Rough and smooth variants of Mycobacterium abscessus are differentially controlled by host immunity during chronic infection of adult zebrafish

Rough and smooth variants of Mycobacterium abscessus are differentially controlled by host immunity during chronic infection of adult zebrafish

Nature Communications

10.1038/s41467-022-28638-5

http://dx.doi.org/10.1038/s41467-022-28638-5

Julia Y. Kam, Elinor Hortle, Elizabeth Krogman, Sherridan E. Warner, Kathryn Wright, Kaiming Luo, Tina Cheng, Pradeep Manuneedhi Cholan, Kazu Kikuchi, James A. Triccas, Warwick J. Britton, Matt D. Johansen, Laurent Kremer, Stefan H. Oehlers

General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry

17 February 2022

Kam, J. Y., Hortle, E., Krogman, E., Warner, S. E., Wright, K., Luo, K., Cheng, T., Manuneedhi Cholan, P., Kikuchi, K., Triccas, J. A., Britton, W. J., Johansen, M. D., Kremer, L., & Oehlers, S. H. (2022). Rough and smooth variants of Mycobacterium abscessus are differentially controlled by host immunity during chronic infection of adult zebrafish. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-28638-5

AbstractPrevalence of Mycobacterium abscessus infections is increasing in patients with respiratory comorbidities. After initial colonisation, M. abscessus smooth colony (S) variants can undergo an irreversible genetic switch into highly inflammatory, rough colony (R) variants, often associated with a decline in pulmonary function. Here, we use an adult zebrafish model of chronic infection with R and S variants to study M. abscessus pathogenesis in the context of fully functioning host immunity. We show that infection with an R variant causes an inflammatory immune response that drives necrotic granuloma formation through host TNF signalling, mediated by the tnfa, tnfr1 and tnfr2 gene products. T cell-dependent immunity is stronger against the R variant early in infection, and regulatory T cells associate with R variant granulomas and limit bacterial growth. In comparison, an S variant proliferates to high burdens but appears to be controlled by TNF-dependent innate immunity early during infection, resulting in delayed granuloma formation. Thus, our work demonstrates the applicability of adult zebrafish to model persistent M. abscessus infection, and illustrates differences in the immunopathogenesis induced by R and S variants during granulomatous infection.

Attribution 4.0 International (CC BY 4.0)

Australian National Health and Medical Research Council CJ Martin Early Career Fellowship APP1053407 and Project Grant APP1099912; The University of Sydney Fellowship G197581; NSW Ministry of Health under the NSW Health Early-Mid Career Fellowships Scheme H18/31086; the Kenyon Family Foundation Inflammation Award; Australian-French Association for Research and Innovation (AFRAN) Initiative; The University of Sydney Marie Bashir Institute 2019 Seed Funding to S.H.O. Sydney Medical School Summer Scholarship to J.Y.K. Post-doctoral fellowship granted by Labex EpiGenMed, an “Investissements d’avenir” program ANR-10-LABX-12-01 to M.D.J.; The Fondation pour la Recherche Médicale DEQ20150331719 to L.K.

https://oar.a-star.edu.sg/communities-collections/articles/18231

2041-1723

A*STAR Infectious Diseases Labs

https://doi.org/10.1038/s41467-022-28638-5