In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 7 ( 2023-7-7), p. e1011495-
Abstract:
Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011495
DOI:
10.1371/journal.ppat.1011495.g001
DOI:
10.1371/journal.ppat.1011495.g002
DOI:
10.1371/journal.ppat.1011495.g003
DOI:
10.1371/journal.ppat.1011495.g004
DOI:
10.1371/journal.ppat.1011495.g005
DOI:
10.1371/journal.ppat.1011495.g006
DOI:
10.1371/journal.ppat.1011495.g007
DOI:
10.1371/journal.ppat.1011495.g008
DOI:
10.1371/journal.ppat.1011495.g009
DOI:
10.1371/journal.ppat.1011495.s001
DOI:
10.1371/journal.ppat.1011495.s002
DOI:
10.1371/journal.ppat.1011495.s003
DOI:
10.1371/journal.ppat.1011495.s004
DOI:
10.1371/journal.ppat.1011495.s005
DOI:
10.1371/journal.ppat.1011495.s006
DOI:
10.1371/journal.ppat.1011495.s007
DOI:
10.1371/journal.ppat.1011495.s008
DOI:
10.1371/journal.ppat.1011495.r001
DOI:
10.1371/journal.ppat.1011495.r002
DOI:
10.1371/journal.ppat.1011495.r003
DOI:
10.1371/journal.ppat.1011495.r004
DOI:
10.1371/journal.ppat.1011495.r005
DOI:
10.1371/journal.ppat.1011495.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1