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

Front Immunol. 2022 Mar 28:13:862992. doi: 10.3389/fimmu.2022.862992. eCollection 2022.

Abstract

Pattern recognition receptors Mincle and NOD2 have been implicated in mycobacterial immunity. However, knockout (KO) animal infection studies with Mycobacterium tuberculosis (Mtb) have had mild/delayed phenotypes. Given that genetic susceptibility to infectious diseases can be polygenic, we hypothesized that murine double knockout (DKO) of Mincle and Nod2 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 in vivo infections with Mtb 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, Nod2-KO mice had reduced survival compared to wildtype mice, and Mincle-KO survival was intermediate. Unexpectedly, dual disruption had no further effect; rather, DKO mice phenocopied Nod2-KO mice. We observed that Mtb-related death, exclusively in mice with disrupted Nod2, 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.

Keywords: Mincle; Mycobacterium tuberculosis; NOD2; innate immunity; pattern recognition receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Lectins, C-Type* / genetics
  • Lung
  • Membrane Proteins* / genetics
  • Mice
  • Mice, Knockout
  • Mycobacterium tuberculosis
  • Nod2 Signaling Adaptor Protein* / genetics
  • Receptors, Pattern Recognition
  • Tuberculosis*

Substances

  • Clecsf8 protein, mouse
  • Lectins, C-Type
  • Membrane Proteins
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • Receptors, Pattern Recognition

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