MTORC1-mediated polarization of M1 macrophages and their accumulation in the liver correlate with immunopathology in fatal ehrlichiosis

Mohamed Haloul,Nahed Ismail,Edson R A Oliveira,Muhamuda Kader,Jakob Z Wells,Tyler R Tominello,Abdeljabar El Andaloussi,Cecelia C Yates

doi:10.1038/s41598-019-50320-y

Abstract

A polarized macrophage response into inflammatory (M1) or regenerative/anti-inflammatory (M2) phenotypes is critical in host response to multiple intracellular bacterial infections. Ehrlichia is an obligate Gram-negative intracellular bacterium that causes human monocytic ehrlichiosis (HME): a febrile illness that may progress to fatal sepsis with multi-organ failure. We have shown that liver injury and Ehrlichia-induced sepsis occur due to dysregulated inflammation. Here, we investigated the contribution of macrophages to Ehrlichia-induced sepsis using murine models of mild and fatal ehrlichiosis. Lethally-infected mice showed accumulation of M1 macrophages (iNOS-positive) in the liver. In contrast, non-lethally infected mice showed polarization of M2 macrophages and their accumulation in peritoneum, but not in the liver. Predominance of M1 macrophages in lethally-infected mice was associated with expansion of IL-17-producing T, NK, and NKT cells. Consistent with the in vivo data, infection of bone marrow-derived macrophages (BMM) with lethal Ehrlichia polarized M0 macrophages into M1 phenotype under an mTORC1-dependent manner, while infection with non-lethal Ehrlichia polarized these cells into M2 types. This work highlights that mTORC1-mediated polarization of macrophages towards M1 phenotype may contribute to induction of pathogenic immune responses during fatal ehrlichiosis. Targeting mTORC1 pathway may provide a novel aproach for treatment of HME.

Highlights

Human monocytic ehrlichiosis (HME) is an emerging life-threatening tick-borne disease caused by the obligate intracellular bacterium Ehrlichia chaffeensis
We investigated the contribution of dysregulated effector functions involving macrophage polarization to the pathogenesis of Ehrlichiosis
Using murine models of lethal and nonlethal ehrlichiosis, we showed that lethal Ehrlichia-induced sepsis is associated with accumulation of infiltrating pro-inflammatory M1 macrophages/monocytes in the liver tissue

Summary

Introduction

Human monocytic ehrlichiosis (HME) is an emerging life-threatening tick-borne disease caused by the obligate intracellular bacterium Ehrlichia chaffeensis. Macrophages are important innate cells involved in homeostatic and pathological processes during infections, as they link innate and adaptive responses[7,8,9] These cells are described as either resident cells, which are generally associated with maintenance of tissue integrity[10,11,12], or monocyte-derived, that under specific environmental conditions play a major role in modulating inflammation[13,14,15]. We investigated the macrophage heterogeneity in murine models of mild and fatal ehrlichiosis caused by infection of C57BL/6 mice with mildly virulent Ehrlichia muris or highly virulent Ixodes ovatus ehrlichia (IOE). We show that IOE-induced mTORC1 activation may account for macrophage polarization into M1 phenotype during fatal Ehrlichia infection

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Results

Conclusion