Tax1bp1 promotes inflammatory signaling and necrosis during Mycobacterium tuberculosis infection of alveolar macrophages

Crosstalk between autophagy, host cell death, and inflammatory host responses to bacterial pathogens enables effective innate immune responses that limit bacterial growth while reducing coincidental host damage. Mycobacterium tuberculosis 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. How protective inflammatory responses are achieved during Mycobacterium tuberculosis (Mtb) infection and the differences in these responses in macrophage subtypes are obscure. Here, we discovered that the autophagy receptor Tax1bp1 plays a critical role in enhancing inflammatory cytokine production and promoting the susceptibility of mice to infection with Mtb. These results were surprising because Tax1bp1 instead restricts Mtb growth during infection of bone marrow-derived macrophages (BMDMs), as we previously showed (Budzik et al. 2020), and terminates cytokine production in response to cytokine stimulation or viral infection. Tax1bp1 also leads to increases in bacterial growth and inflammatory responses during infection of mice with Listeria monocytogenes, an intracellular pathogen that is not effectively targeted to canonical autophagy. In contrast to its role in restricting Mtb growth in BMDMs, Tax1bp1 promotes Mtb growth in AMs, neutrophils, and recruited monocyte-derived cells from the bone marrow. In Mtb-infected AMs, Tax1bp1 enhances necrosis and inflammatory cytokine synthesis while restraining apoptosis, changing the mode of host cell death to favor Mtb replication. Similar to Tax1bp1-deficiency in AMs, the expression of phosphosite-deficient Tax1bp1 restricts Mtb growth. Together, these results show that Tax1bp1 plays a crucial role in linking the regulation of autophagy, cell death, and pro-inflammatory host responses to augment susceptibility to bacterial infection.