Different Leishmania Species Drive Distinct Neutrophil Functions

Hurrell, Benjamin P.; Regli, Ivo B; Tacchini‐Cottier, Fabienne

doi:10.1016/j.pt.2016.02.003

Cited by 93 publications

(105 citation statements)

References 70 publications

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“…Although most parasites reside in macrophages throughout chronic infection, recent studies document the fact that neutrophils are rapidly recruited to the inoculation site, where they internalize parasites. The ultimate impact of neutrophils on the outcome of leishmaniasis remains controversial, in part owing to different methods used for neutrophil depletion and the use of different parasite species and mouse strains in studies [4,5]. Nonetheless, several studies support the observation that neutrophils help the parasite establish infection [6].…”

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confidence: 99%

A Subset of Neutrophils Expressing Markers of Antigen-Presenting Cells in Human Visceral Leishmaniasis

et al. 2016

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confidence: 99%

A Subset of Neutrophils Expressing Markers of Antigen-Presenting Cells in Human Visceral Leishmaniasis

et al. 2016

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“…This concentration was found to correlate with the amount of protein present in ϳ2 ϫ 10 5 parasites. During Leishmania infection, most sand flies transmit 10 3 -10 5 parasites per blood meal (48). Earlier reports indicate that tissue damage to the skin caused by the infected sand fly bites is important to induce neutrophil recruitment within the first 90 min, further indicating that the initial neutrophil recruitment in the case of a natural infection is parasite-independent (46).…”

Section: Discussionmentioning

confidence: 99%

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

Anand¹,

Madhubala

2016

Journal of Biological Chemistry

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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...

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“…Many studies examine early Leishmania-host cell interactions by document responses of mammalian cell populations in bulk culture [9]. However, methods examining the phenotypic responses of infected immune cells on a percell basis have been invaluable in increasing our understanding of early disease pathogenesis [5,10]. …”

Section: Introductionmentioning

confidence: 99%

“…They are the first cell to migrate to, and take up parasites at the site of in vivo infection with either L. major [5,18–20] or with L. infantum [6] species. Indeed, there appears to be distinct differences in the way various species of Leishmania result in activation and otherwise affect neutrophils [10,21–23]. In the context of disease progression, it has been suggested that, rather than control the infection, neutrophils exacerbate disease onset either by delaying apoptosis, by impairing activation of dendritic cells, or by serving as a vehicle route for silent entry of the parasite [4,24–26].…”

Section: Introductionmentioning

confidence: 99%

Infection and Activation of Human Neutrophils with Fluorescent Leishmania infantum

Cj²,

2016

J Immunol Tech Infect Dis

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Neutrophils (PMNs) are recruited in high numbers to sites of host infection by the protozoan parasites of the genus Leishmania. Although PMNs are capable of phagocytizing Leishmania parasites and are potent producers of anti-microbial compounds including reactive oxygen species (ROS), they are unable to control the establishment of infection. Prior studies document production of ROS in isolated PMNs incubated with Leishmania under conditions allowing phagocytosis, but without a measure of single cells’ responses it cannot be discerned whether PMN activation and ROS production is suppressed or ineffective in the cells that internalize the parasite. To address these interactions, we engineered a strain of fluorescent, mCherry-expressing Leishmania infantum (mCherry-Li). By infecting isolated human PMNs in vitro with mCherry-Li, we observed ready association of the parasites with PMNs in a time- and dose-dependent fashion. We also examined production of PMN ROS (using the fluorescent compound DHR123) and PMN activation (as evidence by loss of surface CD62L expression). Whereas many Li-associated (mCherry+) PMNs responded to parasite interactions and uptake with ROS production and/or activation, a proportion exhibited neither response. Furthermore, a large proportion of mCherry - “bystander” PMNs displayed both ROS production and activation. The heterogeneous response of PMNs to Leishmania exposure leads us to hypothesize, first, that some PMNs exhibit decreased activation upon phagocytosis of Leishmania, and could support their maintenance. Second, responses of bystander PMNs may contribute to a local inflammatory environment that is ineffective at parasite clearance.

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Different Leishmania Species Drive Distinct Neutrophil Functions

Cited by 93 publications

References 70 publications

A Subset of Neutrophils Expressing Markers of Antigen-Presenting Cells in Human Visceral Leishmaniasis

A Subset of Neutrophils Expressing Markers of Antigen-Presenting Cells in Human Visceral Leishmaniasis

Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

Infection and Activation of Human Neutrophils with Fluorescent Leishmania infantum

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