Anti-bacterial mast cell activities and their role during Mycobacterium tuberculosis infection

Abstract

Tuberculosis (TB) is still considered part of the top 10 mortal diseases caused by a single infectious agent. Thus, understanding the immune mechanisms during TB infection is essential to find new therapeutic and prophylactic approaches. Different immune cells have been widely studied to understand TB pathology. However, mast cells (MCs), which are important innate immune cells, have been little explored. Their strategic location and ability to secrete a wide repertoire of pro and anti-inflammatory molecules make MCs relevant against infections. To better define general strategies used by MCs against bacterial threats, using an in vitro model of human MCs (hMCs), we first characterized MC functions by means of degranulation, cytokine secretion, MC extracellular traps (MCETs) formation and production of reactive oxygen species (ROS) upon Escherichia coli, Listeria monocytogenes, Staphylococcus aureus, and Streptococcus pneumoniae stimulation. Our data showed that while L. monocytogenes induce degranulation, MCET formation and cytokine release in the absence of ROS in MCs, S. pneumoniae promote ROS production without inducing MCET and degranulation and while E. coli promote MC degranulation in the absence of MCET and ROS, S. aureus induce a selective release of prostaglandin D2 without degranulation. Thus, MCs display an individualized pattern of response depending on the bacterial type. Next, we characterized MC location, numbers and predominant phenotype in human lung post-mortem samples of patients affected by TB. Using fluorescent staining to identify MCs in lung infected tissue, we found MCs located at inflammatory sites, close to periphery of granulomas and predominantly abundant at fibrotic sites. We also found a co-localization of MCs with IL-17 and TGF- which are relevant for granuloma formation and fibrogenesis respectively. Thus, we proposed MCs as contributors to the early inflammatory stage and the late fibrotic phase of TB pathology. Finally, to better define the means of interaction between MCs and mycobacteria, we investigated the outcome of direct crosstalk between MCs and BCG, which is an attenuated strain of Mycobacterium bovis that fails to protect the adult infection. We found that MCs only respond to BCG when exposed to IL-33 pre-treatment by the release of IL-8 and MCP-1. Furthermore IL-33 enhanced both CD48-MC expression and number of MC-BCG interactions. Thus, IL-33 may serve to pre-activate MCs and potentiate inflammatory responses against BCG. Altogether the current study proposed MCs as important mediators during TB and as potential targets for vaccine boosters.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Rob Lindsay (Supervisor) & Silvia Bulfone-Paus (Supervisor)