IL-10 and TGF-β Induced Arginase Expression Contributes to Deficient Nitric Oxide Response in Human Visceral Leishmaniasis.

Manu Kupani,Rajiv Kumar,Smriti Sharma,Rajeev Kumar Pandey,Shyam Sundar,Sanjana Mehrotra

doi:10.3389/fcimb.2020.614165

Abstract

Nitric oxide (NO) is an anti-microbial effector of the innate immune system which plays major role in non-specific killing of various pathogens including protozoan parasites. However, due to subversion of the host’s immune processes by pathogens, suboptimal production of NO is frequently found in many infection models. Previous studies have shown suppressed NO production during Leishmania donovani infection, the causative agent of visceral leishmaniasis (VL). Availability of L-Arginine, a semi-essential amino acid is required for inducible nitric oxide synthase (iNOS) mediated NO production. However, arginase is another enzyme, which if expressed concomitantly, may strongly compete for L-Arginine, and suppress NO production by iNOS. In the present study, plasma nitrite and arginase levels were measured in VL patients before and after successful drug treatment, endemic and non-endemic healthy donors. We observed significantly lower NO levels in the plasma of VL patients as compared to endemic controls, which improved significantly post-treatment. Significantly elevated arginase activity was also observed in the plasma of VL patients, which may be associated with NO deficiency. VL patients also showed significantly higher levels of IL-10 and TGF-β, which are known to regulate expression of arginase in various immune cells. In vitro studies with human peripheral blood mononuclear cells (PBMCs) further corroborated the role of IL-10 and TGF-β in arginase mediated suppression of NO production.

Highlights

Leishmaniasis represents a complex of diseases with a spectrum of severity ranging from cutaneous non-healing lesions to a potentially fatal visceralizing phenotype, depending upon the species of the Leishmania parasite involved and host-parasite interaction (Roberts, 2005)
We further examined the level of arginase activity and if it affected Nitric oxide (NO) production in visceral leishmaniasis (VL) patients
It must be noted that endemic controls (EC) were healthy household contacts of the VL patients recruited in the study and were serologically negative

Summary

Introduction

Leishmaniasis represents a complex of diseases with a spectrum of severity ranging from cutaneous non-healing lesions to a potentially fatal visceralizing phenotype, depending upon the species of the Leishmania parasite involved and host-parasite interaction (Roberts, 2005). The clinical outcome of these infections may depend upon several non-specific innate immune responses (Gurung and Kanneganti, 2015) and two functionally discrete immune responses, i.e., a proinflammatory T-helper (Th) type and an anti-inflammatory Th2 response (Miralles et al, 1994; Sundar et al, 1997). In human VL, a mixed Th1-Th2 phenotype is reported and despite presence of Th1 cytokines in the patients, a major role of the regulatory cytokines in VL etiology has been reported. Past studies from our group and others have shown a direct role of IL-10 in the pathogenesis of human VL (Caldas et al, 2005; Gautam et al, 2011). Earlier thought to be a Th2 cytokine, IL-10 is produced by CD4+ FoxP3+ CD25+ regulatory T cells (Treg) as well as IFN- g producing Treg cells (Tr1 cells) in humans (Moore et al, 2001; Spellberg and Edwards, 2001; Nylen et al, 2007; Chihara et al, 2016)

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