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Runx proteins mediate protective immunity against Leishmania donovani infection by promoting CD40 expression on dendritic cells

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Runx proteins mediate protective immunity against Leishmania donovani infection by promoting CD40 expression on dendritic cells
 
Creator Md. Nausad, Akhtar
Mishra, Manish
Yadav, Vinod
Gujar, Ravindra
Lal, Sunaina
Kumar, Raj
Khatri, Neeraj
Sen, Pradip
 
Subject QR Microbiology
 
Description The level of CD40 expression on dendritic cells (DCs) plays a decisive role in disease protection during Leishmania donovani (LD) infection. However, current understanding of the molecular regulation of CD40 expression remains elusive. Using molecular, cellular and functional approaches, we identified a role for Runx1 and Runx3 transcription factors in the regulation of CD40 expression in DCs. In response to lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα) or antileishmanial drug sodium antimony gluconate (SAG), both Runx1 and Runx3 translocated to the nucleus, bound to the CD40 promoter and upregulated CD40 expression on DCs. These activities of Runx proteins were mediated by the upstream phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Notably, LD infection attenuated LPS- or TNFα-induced CD40 expression in DCs by inhibiting PI3K-Akt-Runx axis via protein tyrosine phosphatase SHP-1. In contrast, CD40 expression induced by SAG was unaffected by LD infection, as SAG by blocking LD-induced SHP-1 activation potentiated PI3K-Akt signaling to drive Runx-mediated CD40 upregulation. Adoptive transfer experiments further showed that Runx1 and Runx3 play a pivotal role in eliciting antileishmanial immune response of SAG-treated DCs in vivo by promoting CD40-mediated type-1 T cell responses. Importantly, antimony-resistant LD suppressed SAG-induced CD40 upregulation on DCs by blocking the PI3K-Akt-Runx pathway through sustained SHP-1 activation. These findings unveil an immunoregulatory role for Runx proteins during LD infection.
 
Publisher Public Library of Science (PLoS)
 
Date 2020-12-28
 
Type Article
PeerReviewed
 
Relation https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009136
http://crdd.osdd.net/open/2635/
 
Identifier Md. Nausad, Akhtar and Mishra, Manish and Yadav, Vinod and Gujar, Ravindra and Lal, Sunaina and Kumar, Raj and Khatri, Neeraj and Sen, Pradip (2020) Runx proteins mediate protective immunity against Leishmania donovani infection by promoting CD40 expression on dendritic cells. PLoS Pathogens, 16 (12). e1009136. ISSN 1553-7374