foxp3, TGF-beta and IL-10 in American cutaneous leishmaniasis lesions. Arch Dermatol Res 2014; 306(2): 163-171.  Back to cited text no. 59
Roncarolo MG, Gregori S, Bacchetta R, Battaglia M. Tr1 cells and the counter-regulation of immunity: Natural mechanisms and therapeutic applications. Curr Top Microbiol Immunol 2014; 380: 39-68.  Back to cited text no. 60
Ato M, Stager S, Engwerda CR, Kaye PM. Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nat Immunol 2002; 3(12): 1185-1191.  Back to cited text no. 61
Nylen S, Maurya R, Eidsmo L, Manandhar KD, Sundar S, Sacks D. Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis. J Exp Med 2007; 204(4): 805-817.  Back to cited text no. 62
Moulik S, Karmakar J, Joshi S, Dube A, Mandal C, Chatterjee M. Status of IL-4 and IL-10 driven markers in experimental models of visceral leishmaniasis. Parasite Immunol 2021; 43(1): e12783.  Back to cited text no. 63
Murphy ML, Wille U, Villegas EN, Hunter CA, Farrell JP. IL-10 mediates susceptibility to Leishmania donovani infection. Eur J Immunol 2001; 31(10): 2848-2856.  Back to cited text no. 64
Gautam S, Kumar R, Maurya R, Nylen S, Ansari N, Rai M, et al. IL-10 neutralization promotes parasite clearance in splenic aspirate cells from patients with visceral leishmaniasis. J Infect Dis 2011; 204(7): 1134-1137.  Back to cited text no. 65
Walker LS. Treg and CTLA-4: Two intertwining pathways to immune tolerance. J Autoimmun 2013; 45: 49-57.  Back to cited text no. 66
Gardner D, Jeffery LE, Sansom DM. Understanding the CD28/CTLA-4 (CD152) pathway and its implications for costimulatory blockade. Am J Transplant 2014; 14(9): 1985-1991.  Back to cited text no. 67
Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3(5): 541-547.  Back to cited text no. 68
Ise W, Kohyama M, Nutsch KM, Lee HM, Suri A, Unanue ER, et al. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol 2010; 11(2): 129-135.  Back to cited text no. 69
de Souza TL, da Silva AVA, Pereira LOR, Figueiredo FB, Mendes Junior AAV, Menezes RC, et al. Pro-cellular exhaustion markers are associated with splenic microarchitecture disorganization and parasite load in dogs with visceral leishmaniasis. Sci Rep 2019; 9(1): 12962.  Back to cited text no. 70
Brown JA, Titus RG, Nabavi N, Glimcher LH. Blockade of CD86 ameliorates Leishmania major infection by down-regulating the Th2 response. J Infect Dis 1996; 174(6): 1303-1308.  Back to cited text no. 71
Murphy ML, Engwerda CR, Gorak PM, Kaye PM. B7-2 blockade enhances T cell responses to Leishmania donovani. J Immunol 1997; 159(9): 4460-4466.  Back to cited text no. 72
Murray HW, Lu CM, Brooks EB, Fichtl RE, DeVecchio JL, Heinzel FP. Modulation of T-cell costimulation as immunotherapy or immunochemotherapy in experimental visceral leishmaniasis. Infect Immun 2003; 71(11): 6453-6462.  Back to cited text no. 73
Ansari NA, Kumar R, Gautam S, Nylen S, Singh OP, Sundar S, et al. IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis. J Immunol 2011; 186(7): 3977-3985.  Back to cited text no. 74
Montes de Oca M, de Labastida Rivera F, Winterford C, Frame TCM, Ng SS, Amante FH, et al. IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection. PLoS Pathog 2020; 16(10): e1008994. doi: 10.1371/journal.ppat.1008994.  Back to cited text no. 75
Rosas LE, Satoskar AA, Roth KM, Keiser TL, Barbi J, Hunter C, et al. Interleukin-27R (WSX-1/T-cell cytokine receptor) gene-deficient mice display enhanced resistance to Leishmania donovani infection but develop severe liver immunopathology. Am J Pathol 2006; 168(1): 158-169.  Back to cited text no. 76
Plitas G, Rudensky AY. Regulatory T cells: Differentiation and function. Cancer Immunol Res 2016; 4(9): 721-725.  Back to cited text no. 77
Rai AK, Thakur CP, Singh A, Seth T, Srivastava SK, Singh P, et al. Regulatory T cells suppress T cell activation at the pathologic site of human visceral leishmaniasis. PLoS One 2012; 7(2): e31551. doi: 10.1371/journal.pone.0031551.  Back to cited text no. 78
Bhattacharya P, Ghosh S, Ejazi SA, Rahaman M, Pandey K, Ravi Das VN, et al. Induction of IL-10 and TGFbeta from CD4+CD25+FoxP3+ T cells correlates with parasite load in Indian Kala-azar patients infected with Leishmania donovani. PLoS Negl Trop Dis 2016; 10(2): e0004422. doi: 10.1371/journal.pntd.0004422.  Back to cited text no. 79
Colmenares M, Corbi AL, Turco SJ, Rivas L. The dendritic cell receptor DC-SIGN discriminates among species and life cycle forms of Leishmania. J Immunol 2004; 172(2): 1186-1190.  Back to cited text no. 80
Ghosh M, Pal C, Ray M, Maitra S, Mandal L, Bandyopadhyay S. Dendritic cell-based immunotherapy combined with antimony-based chemotherapy cures established murine visceral leishmaniasis. J Immunol 2003; 170(11): 5625-5629.  Back to cited text no. 81
Schonrich G, Raftery MJ. The PD-1/PD-L1 axis and virus infections: A delicate balance. Front Cell Infect Microbiol 2019; 9: 207.  Back to cited text no. 82
Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999; 5(12): 1365-1369.  Back to cited text no. 83
Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001; 291(5502): 319-322.  Back to cited text no. 84
de Freitas ESR, Galvez RI, Pereira VRA, de Brito MEF, Choy SL, Lotter H, et al. Programmed cell death ligand (PD-L)-1 contributes to the regulation of CD4(+) T effector and regulatory T cells in cutaneous leishmaniasis. Front Immunol 2020; 11: 574491.  Back to cited text no. 85
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: Implications for tumor immunotherapy. Cancer Immunol Immunother 2005; 54(4): 307-314.  Back to cited text no. 86
Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O'Shea MA, et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL- 21 induce the expression of programmed death-1 and its ligands. J Immunol 2008; 181(10): 6738-6746.  Back to cited text no. 87
Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali MA, et al. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol 2011; 12(7): 663-671.  Back to cited text no. 88
Austin JW, Lu P, Majumder P, Ahmed R, Boss JM. STAT3, STAT4, NFATc1, and CTCF regulate PD-1 through multiple novel regulatory regions in murine T cells. J Immunol 2014; 192(10): 4876-4886.  Back to cited text no. 89
Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002; 169(10): 5538-5545.  Back to cited text no. 90
Mazanet MM, Hughes CC. B7-H1 is expressed by human endothelial cells and suppresses T cell cytokine synthesis. J Immunol 2002; 169(7): 3581-3588.  Back to cited text no. 91
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med 2002; 8(8): 793-800.  Back to cited text no. 92
Constantinidou A, Alifieris C, Trafalis DT. Targeting programmed cell death-1 (PD-1) and ligand (PD-L1): A new era in cancer active immunotherapy. Pharmacol Ther 2019; 194: 84-106.  Back to cited text no. 93
Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007; 13(1): 84-88.  Back to cited text no. 94
Rebech GT, Venturin GL, Siqueira Ito LT, Bragato JP, de Carvalho Fonseca BS, Melo LM, et al. PD-1 regulates leishmanicidal activity and IL-17 in dogs with leishmaniasis. Vet Immunol Immunopathol 2020; 219: 109970.  Back to cited text no. 95
Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 2012; 5(230): ra46. doi: 10.1126/scisignal.2002796.  Back to cited text no. 96
Pyzik M, Piccirillo CA. TGF-beta1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets. J Leukoc Biol 2007; 82(2): 335-346.  Back to cited text no. 97
Chang CH, Curtis JD, Maggi LB, Jr., Faubert B, Villarino AV, O'Sullivan D, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013; 153(6): 1239-1251.  Back to cited text no. 98
Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 2015; 6: 6692.  Back to cited text no. 99
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366(26): 2455-2465.  Back to cited text no. 100
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372(4): 320-330.  Back to cited text no. 101
Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 2004; 101(49): 17174-17179.  Back to cited text no. 102
Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: Signaling, cancer, and beyond. Adv Exp Med Biol 2020; 1248: 33-59.  Back to cited text no. 103
Han Y, Liu D, Li L. PD-1/PD-L1 pathway: Current researches in cancer. Am J Cancer Res 2020; 10(3): 727-742.  Back to cited text no. 104
Bardhan K, Anagnostou T, Boussiotis VA. The PD1: PD-L1/2 pathway from discovery to clinical implementation. Front Immunol 2016; 7: 550.  Back to cited text no. 105
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti- PD-1 antibody in cancer. N Engl J Med 2012; 366(26): 2443-2454.  Back to cited text no. 106
Cha JH, Chan LC, Li CW, Hsu JL, Hung MC. Mechanisms controlling PD-L1 expression in cancer. Mol Cell 2019; 76(3): 359-370.  Back to cited text no. 107
Buggert M, Tauriainen J, Yamamoto T, Frederiksen J, Ivarsson MA, Michaelsson J, et al. T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog 2014; 10(7): e1004251. doi: 10.1371/journal.ppat.1004251.  Back to cited text no. 108
Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 2006; 80(22): 11398-11403.  Back to cited text no. 109
Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009; 10(1): 29-37.  Back to cited text no. 110
Bhadra R, Gigley JP, Weiss LM, Khan IA. Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD- 1-PDL-1 blockade. Proc Natl Acad Sci U S A 2011; 8(22): 9196-9201.  Back to cited text no. 111
Furtado R, Chorro L, Zimmerman N, Guillen E, Spaulding E, Chin SS, et al. Blockade of LAG-3 in PD-L1-deficient mice enhances clearance of blood stage malaria independent of humoral responses. Front Immunol 2020; 11: 576743.  Back to cited text no. 112
Filippis C, Arens K, Noubissi Nzeteu GA, Reichmann G, Waibler Z, Crauwels P, et al. Nivolumab enhances in vitro effector functions of PD-1(+) T-lymphocytes and Leishmania-infected human myeloid cells in a host cell-dependent manner. Front Immunol 2017; 8: 1880.  Back to cited text no. 113
da Fonseca-Martins AM, Ramos TD, Pratti JES, Firmino-Cruz L, Gomes DCO, Soong L, et al. Immunotherapy using anti-PD-1 and anti-PD-L1 in Leishmania amazonensis-infected BALB/c mice reduce parasite load. Sci Rep 2019; 9(1): 20275.  Back to cited text no. 114
Parzych KR, Klionsky DJ. An overview of autophagy: Morphology, mechanism, and regulation. Antioxid Redox Signal 2014; 20(3): 460-473.  Back to cited text no. 115
Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 2013; 13(10): 722-737.  Back to cited text no. 116
Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med 2013; 368(19): 1845-1846.  Back to cited text no. 117
Wang Y, Zhang H. Regulation of autophagy by mTOR signaling pathway. Adv Exp Med Biol 2019; 1206: 67-83.  Back to cited text no. 118
Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 2010; 90(4): 1383-1435.  Back to cited text no. 119
Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 2018; 19(6): 349-364.  Back to cited text no. 120
Lamark T, Johansen T. Aggrephagy: Selective disposal of protein aggregates by macroautophagy. Int J Cell Biol 2012; 2012: 736905.  Back to cited text no. 121
Sacks D, Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol 2002; 2(11): 845-858.  Back to cited text no. 122
Deretic V, Levine B. Autophagy balances inflammation in innate immunity. Autophagy 2018; 14(2): 243-251.  Back to cited text no. 123
Tao S, Drexler I. Targeting autophagy in innate immune cells: Angel or demon during infection and vaccination? Front Immunol 2020; 11: 460.  Back to cited text no. 124
Matte C, Casgrain PA, Seguin O, Moradin N, Hong WJ, Descoteaux A. Leishmania major promastigotes evade LC3-associated phagocytosis through the action of GP63. PLoS Pathog 2016; 12(6): e1005690. doi: 10.1371/journal.ppat.1005690.  Back to cited text no. 125
Martinez J, Almendinger J, Oberst A, Ness R, Dillon CP, Fitzgerald P, et al. Microtubule-associated protein 1 light chain 3 alpha (LC3)- associated phagocytosis is required for the efficient clearance of dead cells. Proc Natl Acad Sci U S A 2011; 108(42): 17396-17401.  Back to cited text no. 126
Pinheiro RO, Nunes MP, Pinheiro CS, D'Avila H, Bozza PT, Takiya CM, et al. Induction of autophagy correlates with increased parasite load of Leishmania amazonensis in BALB/c but not C57BL/6 macrophages. Microbes Infect 2009; 11(2): 181-190.  Back to cited text no. 127
Dengjel J, Schoor O, Fischer R, Reich M, Kraus M, Muller M, et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci U S A 2005; 102(22): 7922-7927.  Back to cited text no. 128
Thomas SA, Nandan D, Kass J, Reiner NE. Countervailing, time- dependent effects on host autophagy promotes intracellular survival of Leishmania. J Biol Chem 2018; 293(7): 2617-2630.  Back to cited text no. 129
Evans RJ, Sundaramurthy V, Frickel EM. The interplay of host autophagy and eukaryotic pathogens. Front Cell Dev Biol 2018; 6: 118.  Back to cited text no. 130
Kumar A, Das S, Mandal A, Verma S, Abhishek K, Kumar A, et al. Leishmania infection activates host mTOR for its survival by M2 macrophage polarization. Parasite Immunol 2018; 40(11): e12586.  Back to cited text no. 131
Cavalcante-Costa VS, Costa-Reginaldo M, Queiroz-Oliveira T, Oliveira ACS, Couto NF, Dos Anjos DO, et al. Leishmania amazonensis hijacks host cell lysosomes involved in plasma membrane repair to induce invasion in fibroblasts. J Cell Sci 2019; 132(6): jcs226183. doi:  Back to cited text no. 132
Coers J, Brown HM, Hwang S, Taylor GA. Partners in anti-crime: How interferon-inducible GTPases and autophagy proteins team up in cell-intrinsic host defense. Curr Opin Immunol 2018; 54: 93-101.  Back to cited text no. 133
Khadir F, Shaler CR, Oryan A, Rudak PT, Mazzuca DM, Taheri T, et al. Therapeutic control of leishmaniasis by inhibitors of the mammalian target of rapamycin. PLoS Negl Trop Dis 2018; 12(8): e0006701.  Back to cited text no. 134
Tousif S, Singh Y, Prasad DV, Sharma P, Van Kaer L, Das G. T cells from programmed death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection. PLoS One 2011; 6(5): e19864. doi:  Back to cited text no. 135
Jiang GM, Tan Y, Wang H, Peng L, Chen HT, Meng XJ, et al. The relationship between autophagy and the immune system and its applications for tumor immunotherapy. Mol Cancer 2019; 18(1): 17.  Back to cited text no. 136
Maher CM, Thomas JD, Haas DA, Longen CG, Oyer HM, Tong JY, et al. Small-molecule sigma1 modulator induces autophagic degradation of PD-L1. Mol Cancer Res 2018; 16(2): 243-255.  Back to cited text no. 137
Wang X, Wu WKK, Gao J, Li Z, Dong B, Lin X, et al. Autophagy inhibition enhances PD-L1 expression in gastric cancer. J Exp Clin Cancer Res 2019; 38(1): 140.  Back to cited text no. 138
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25(21): 9543-9553.  Back to cited text no. 139
Wen ZF, Liu H, Gao R, Zhou M, Ma J, Zhang Y, et al. Tumor cell- released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1. J Immunother Cancer 2018; 6(1): 151.  Back to cited text no. 140


  [Figure 1], [Figure 2], [Figure 3]

This article has been cited by
1 New developments in the treatment of cutaneous leishmaniasis
Rasit Dinc
Asian Pacific Journal of Tropical Medicine. 2022; 15(5): 196
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
1. Introduction
2. The immune re...
3. Immune evasio...
4. Immunosuppres...
5. Autophagy
6. Conclusions
Article Figures

 Article Access Statistics
    PDF Downloaded342    
    Comments [Add]    
    Cited by others 1    

Recommend this journal