The pathogenicity and virulence of Leishmania - interplay of virulence factors with host defenses

Abstract

Leishmaniasis is a group of disease caused by the intracellular protozoan parasite of the genus Leishmania. Infection by different species of Leishmania results in various host immune responses, which usually lead to parasite clearance and may also contribute to pathogenesis and, hence, increasing the complexity of the disease. Interestingly, the parasite tends to reside within the unfriendly environment of the macrophages and has evolved various survival strategies to evade or modulate host immune defense. This can be attributed to the array of virulence factors of the vicious parasite, which target important host functioning and machineries. This review encompasses a holistic overview of leishmanial virulence factors, their role in assisting parasite-mediated evasion of host defense weaponries, and modulating epigenetic landscapes of host immune regulatory genes. Furthermore, the review also discusses the diagnostic potential of various leishmanial virulence factors and the advent of immunomodulators as futuristic antileishmanial drug therapy.

Keywords: Leishmania; diagnosis; immunomodulators; macrophage; ncRNAs; signaling pathways; therapeutics; virulence factor.

Figure 1.

Role of leishmanial virulence factors in entry and trans-differentiation of parasites. (1) Entry of promastigotes through skin via bite of sand fly, (2) uptake of promastigotes by neutrophils, (3) safe transport of promastigotes from neutrophils to macrophages by “Trojan Horse” mechanism, (4) formation of parasitophorus vacuoles (PVs) by prevention of phago-lysosomal fusion, (5) trans-differentiation of promastigotes to amastigotes inside PVs (LPG: lipophosphoglycan; HSPs: heat shock proteins; and GPI: glycosyl phosphatidyl inositol). Image created through paid version of Biorender.

Figure 2.

Leishmania suppresses ROS and RNS generation for successful survival within the host cell. In order to tackle the burst of ROS and RNS on infection within the host, Leishmania has evolved various virulence factors as well as mechanisms. LPG of Leishmania sp. inhibits PKC activation, which is necessary for the formation of NADPH oxidase complex, thus, blocking ROS generation. For suppression of mitochondrial ROS generation, the parasite viciously exploits the mitochondrial membrane protein, UCP2. Apart from these strategies, the parasite has also been reported to upregulate host antioxidants like HO-1 and SOD1. In order to suppress NO production, the parasite exploits the host PTP like SHP-1 by virtue of virulence factors like EF-1α and GP63. SHP-1 blocks JNK and ERK activation, required for NO production. Leishmania also upregulates host arginase-1, which inhibits the harmful effects of NO. Apart from facilitating the parasite to overcome the effects of NO, host arginase also provides polyamines for parasite salvage (ROS: reactive oxygen species; RNS: reactive nitrogen species; LPG: lipopohosphoglycans; UCP2: uncoupling protein 2; HO-1: hemeoxygenase 1; SOD-1: superoxide dismutase-1; PTP: protein tyrosine phosphatase; SHP-1: Src homology 2 domain-containing protein tyrosine phosphatase 1; NO: nitric oxide; and EF-1α: elongation factor-1α). Image created through paid version of Biorender.

Figure 3.

Leishmania overrides important MAPK and TLR signaling for successful survival. Stimulation of TLRs triggers a signaling pathways that ultimately culminates in the activation and nuclear translocation of the transcription factor such as NFκB. Activation of MAPKs such as p38, JNK, and ERK1/2, through phosphorylation by upstream kinases, leads to the activation of the transcription factors-AP-1 and IRFs. Activation of NFκB, AP-1, and IRFs transcription factors activate the expression of pro-inflammatory genes and genes involved in host immune defense like IL-12, IL-1β, NLRP3, etc. In order to regulate TLR-mediated NFκB activation, the parasite upregulates the host deubiquitinases such as A20, which removes the necessary ubiquitination from TRAF6 and blocks its interaction with TAB/TAK complex. In order to block MAPK activation, the parasite exploits host PTPs like SHP-1, MKP-1, and PP2A. Furthermore, cysteine proteases of some species of Leishmania degrade ERK1/2 and JNK (NLRP3: Nod-like receptor protein 3; AP-1: activator protein 1; IRFs: interferon regulatory factors; SHP-1: Src homology 2 domain-containing protein tyrosine phosphatase 1; MKP-1: MAPK phosphatase 1; and PP2A: protein phosphatase 2A). Image created through paid version of Biorender.