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Identification of Virulence Markers of Mycobacterium abscessus for Intracellular Replication in Phagocytes
Published on: September 27, 2018
Increased Virulence of Outer Membrane Porin Mutants of Mycobacterium abscessus
Vinicius C N de Moura1, Deepshikha Verma1, Isobel Everall2,3
1Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States.
Abstract:
Chronic pulmonary infections caused by non-tuberculous mycobacteria of the Mycobacterium abscessus complex (MABSC) are emerging as a global health problem and pose a threat to susceptible individuals with structural lung disease such as cystic fibrosis. The molecular mechanisms underlying the pathogenicity and intrinsic resistance of MABSC to antibiotics remain largely unknown. The involvement of Msp-type porins in the virulence and biocide resistance of some rapidly growing non-tuberculous mycobacteria and the finding of deletions and rearrangements in the porin genes of serially collected MABSC isolates from cystic fibrosis patients prompted us to investigate the contribution of these major surface proteins to MABSC infection. Inactivation by allelic replacement of the each of the two Msp-type porin genes of M. abscessus subsp. massiliense CIP108297, mmpA and mmpB, led to a marked increase in the virulence and pathogenicity of both mutants in murine macrophages and infected mice. Neither of the mutants were found to be significantly more resistant to antibiotics. These results suggest that adaptation to the host environment rather than antibiotic pressure is the key driver of the emergence of porin mutants during infection.
Insights
Chronic pulmonary infections from Mycobacterium abscessus (MABSC) are increasing. Porin gene mutations enhance MABSC virulence, suggesting host adaptation, not antibiotic resistance, drives infection progression.
Area of Science:
- Microbiology
- Infectious Diseases
- Genetics
Background:
- Chronic pulmonary infections caused by Mycobacterium abscessus complex (MABSC) are a growing global health concern.
- MABSC poses a significant threat to individuals with underlying lung conditions like cystic fibrosis.
- The molecular basis of MABSC pathogenicity and antibiotic resistance is poorly understood.
Purpose of the Study:
- To investigate the role of Msp-type porins in MABSC virulence and pathogenicity.
- To determine if porin gene mutations contribute to antibiotic resistance in MABSC.
- To understand the evolutionary drivers of MABSC adaptation during infection.
Main Methods:
- Inactivation of Msp-type porin genes (mmpA and mmpB) in M. abscessus subsp. massiliense using allelic replacement.
- Assessment of mutant virulence and pathogenicity in murine macrophages and infected mice.
- Evaluation of antibiotic resistance profiles of the generated mutants.
Main Results:
- Inactivation of mmpA or mmpB significantly increased MABSC virulence and pathogenicity in both cellular and animal models.
- The porin mutants did not exhibit increased resistance to antibiotics.
- These findings indicate that porin alterations are linked to enhanced MABSC host adaptation.
Conclusions:
- Msp-type porins play a crucial role in modulating MABSC pathogenicity.
- Host adaptation, rather than antibiotic pressure, appears to be the primary driver for the emergence of porin mutants during MABSC infections.
- Targeting porin function could be a potential strategy to combat MABSC infections.
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