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Ly6Chi inflammatory monocytes promote susceptibility to Leishmania donovani infection

Journal Article · · Scientific Reports
 [1];  [2];  [3];  [4];  [5];  [2];  [6];  [7]
  1. The Ohio State University Medical Center, Columbus, OH (United States). Dept. of Pathology; DOE/OSTI
  2. The Ohio State University Medical Center, Columbus, OH (United States). Dept. of Pathology
  3. The Ohio State University, Columbus, OH, (United States). Dept. of Environmental Health Sciences, College of Public Health
  4. The Ohio State University, Columbus, OH (United States). Div. of Pediatric Dentistry, College of Dentistry
  5. The Ohio State University Medical Center, Columbus, OH (United States). Dept. of Pathology; Baskent University, Ankara, Turkey. Dept. of Medical Microbiology, Faculty of Medicine
  6. U.S. Food and Drug Administration (FDA), Silver Spring, Maryland (United States). Div. of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research
  7. The Ohio State University Medical Center, Columbus, OH (United States). Dept. of Pathology; The Ohio State University, Columbus, OH, (United States). Dept. of Microbiology, Wexner Medical Center
+ Show Author Affiliations

Ly6Chi inflammatory monocytes (iMO) are critical for host defense against toxoplasmosis and malaria but their role in leishmaniasis is unclear. In this study, we report a detrimental role of Ly6Chi iMOs in visceral leishmaniasis (VL) caused by Leishmania donovani. We demonstrate that Ly6Chi iMOs are continuously recruited into the spleen and liver during L. donovani infection and they are preferential targets for the parasite. Using microarray-based gene expression profiling, we show that Ly6Chi iMOs isolated from the infected liver and spleen have distinct phenotypic and activation profiles. Furthermore, we demonstrate that blocking the recruitment of Ly6Chi iMOs into the liver and spleen during L. donovani infection using a CCR2 antagonist reduces the frequency of the pathogenic IFN-γ/IL10 dual producer CD4+ T cells in the spleen and leads to a significant reduction in parasite loads in the liver and spleen. Using STAT1-/- mice we show that STAT1 is critical for mediating the recruitment of Ly6Chi iMOs into organs during L. donovani infection, and adaptive transfer of wild type Ly6Chi iMOs into STAT1-/- recipients renders them susceptible to disease. Our findings reveal an unexpected pathogenic role for Ly6Chi iMOs in promoting parasite survival in VL and open the possibility of targeting this population for host-directed therapy during VL.

Research Organization:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC); U.S. Food and Drug Administration (FDA); U.S. Environmental Protection Agency (EPA)
Grant/Contract Number:
SC0014669
OSTI ID:
1624360
Journal Information:
Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 7; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (7)

CD11c-expressing Ly6C+CCR2+ monocytes constitute a reservoir for efficient Leishmania proliferation and cell-to-cell transmission journal October 2018
The IL-33/ST2 Axis in Immune Responses Against Parasitic Disease: Potential Therapeutic Applications journal April 2020
IRF-5 Expression in Myeloid Cells Is Required for Splenomegaly in L. donovani Infected Mice journal January 2020
Nucleic acid sensing activates the innate cytosolic surveillance pathway and promotes parasite survival in visceral leishmaniasis journal July 2019
Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy journal April 2018
The Potent ITK/BTK Inhibitor Ibrutinib Is Effective for the Treatment of Experimental Visceral Leishmaniasis Caused by Leishmania donovani journal September 2018
Myeloid cell recruitment versus local proliferation differentiates susceptibility from resistance to filarial infection journal January 2018

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