Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection

PLoS Pathogens
Johannes NemethAlan Diercks

Abstract

Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb ("contained Mtb infection", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge. Protection is associated with elevated activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. Systems approaches, as well as ex vivo functional assays and in vivo infection experiments, demonstrate that CMTB reconfigures tissue resident alveolar macrophages via low grade interferon-γ exposure. These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses.

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Citations

Dec 8, 2020·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Emily B Wong
Dec 1, 2020·AIDS·Moises A HuamanChris T Longenecker
Jan 4, 2021·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Moises A HuamanChris T Longenecker
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Mar 12, 2021·The Journal of Infectious Diseases·Fergal J DuffyJohannes Nemeth

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Methods Mentioned

BETA
flow cytometry
ELISA
FACS
bronchoalveolar
lavage
dissection
bronchoalveolar lavage
RNA-seq
Flow

Software Mentioned

Gene Set Enrichment Analysis ( GSEA )
bedGraphToBigWig
R package DiffBind
SMARTer Input
Ensembl
GSNAP aligner
R package edgeR
subRead
MACS2
FlowJo

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