Journal Article

In-situ proliferation contributes to the accumulation of myeloid cells in the spleen during progressive experimental visceral leishmaniasis

Melby, Peter C., Medina-Colorado, Audrie A., Osorio, E. Yaneth, Travi, Bruno L.

2020

Overview

Visceral leishmaniasis (VL) is characterized by expansion of myeloid cells in the liver and spleen, which leads to a severe splenomegaly associated with higher risk of mortality. This increased cellularity is thought to be a consequence of recruitment of cells to the viscera. We studied whether the local proliferation of splenic myeloid cells contributes to increased splenic cellularity. We found that a monocyte-like population of adherent splenic cells from Leishmania donovani -infected hamsters had enhanced replicative capacity ex vivo and in vivo (BrdU incorporation, p<0.0001). In vitro assays demonstrated that proliferation was more pronounced in the proinflammatory M1 environment and that intracellular infection prevented proliferation. Secondary analysis of the published splenic transcriptome in the hamster model of progressive VL revealed a gene expression signature that included division of tumoral cells (Z = 2.0), cell cycle progression (Z = 2.3), hematopoiesis (Z = 2.8), proliferation of stem cells (Z = 2.5) and overexpression of proto-oncogenes. Regulators of myeloid cell proliferation were predicted in-silico (CSF2, TLR4, IFNG, IL-6, IL-4, RTK signaling, and STAT3). The in-silico prediction was confirmed with chemical inhibitors of PI3K/AKT, MAPK and STAT3 which decreased splenic myeloid cell division ex vivo . Hamsters infected with L . donovani treated with a STAT3 inhibitor had reduced in situ splenic myeloid proliferation (p = 0.03) and parasite burden. We conclude that monocyte-like myeloid cells have increased STAT3-dependent proliferation in the spleen of hamsters with visceral leishmaniasis and that inhibition of STAT3 reduces myeloid cell proliferation and parasite burden.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Animals / Biology and Life Sciences / Cell cycle / Cell division / Cell proliferation / Cell Proliferation - physiology / Cytokines - metabolism / Development and progression / Disease Models, Animal / Female / Gene expression / Hamsters / Hematopoiesis / Hepatocytes / Inflammation / Interleukin 4 / Interleukin 6 / Kinases / Leishmania donovani - metabolism / Leishmania donovani - pathogenicity / Leishmaniasis, Visceral - immunology / Leishmaniasis, Visceral - physiopathology / Liver - immunology / Liver - metabolism / Macrophages - metabolism / MAP kinase / Medicine and Health Sciences / Mesocricetus / Monocytes / Mortality risk / Myeloid cells / Myeloid Cells - metabolism / Myeloid Cells - physiology / Parasites / Parasitic diseases / Phosphatidylinositol 3-Kinases - metabolism / Physiological aspects / Proto-oncogenes / Secondary analysis / Signal Transduction / Spleen / Spleen - immunology / Spleen - metabolism / Splenomegaly / Stat3 protein / Stem cell transplantation / Stem cells / TLR4 protein / Toll-like receptors / Transcriptome / Tropical diseases / Vector-borne diseases / Viscera / Visceral leishmaniasis / White blood cells