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 ORCID logo ; Kaiming Luo ; Tina Cheng ORCID logo ; Pradeep Manuneedhi Cholan ; Kazu Kikuchi ; James A Triccas ORCID logo ; +4 more... Warwick J Britton ORCID logo ; Matt D Johansen ORCID logo ; Laurent Kremer ORCID logo ; Stefan H Oehlers ORCID logo ; (2022) Rough and smooth variants of Mycobacterium abscessus are differentially controlled by host immunity during chronic infection of adult zebrafish. Nature communications, 13 (1). 952-. ISSN 2041-1723 DOI: 10.1038/s41467-022-28638-5
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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.


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