MDA5 RNA sensing pathway activation by <i>Mycobacterium tuberculosis</i> promotes innate immune subversion and pathogen survival

C. Korin Bullen; Alok K. Singh; Stefanie Krug; Shichun Lun; Preeti Thakur; Geetha Srikrishna; William R. Bishai

doi:10.1172/jci.insight.166242

MDA5 RNA sensing pathway activation by Mycobacterium tuberculosis promotes innate immune subversion and pathogen survival

C. Korin Bullen,¹ Alok K. Singh,¹ Stefanie Krug,¹ Shichun Lun,¹ Preeti Thakur,² Geetha Srikrishna,³ and William R. Bishai¹

Published September 19, 2023 - More info

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Abstract

Host cytosolic sensing of Mycobacterium tuberculosis (M.tb) RNA by the RIG I-like receptor (RLR) family perturbs innate immune control within macrophages; however, a distinct role of MDA5, a member of the RLR family, in M.tb pathogenesis has yet to be fully elucidated. To further define the role of MDA5 in M.tb pathogenesis, we evaluated M.tb intracellular growth and innate immune responses in wild-type and Mda5-/- macrophages. Transfection of M.tb RNA strongly induced pro-inflammatory cytokine production in WT macrophages, which was abrogated in Mda5^-/-macrophages. M.tb infection in macrophages induced MDA5 protein expression, accompanied by an increase in MDA5 activation as assessed by multimer formation. IFNγ-primed Mda5^-/- macrophages effectively contained intracellular M.tb proliferation to a significantly greater degree than WT macrophages. Further comparisons of WT versus Mda5^-/- macrophages revealed that during M.tb infection MDA5 contributes to IL-1β production and inflammasome activation, and that loss of MDA5 leads to a significant increase in autophagy. In the mouse TB model, loss of MDA5 conferred host survival benefits with a concomitant reduction in M.tb bacillary burden. These data reveal that loss of MDA5 is host-protective during M.tb infection in vitro and in vivo, suggesting M.tb exploits MDA5 to subvert immune containment.

MDA5 RNA sensing pathway activation by Mycobacterium tuberculosis promotes innate immune subversion and pathogen survival

C. Korin Bullen,¹ Alok K. Singh,¹ Stefanie Krug,¹ Shichun Lun,¹ Preeti Thakur,² Geetha Srikrishna,³ and William R. Bishai¹

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MDA5 RNA sensing pathway activation by Mycobacterium tuberculosis promotes innate immune subversion and pathogen survival

C. Korin Bullen,1 Alok K. Singh,1 Stefanie Krug,1 Shichun Lun,1 Preeti Thakur,2 Geetha Srikrishna,3 and William R. Bishai1

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C. Korin Bullen,¹ Alok K. Singh,¹ Stefanie Krug,¹ Shichun Lun,¹ Preeti Thakur,² Geetha Srikrishna,³ and William R. Bishai¹