Tax1bp1 enhances bacterial virulence and promotes inflammatory responses duringMycobacterium tuberculosisinfection of alveolar macrophages
Authors: Chin Jeffrey , Abeydeera Nalin , Repasy Teresa , Rivera-Lugo Rafael , Mitchell Gabriel , Nguyen Vinh Q , Zheng Weihao , Richards Alicia , Swaney Danielle L , Krogan Nevan J , Ernst Joel D , Cox Jeffery S , Budzik Jonathan M 
Published: December 2024

Crosstalk between autophagy, host cell death, and inflammatory host responses to bacterial pathogens enables effective innate immune responses that limit bacterial growth while minimizing coincidental host damage.Mycobacterium tuberculosis(Mtb) thwarts innate immune defense mechanisms in alveolar macrophages (AMs) during the initial stages of infection and in recruited bone marrow-derived cells during later stages of infection. However, how protective inflammatory responses are achieved duringMtbinfection and the variation of the response in different macrophage subtypes remain obscure. Here, we show that the autophagy receptor Tax1bp1 plays a critical role in enhancing inflammatory cytokine production and increasing the susceptibility of mice toMtbinfection. Surprisingly, although Tax1bp1 restrictsMtbgrowth during infection of bone marrow-derived macrophages (BMDMs) (Budziket al.2020) and terminates cytokine production in response to cytokine stimulation or viral infection, Tax1bp1 instead promotesMtbgrowth in AMs, neutrophils, and a subset of recruited monocyte-derived cells from the bone marrow. Tax1bp1 also leads to increases in bacterial growth and inflammatory responses during infection of mice withListeria monocytogenes, an intracellular pathogen that is not effectively targeted to canonical autophagy. InMtb-infected AMs but not BMDMs, Tax1bp1 enhances necrotic-like cell death early after infection, reprogramming the mode of host cell death to favorMtbreplication in AMs. Tax1bp1’s impact on host cell death is a mechanism that explains Tax1bp1’s cell type-specific role in the control ofMtbgrowth. Similar toTax1bp1-deficiency in AMs, the expression of phosphosite-deficient Tax1bp1 restrictsMtbgrowth. Together, these results show that Tax1bp1 plays a crucial role in linking the regulation of autophagy, cell death, and pro-inflammatory host responses and enhancing susceptibility to bacterial infection.

Author Summary

Although macrophages are the first innate immune cells to encounterMycobacterium tuberculosisduring infection,M. tuberculosishas evolved the ability to persist in them. Recent studies highlight that some types of macrophages are more permissive toM. tuberculosisreplication and survival than others, but the mechanisms for cell type-specific differences inM. tuberculosisgrowth are only beginning to be understood. We found that the host factor, Tax1bp1 (Tax-1 binding protein 1), supportsM. tuberculosisgrowth during animal infection and in specific subsets of innate immune cells, including alveolar macrophages while restrictingM. tuberculosisin bone marrow-derived macrophages. We also found that Tax1bp1 has a similar phenotype in enhancing the pathogenesis of another intracellular pathogen,Listeria monocytogenes.Compared to bone marrow-derived macrophages, in alveolar macrophages, Tax1bp1 enhances the release of inflammatory mediators and leads to necrotic-like host cell death, which is known to enhanceM. tuberculosisgrowth. Phosphorylation of Tax1bp1 in alveolar macrophages promotesM. tuberculosisgrowth. Our research highlights that Tax1bp1 is a host target for host-directed therapy againstM. tuberculosisand controls host responses toM. tuberculosisin a cell type-specific manner.