| Autor: |
Hortle, Elinor, Kam, Julia Y, Krogman, Elizabeth, Warner, Sherridan E, Manuneedhi Cholan, Pradeep, Kikuchi, Kazu, Triccas, James A, Britton, Warwick J, Johansen, Matt D, Kremer, Laurent, Oehlers, Stefan H |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| DOI: |
10.1101/856948 |
| Popis: |
Infections caused by Mycobacterium abscessus are increasing in prevalence within patient groups with respiratory comorbidities including Cystic Fibrosis or Chronic Obstructive Pulmonary Disease. Initial colonisation by the smooth colony M. abscessus (S) can be followed by an irreversible genetic switch into a highly inflammatory rough colony M. abscessus (R), often associated with a decline in pulmonary function. Currently available animal models such as the embryonic zebrafish, have largely explored the role of innate immunity in the pathogenesis of M. abscessus, and demonstrated that infection with the R variant produces a hyperinflammatory infection due to the presence of large extracellular cords, whereas the S variant produces a chronic persistent infection. However, our understanding of the role of adaptive immunity in M. abscessus pathogenesis is largely unknown. Here, we have used intraperitoneal infection of adult zebrafish to model M. abscessus pathogenesis in the context of fully functioning host immunity. We find infection with the R variant penetrates host organs causing an inflammatory immune response leading to necrotic granuloma and abscess formation within 2 weeks. The R bacilli are targeted by T cell-mediated immunity and burden is progressively reduced. Strikingly, the S variant colonises host internal surfaces at high loads and is met with a robust innate immune response but little T cell-mediated immunity. Invasive granuloma formation is delayed in S variant infection compared to R variant infection upon which T cell-mediated immunity is required to control infection. In mixed infections, the S variant outcompetes the R variant in an adaptive-immunity dependent manner. We also find the R variant activates innate immunity to detriment of S variant M. abscessus in mixed infections. These findings demonstrate the applicability of the adult zebrafish to model persistent M. abscessus infection and provide insight into the immunopathogenesis of chronic M. abscessus infection. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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