Leishmania donovani Subverts Host Immune Response by Epigenetic Reprogramming of Macrophage M(Lipopolysaccharides + IFN-γ)/M(IL-10) Polarization

Summary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins of Leishmania parasite; however, related studies are meagre. We have identified a novel secretory Leishmania donovani glycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude that Leishmania donovani Mevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement of Leishmania in the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions.

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Leishmania donovani Exploits Host Deubiquitinating Enzyme A20, a Negative Regulator of TLR Signaling, To Subvert Host Immune Response

The Journal of Immunology ◽

10.4049/jimmunol.1102845 ◽

2012 ◽

Vol 189 (2) ◽

pp. 924-934 ◽

Cited By ~ 58

Author(s):

Supriya Srivastav ◽

Susanta Kar ◽

Ajit G. Chande ◽

Robin Mukhopadhyaya ◽

Pijush K. Das

Keyword(s):

Immune Response ◽

Leishmania Donovani ◽

Host Immune Response ◽

Negative Regulator ◽

Deubiquitinating Enzyme ◽

Tlr Signaling

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Dysregulation of TNF-α and IFN-γ expression is a common host immune response in a chronically infected mouse model of melioidosis when comparing multiple human strains of Burkholderia pseudomallei

BMC Immunology ◽

10.1186/s12865-020-0333-9 ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 2

Author(s):

Kei Amemiya ◽

Jennifer L. Dankmeyer ◽

Jeremy J. Bearss ◽

Xiankun Zeng ◽

Spencer W. Stonier ◽

...

Keyword(s):

Immune Response ◽

Mouse Model ◽

Infected Mouse ◽

Burkholderia Pseudomallei ◽

Host Immune Response ◽

Tnf Α ◽

Ifn Γ

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Cytosolic tryparedoxin of Leishmania donovani modulates host immune response in visceral leishmaniasis

Cytokine ◽

10.1016/j.cyto.2018.03.010 ◽

2018 ◽

Vol 108 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Shashi Shekhar Suman ◽

Ajay Amit ◽

Krishn Pratap Singh ◽

Parool Gupta ◽

Asif Equbal ◽

...

Keyword(s):

Immune Response ◽

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Host Immune Response

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Poxvirus-Encoded Gamma Interferon Binding Protein Dampens the Host Immune Response to Infection

Journal of Virology ◽

10.1128/jvi.01927-06 ◽

2007 ◽

Vol 81 (7) ◽

pp. 3346-3353 ◽

Cited By ~ 29

Author(s):

Isaac G. Sakala ◽

Geeta Chaudhri ◽

R. Mark Buller ◽

Anthony A. Nuara ◽

Hongdong Bai ◽

...

Keyword(s):

Immune Response ◽

Virus Replication ◽

Deletion Mutant ◽

Binding Protein ◽

Small Animal ◽

Host Immune Response ◽

Gamma Interferon ◽

Mutant Virus ◽

Ifn Γ

ABSTRACT Ectromelia virus (ECTV), a natural mouse pathogen and the causative agent of mousepox, is closely related to variola virus (VARV), which causes smallpox in humans. Mousepox is an excellent surrogate small-animal model for smallpox. Both ECTV and VARV encode a multitude of host response modifiers that target components of the immune system and that are thought to contribute to the high mortality rates associated with infection. Like VARV, ECTV encodes a protein homologous to the ectodomain of the host gamma interferon (IFN-γ) receptor 1. We generated an IFN-γ binding protein (IFN-γbp) deletion mutant of ECTV to study the role of viral IFN-γbp (vIFN-γbp) in host-virus interaction and also to elucidate the contribution of this molecule to the outcome of infection. Our data show that the absence of vIFN-γbp does not affect virus replication per se but does have a profound effect on virus replication and pathogenesis in mice. BALB/c mice, which are normally susceptible to infection with ECTV, were able to control replication of the mutant virus and survive infection. Absence of vIFN-γbp from ECTV allowed the generation of an effective host immune response that was otherwise diminished by this viral protein. Mice infected with a vIFN-γbp deletion mutant virus, designated ECTV-IFN-γbpΔ, produced increased levels of IFN-γ and generated robust cell-mediated and antibody responses. Using several strains of mice that exhibit differential degrees of resistance to mousepox, we show that recovery or death from ECTV infection is determined by a balance between the host's ability to produce IFN-γ and the virus' ability to dampen its effects.

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Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice

Infection and Immunity ◽

10.1128/iai.00184-15 ◽

2015 ◽

Vol 83 (10) ◽

pp. 3800-3815 ◽

Cited By ~ 32

Author(s):

Parna Bhattacharya ◽

Ranadhir Dey ◽

Pradeep K. Dagur ◽

Michael Kruhlak ◽

Nevien Ismail ◽

...

Keyword(s):

Nitric Oxide ◽

Immune Response ◽

T Cells ◽

Leishmania Donovani ◽

Content Type ◽

M1 Macrophage ◽

Tnf Α ◽

Ifn Γ ◽

Classically Activated

Visceral leishmaniasis (VL) causes significant mortality and there is no effective vaccine. Previously, we have shown that genetically modifiedLeishmania donovaniparasites, here described as live attenuated parasites, induce a host protective adaptive immune response in various animal models. In this study, we demonstrate an innate immune response upon infection with live attenuated parasites in macrophages from BALB/c mice bothin vitroandin vivo. In vitroinfection of macrophages with live attenuated parasites (compared to that with wild-type [WT]L. donovaniparasites) induced significantly higher production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-12 [IL-12], gamma interferon [IFN-γ], and IL-6), chemokines (monocyte chemoattractant protein 1/CCL-2, macrophage inflammatory protein 1α/CCL-3, and IP-10), reactive oxygen species (ROS), and nitric oxide, while concomitantly reducing anti-inflammatory cytokine IL-10 and arginase-1 activities, suggesting a dominant classically activated/M1 macrophage response. The classically activated response in turn helps in presenting antigen to T cells, as observed with robust CD4+T cell activationin vitro. Similarly, parasitized splenic macrophages from live attenuated parasite-infected mice also demonstrated induction of an M1 macrophage phenotype, indicated by upregulation of IL-1β, TNF-α, IL-12, and inducible nitric oxide synthase 2 and downregulation of genes associated with the M2 phenotype, i.e., the IL-10, YM1, Arg-1, and MRC-1 genes, compared to WTL. donovani-infected mice. Furthermore, anex vivoantigen presentation assay showed macrophages from live attenuated parasite-infected mice induced higher IFN-γ and IL-2 but significantly less IL-10 production by ovalbumin-specific CD4+T cells, resulting in proliferation of Th1 cells. These data suggest that infection with live attenuated parasites promotes a state of classical activation (M1 dominant) in macrophages that leads to the generation of protective Th1 responses in BALB/c mice.

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Infection Outcome and Cytokine Gene Expression in Brugia pahangi- Infected Gerbils (Meriones unguiculatus) Sensitized with Brucella abortus

Infection and Immunity ◽

10.1128/iai.70.11.5938-5945.2002 ◽

2002 ◽

Vol 70 (11) ◽

pp. 5938-5945 ◽

Cited By ~ 15

Author(s):

Sharon R. Chirgwin ◽

Philip H. Elzer ◽

Sharon U. Coleman ◽

Jena M. Nowling ◽

Sue D. Hagius ◽

...

Keyword(s):

Immune Response ◽

Brucella Abortus ◽

Cellular Response ◽

Clinical Manifestations ◽

Host Immune Response ◽

Cytokine Gene Expression ◽

Mrna Levels ◽

Th2 Response ◽

Cellular Environment ◽

Ifn Γ

ABSTRACT Filarial infections have been associated with the development of a strongly polarized Th2 host immune response and a severe impairment of mitogen-driven proliferation and type 1 cytokine production in mice and humans. The role of this polarization in the development of the broad spectra of clinical manifestations of lymphatic filariasis is still unknown. Recently, data gathered from humans as well as from immunocompromised mouse models suggest that filariasis elicits a complex host immune response involving both Th1 and Th2 components. However, responses of a similar nature have not been reported in immunologically intact permissive models of Brugia infection. Brucella abortus-killed S19 was inoculated into the Brugia-permissive gerbil host to induce gamma interferon (IFN-γ) production. Gerbils were then infected with B. pahangi, and the effect of the polarized Th1 responses on worm establishment and host cellular response was measured. Animals infected with both B. abortus and B. pahangi showed increased IFN-γ and interleukin-10 (IL-10) and decreased IL-4 and IL-5 mRNA levels compared with those in animals infected with B. pahangi alone. These data suggest that the prior sensitization with B. abortus may induce a down regulation of the Th2 response associated with Brugia infection. This reduced Th2 response was associated with a reduced eosinophilia and an increased neutrophilia in the peritoneal exudate cells. The changes in cytokine and cellular environment did not inhibit the establishment of B. pahangi intraperitoneally. The data presented here suggest a complex relationship between the host immune response and parasite establishment and survival that cannot be simply ascribed to the Th1/Th2 paradigm.

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An Insight Into Systemic Immune Response in Leishmania donovani Mediated Atypical Cutaneous Leishmaniasis in the New Endemic State of Himachal Pradesh, India

Frontiers in Immunology ◽

10.3389/fimmu.2021.765684 ◽

2022 ◽

Vol 12 ◽

Author(s):

Lovlesh Thakur ◽

Priyanka Madaan ◽

Aklank Jain ◽

Vinay Shankar ◽

Ajeet Negi ◽

...

Keyword(s):

Immune Response ◽

Cutaneous Leishmaniasis ◽

Expression Pattern ◽

Leishmania Donovani ◽

Parasite Species ◽

Himachal Pradesh ◽

Systemic Immune Response ◽

Immune Correlates ◽

Ifn Γ ◽

Endemic State

Leishmaniasis continues to afflict known and newer endemic sites despite global efforts towards its control and elimination. In this regard, the emergence of newer endemic sites with unusual disease formats is recognized wherein Leishmania donovani complex classically known to cause visceral disease is demonstrated to cause cutaneous manifestation. In this context, atypical cutaneous leishmaniasis (CL) cases caused by L. donovani genetic variants from the newer endemic state of Himachal Pradesh (HP) in India are beginning to be understood in terms of parasite determinants. The atypical CL manifestation further needs to be explored to define host immune correlates with a possible role in driving the unusual disease progression. In the given study, we performed comprehensive systemic-immune profiling of the atypical CL patients from the study area in HP, India, in comparison with the classical visceral leishmaniasis (VL) patients from the northeast region of India. The systemic immune response was studied using ELISA-based assessment of Th1, Th2, Th17, Treg, and Th22 specific plasma cytokine expression pattern and parasite-specific total serum IgG/IgG subclasses. The specified immune correlates are known to exhibit heterogeneous association with the different infecting parasite species, infection load, and co-lateral host immunopathology in classical CL and VL. In the atypical CL patient group, altered expression of IL-10 emerged as the key finding that could potentially fine-tune the Th1/Th17/Th22 effector cytokine axis towards a localized cutaneous manifestation. A reduced expression of IL-10 along with a high IFN-γ/IL-10 ratio as a readout of effective parasite killing defined atypical cutaneous outcome. In contrast, high circulatory IL-10 levels and a depressed IFN-γ/IL-10 ratio were seen in classical VL patients in line with an ineffective parasite-killing cytokine response. Overall, the study highlights new knowledge on host immune correlates in terms of cytokine expression pattern and IgG subclasses that underline atypical disease manifestation such that L. donovani, a generally visceralizing parasite species cause skin localized cutaneous lesions.

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Immune Responses Induced by the Leishmania (Leishmania) donovani A2 Antigen, but Not by the LACK Antigen, Are Protective against Experimental Leishmania (Leishmania) amazonensis Infection

Infection and Immunity ◽

10.1128/iai.71.7.3988-3994.2003 ◽

2003 ◽

Vol 71 (7) ◽

pp. 3988-3994 ◽

Cited By ~ 156

Author(s):

Eduardo Antonio Ferraz Coelho ◽

Carlos Alberto Pereira Tavares ◽

Fernando Aécio Amorim Carvalho ◽

Karina Figueiredo Chaves ◽

Kadima Nayara Teixeira ◽

...

Keyword(s):

Immune Response ◽

Protective Effect ◽

Leishmania Donovani ◽

Leishmania Amazonensis ◽

Interleukin 12 ◽

Specific Antibodies ◽

Etiologic Agents ◽

Ifn Γ ◽

Humoral Responses ◽

Th1 Immune Response

ABSTRACT Leishmania amazonensis is one of the major etiologic agents of a broad spectrum of clinical forms of leishmaniasis and has a wide geographical distribution in the Americas, which overlaps with the areas of transmission of many other Leishmania species. The LACK and A2 antigens are shared by various Leishmania species. A2 was previously shown to induce a potent Th1 immune response and protection against L. donovani infection in BALB/c mice. LACK is effective against L. major infection, but no significant protection against L. donovani infection was observed, in spite of the induction of a potent Th1 immune response. In an attempt to select candidate antigens for an American leishmaniasis vaccine, we investigated the protective effect of these recombinant antigens (rLACK and rA2) and recombinant interleukin-12 (rIL-12) against L. amazonensis infection in BALB/c mice. As expected, immunization with either rA2-rIL-12 or rLACK-rIL-12 induced a robust Th1 response prior to infection. However, only the BALB/c mice immunized with rA2-rIL-12 were protected against infection. Sustained gamma interferon (IFN-γ) production, high levels of anti-A2 antibodies, and low levels of parasite-specific antibodies were detected in these mice after infection. In contrast, mice immunized with rLACK-rIL-12 displayed decreased levels of IFN-γ and high levels of both anti-LACK and parasite-specific antibodies. Curiously, the association between rA2 and rLACK antigens in the same vaccine completely inhibited the rA2-specific IFN-γ and humoral responses and, consequently, the protective effect of the rA2 antigen against L. amazonensis infection. We concluded that A2, but not LACK, fits the requirements for a safe vaccine against American leishmaniasis.

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Evidence for Reversal of Immunosuppression by Homeopathic Medicine to a Predominant Th1-type Immune Response in BALB/c Mice Infected with Leishmania donovani

Homeopathy ◽

10.1055/s-0041-1727170 ◽

2021 ◽

Author(s):

Jyoti Joshi ◽

Chetna Bandral ◽

Raj Kumar Manchanda ◽

Anil Khurana ◽

Debadatta Nayak ◽

...

Keyword(s):

Immune Response ◽

Leishmania Donovani ◽

Experimental Approach ◽

Axenic Culture ◽

Parasite Load ◽

Ifn Γ ◽

Immunomodulatory Potential ◽

Pro Inflammatory Cytokines

Abstract Background Visceral leishmaniasis (VL) is a neglected tropical disease that is fatal if treatment is not given. The available chemotherapeutic options are unsatisfactory, and so complementary therapies like homeopathy might be a promising approach. Methods A nosode from a pure axenic culture of Leishmania donovani was prepared and screened for its anti-leishmanial potential both in an in-vitro and an in-vivo experimental approach. Results Leishmania donovani amastigote promastigote nosode (LdAPN 30C) exhibited significant anti-leishmanial activity against the promastigote forms of Leishmania donovani and was found to be safe. A study conducted on VL-infected mice revealed that LdAPN 30C resolved the disease by modulating the host immune response toward the Th1 type through upregulating the pro-inflammatory cytokines (IFN-γ and IL-17) and inducing nitric oxide (NO) levels in the infected macrophages. The hepatic parasite load was also found to be significantly decreased. The nosode was found to be safe, as no histological alterations in the liver or kidney were observed in the animals treated with the LdAPN 30C. Conclusion This is the first study in which an axenic culture of Leishmania donovani has been used for the preparation of a homeopathic medication. The study highlights the anti-leishmanial and immunomodulatory potential of a homeopathic nosode in experimental VL.

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