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

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 and Stefan H. Oehlers ()
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Julia Y. Kam: Tuberculosis Research Program at the Centenary Institute, The University of Sydney
Elinor Hortle: Tuberculosis Research Program at the Centenary Institute, The University of Sydney
Elizabeth Krogman: Tuberculosis Research Program at the Centenary Institute, The University of Sydney
Sherridan E. Warner: Tuberculosis Research Program at the Centenary Institute, The University of Sydney
Kathryn Wright: Tuberculosis Research Program at the Centenary Institute, The University of Sydney
Kaiming Luo: Tuberculosis Research Program at the Centenary Institute, The University of Sydney
Tina Cheng: Tuberculosis Research Program at the Centenary Institute, The University of Sydney
Pradeep Manuneedhi Cholan: Tuberculosis Research Program at the Centenary Institute, The University of Sydney
Kazu Kikuchi: Victor Chang Cardiac Research Institute
James A. Triccas: The University of Sydney, Faculty of Medicine and Health & Marie Bashir Institute
Warwick J. Britton: Tuberculosis Research Program at the Centenary Institute, The University of Sydney
Matt D. Johansen: Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier
Laurent Kremer: Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier
Stefan H. Oehlers: Tuberculosis Research Program at the Centenary Institute, The University of Sydney

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Prevalence 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.

Date: 2022
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DOI: 10.1038/s41467-022-28638-5

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