Mechanisms of Immune Evasion in Leishmaniasis

Gupta, Gaurav; Oghumu, Steve; Satoskar, Abhay R.

doi:10.1016/b978-0-12-407679-2.00005-3

Cited by 209 publications

(173 citation statements)

References 190 publications

Supporting

Mentioning

159

Contrasting

Unclassified

Order By: Relevance

“…Leishmania parasites have the capacity to subvert phagocytosis (27) and modulate cytokine secretion (11,28), thus allowing the parasite to thrive within phagocytic cells and within the host organism as a whole. From previous studies, it has become clear that a range of effector molecules secreted by the Leishmania parasite play a vital role in this process (20,29).…”

Section: Discussionmentioning

confidence: 99%

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

Anand¹,

Madhubala

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes essential for protein synthesis. Apart from their parent aminoacylation activity, several aaRSs perform non-canonical functions in diverse biological processes. The present study explores the twin attributes of Leishmania tyrosyl-tRNA synthetase (LdTyrRS) namely, aminoacylation, and as a mimic of host CXC chemokine. Leishmania donovani is a protozoan parasite. Its genome encodes a single copy of tyrosyl-tRNA synthetase. We first tested the canonical aminoacylation role of LdTyrRS. The recombinant protein was expressed, and its kinetic parameters were determined by aminoacylation assay. To study the physiological role of LdTyrRS in Leishmania, gene deletion mutations were attempted via targeted gene replacement. The heterozygous mutants showed slower growth kinetics and exhibited attenuated virulence. LdTyrRS appears to be an essential gene as the chromosomal null mutants did not survive. Our data also highlights the non-canonical function of L. donovani tyrosyl-tRNA synthetase. We show that LdTyrRS protein is present in the cytoplasm and exits from the parasite cytoplasm into the extracellular medium. The released LdTyrRS functions as a neutrophil chemoattractant. We further show that LdTyrRS specifically binds to host macrophages with its ELR (Glu-Leu-Arg) peptide motif. The ELR-CXCR2 receptor interaction mediates this binding. This interaction triggers enhanced secretion of the proinflammatory cytokines TNF-␣ and IL-6 by host macrophages. Our data indicates a possible immunomodulating role of LdTyrRS in Leishmania infection. This study provides a platform to explore LdTyrRS as a potential target for drug development Aminoacyl-tRNA synthetases (aaRSs) 3 are the central. enzymes in protein translation, providing charged tRNAs for the appropriate construction of peptide chains. The canonical function of aaRSs is to charge specific tRNAs with their cognate amino acids and thereby contribute to accurate mRNA translation during protein synthesis. Thus, aaRSs are essential components of protein synthesis in every living species.Apart from their basic function of charging tRNA molecules for protein synthesis, non-canonical functions like ribosomal RNA biogenesis, angiogenesis, apoptosis, transcriptional regulation, and cell signaling have also been reported for several aaRSs (1, 2). Novel functions of this group of enzymes depend on the addition of one or more new domains or motifs during the course of evolution (3).Tyrosyl-tRNA synthetase (TyrRS) is one such aaRS, which belong to a family of class I synthetases, characterized by a structurally well conserved amino-terminal Rossmann-fold domain, which contains the signature sequences "HIGH" and "KMSKS." The mammalian TyrRS contains a closely homologous endothelial monocyte activating polypeptide II (EMA-PII) domain at the C terminus (4). Under specific conditions, human TyrRS is processed by an elastase enzyme into a free carboxyl-terminal EMAPII-like domain and a second aminoterminal part known as mini-Tyr...

show abstract

Section: Discussionmentioning

confidence: 99%

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

Anand¹,

Madhubala

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Leishmania parasites have devised various mechanisms to circumvent the hosts' attempts at restricting parasite growth and disease establishment (Soong et al 2012 ). In some cases, this involves inducing immunosuppressive conditions that favor parasite proliferation, or interfering with the migration and cellular interactions of critical immune cells involved in immunity against the parasite (Oghumu et al 2010 ;Gupta et al 2013 ). Host genetic and environmental factors also affect immunity to Leishmania .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immunopathology of Leishmaniasis

Natarajan

Oghumu

Thomas

et al. 2014

Pathogenesis of Leishmaniasis

Self Cite

View full text Add to dashboard Cite

While cutaneous leishmaniasis is characterized by lesions proximal to the site of the sandfl y bite, visceral leishmaniasis is associated with immunopathology in the liver and spleen of the infected host. This chapter offers a brief overview of the immune responses generated during infections with cutaneous and visceral leishmaniasis. Insights on how the immune responses generated during cutaneous and visceral leishmaniasis coupled with other host-and pathogen-derived factors determine the clinical pathology and outcome of the disease are also discussed.

show abstract

“…These include remodeling the host cells' phagosomal compartments, interfering with the intracellular signaling pathways, alteration of toll-like receptor pathways, modulation of cytokines and chemokines, modification of T-cell responses, evasion of the host's cellular immunity, and generation of nitric oxide and oxygen oxidative radicals. 6,7 In contrast, carcinogenesis can be influenced by several physiologic, exogenous, environmental, genotypic, and phenotypic factors. 8,9 Leishmaniasis and malignancy are both common health hazards, and some causal associations between these 2 clinical entities have been evidenced in experimental animals and in humans.…”

Section: Introductionmentioning

confidence: 99%

Leishmaniasis and Malignancy: A Review and Perspective

Al-Kamel¹

2017

Clinical Skin Cancer

View full text Add to dashboard Cite

Leishmaniasis, a widely prevalent disease throughout tropical and subtropical regions of the world, is a chronic protozoan infection of humans and mammals that remains grossly underreported and causes significant global morbidity and mortality. Different species of the intracellular protozoan parasites of the genus Leishmania can cause human leishmaniasis, resulting in various visceral, cutaneous, and mucocutaneous manifestations. The risk of leishmaniasis manifesting as a more severe entity is dependent on the infecting parasites' immune evasion potential. Some causal associations between leishmaniasis and malignancy have been evidenced in experimental animals and humans. Leishmania spp. infection can play a significant, direct or indirect, role in the pathogenesis and prognosis of some malignant disorders through numerous pathophysiologic cascades. Aging, chronic ultraviolet radiation exposure, and popular treatment abuse (eg, chameleon saliva, cactus recipes, corrosive chemicals, and topical steroids) have been proposed as the principal triggering factors. Malignancy should be considered in the differential diagnosis of leishmaniasis in endemic regions, such as Yemen. Understanding this relationship could enrich the provision of early diagnosis, proper management, and prompt control of cancer.

show abstract

Mechanisms of Immune Evasion in Leishmaniasis

Cited by 209 publications

References 190 publications

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

Mechanisms of Immunopathology of Leishmaniasis

Leishmaniasis and Malignancy: A Review and Perspective

Contact Info

Product

Resources

About