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Cell wall remodeling–dependent morphotype switch in Mycobacterium avium differentially regulates colonization and tissue persistence

Laschanzky, Katie LU orcid ; Magri Ribeiro, Giulia LU ; Sequeira, Rodrigo ; Cancade, Sacha ; Carlsson, Fredric LU orcid and Lienard, Julia LU (2026) In Proceedings of the National Academy of Sciences of the United States of America 123(16).
Abstract
Species of the Mycobacterium avium complex display two main colony morphologies, smooth transparent (SmT) and smooth opaque (SmO), where SmT is associated with human disease and antimicrobial resistance. Previous studies have suggested that smooth bacteria can reversibly switch between the transparent and opaque forms, but the mechanism underlying morphotype transition has remained unknown. Using a clinical strain of M. avium ssp hominissuis, we show that transparent-to-opaque conversion can occur without reversible genetic rearrangement and is associated with deregulation and mutations in genes involved in peptidoglycan hydrolysis (marP and ripA), an interpretation supported by integrated phenotypic, genomic, and transcriptomic analyses.... (More)
Species of the Mycobacterium avium complex display two main colony morphologies, smooth transparent (SmT) and smooth opaque (SmO), where SmT is associated with human disease and antimicrobial resistance. Previous studies have suggested that smooth bacteria can reversibly switch between the transparent and opaque forms, but the mechanism underlying morphotype transition has remained unknown. Using a clinical strain of M. avium ssp hominissuis, we show that transparent-to-opaque conversion can occur without reversible genetic rearrangement and is associated with deregulation and mutations in genes involved in peptidoglycan hydrolysis (marP and ripA), an interpretation supported by integrated phenotypic, genomic, and transcriptomic analyses. Macrophage infections demonstrate robust SmO morphotype–dependent activation of the NLRP3/ASC inflammasome. Analyses in a murine aerosol instillation model for pulmonary infection show that SmO, while unable to persist in the tissue, exhibits drastically increased capacity to colonize lungs compared to virulent SmT, a feature dependent on inflammasome activation. In contrast, SmT bacteria exhibit poor ability to colonize lungs but persist efficiently in an inflammasome-independent manner, likely explaining the selection for the SmT morphotype in patients. These results indicate a cell wall peptidoglycan remodeling–dependent mechanism for morphotype transition in M. avium and reveal discrete host–pathogen interactions and functional roles for SmT and SmO morphotypes during pulmonary infection. (Less)
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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Mycobacterial pathogenesis, inflammasome activation, MarP, RipA, lung infection, Nontuberculous mycobacteria
in
Proceedings of the National Academy of Sciences of the United States of America
volume
123
issue
16
article number
e2533019123
publisher
National Academy of Sciences
external identifiers
  • pmid:41973921
  • scopus:105035679268
ISSN
1091-6490
DOI
10.1073/pnas.2533019123
project
Characterizing the morphological switch of the opportunistic pathogen Mycobacterium avium
Morphological switch of Mycobacterium avium - mechanisms and impact on pathogenesis
language
English
LU publication?
yes
id
13780b07-39c2-45c8-97e1-ea8f65209d72
date added to LUP
2026-05-19 14:52:10
date last changed
2026-06-04 12:20:59
@article{13780b07-39c2-45c8-97e1-ea8f65209d72,
  abstract     = {{Species of the Mycobacterium avium complex display two main colony morphologies, smooth transparent (SmT) and smooth opaque (SmO), where SmT is associated with human disease and antimicrobial resistance. Previous studies have suggested that smooth bacteria can reversibly switch between the transparent and opaque forms, but the mechanism underlying morphotype transition has remained unknown. Using a clinical strain of M. avium ssp hominissuis, we show that transparent-to-opaque conversion can occur without reversible genetic rearrangement and is associated with deregulation and mutations in genes involved in peptidoglycan hydrolysis (marP and ripA), an interpretation supported by integrated phenotypic, genomic, and transcriptomic analyses. Macrophage infections demonstrate robust SmO morphotype–dependent activation of the NLRP3/ASC inflammasome. Analyses in a murine aerosol instillation model for pulmonary infection show that SmO, while unable to persist in the tissue, exhibits drastically increased capacity to colonize lungs compared to virulent SmT, a feature dependent on inflammasome activation. In contrast, SmT bacteria exhibit poor ability to colonize lungs but persist efficiently in an inflammasome-independent manner, likely explaining the selection for the SmT morphotype in patients. These results indicate a cell wall peptidoglycan remodeling–dependent mechanism for morphotype transition in M. avium and reveal discrete host–pathogen interactions and functional roles for SmT and SmO morphotypes during pulmonary infection.}},
  author       = {{Laschanzky, Katie and Magri Ribeiro, Giulia and Sequeira, Rodrigo and Cancade, Sacha and Carlsson, Fredric and Lienard, Julia}},
  issn         = {{1091-6490}},
  keywords     = {{Mycobacterial pathogenesis; inflammasome activation; MarP; RipA; lung infection; Nontuberculous mycobacteria}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{16}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Cell wall remodeling–dependent morphotype switch in Mycobacterium avium differentially regulates colonization and tissue persistence}},
  url          = {{http://dx.doi.org/10.1073/pnas.2533019123}},
  doi          = {{10.1073/pnas.2533019123}},
  volume       = {{123}},
  year         = {{2026}},
}