Deletion of N-acetylmuramyl-L-alanine amidases alters the host immune response to Mycobacterium tuberculosis infection.

Abstract

Peptidoglycan (PG), a heteropolysaccharide component of the mycobacterial cell wall can be shed during tuberculosis infection with immunomodulatory consequences. As such, changes in PG structure are expected to have important implications on disease progression and host responses during infection with Mycobacterium tuberculosis. Mycobacterial amidases have important roles in remodeling of PG during cell division and are implicated in susceptibility to antibiotics. However, their role in modulating host immunity remains unknown. We assessed the bacterial burden and host immune responses to M. tuberculosis mutants defective for either one of two PG N-acetylmuramyl-L-alanine amidases, Ami1 and Ami4, in bone marrow-derived macrophages (BMDM) and C57BL/6 mice. In infected BMDM, the single deletion of both genes resulted in increased proinflammatory cytokine responses. In mice, infection with the Δami1 mutant led to differential induction of pro-inflammatory cytokines and chemokines, decreased cellular recruitment and reduced lung pathology during the acute phase of the infection. While increased proinflammatory cytokines production was observed in BMDM infected with the Δami4 mutant, these effects did not prevail in mice. Infection using the Δami1 and Δami4 Mtb mutants showed that these genes are dispensable for intracellular mycobacterial growth in macrophages and mycobacterial burden in mice. These findings suggest that both Ami1 and Ami4 in M. tuberculosis are not essential for mycobacterial growth within the host. In summary, we show that amidases are important for modulating host immunity during Mtb infection in murine macrophages and mice.

• Authors: Nathan Scott Kieswetter, Mumin Ozturk, Shelby-Sara Jones, Sibusiso Senzani, Melissa Dalcina Chengalroyen, Frank Brombacher, Bavesh Kana, Reto Guler
• Journal: Virulence (Virulence) Vol. 12 Issue 1 Pg. 1227-1238 (12 2021) ISSN: 2150-5608 [Electronic] United States
• PMID: 33980132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Peptidoglycan
• Amidohydrolases
• Alanine

Topics

• Alanine
• Amidohydrolases (genetics, metabolism)
• Animals
• Cytokines
• Immunity
• Mice
• Mice, Inbred C57BL
• Mycobacterium tuberculosis
• Peptidoglycan
• Tuberculosis