AUTHOR=Dubé Jean-Yves , McIntosh Fiona , Behr Marcel A. 

TITLE=Mice Dually Disrupted for Nod2 and Mincle Manifest Early Bacteriological Control but Late Susceptibility During Mycobacterium tuberculosis Infection

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.862992

DOI=10.3389/fimmu.2022.862992

ISSN=1664-3224

ABSTRACT=<p>Pattern recognition receptors Mincle and NOD2 have been implicated in mycobacterial immunity. However, knockout (KO) animal infection studies with <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>) have had mild/delayed phenotypes. Given that genetic susceptibility to infectious diseases can be polygenic, we hypothesized that murine double knockout (DKO) of <italic>Mincle</italic> and <italic>Nod2</italic> would result in exacerbation of altered immunity to mycobacterial infection leading to a more extreme phenotype than either KO alone. To test this hypothesis, we monitored bacterial burden, immune responses and survival following <italic>in vivo</italic> infections with <italic>Mtb</italic> in DKO mice for comparison to wildtype (WT) and single KOs. Bacterial burden and immune responses were not significantly affected at 3 and 6 weeks after infection in all mutant mice. At later timepoints, <italic>Nod2</italic>-KO mice had reduced survival compared to wildtype mice, and <italic>Mincle</italic>-KO survival was intermediate. Unexpectedly, dual disruption had no further effect; rather, DKO mice phenocopied <italic>Nod2</italic>-KO mice. We observed that <italic>Mtb</italic>-related death, exclusively in mice with disrupted <italic>Nod2</italic>, was accompanied by greater pulmonary cell death and distinct large necrotic foci. Therefore, determining how these receptors contribute to mycobacterial resistance will require analysis of immunophenotypes and their consequences on host pathology.</p>