Genetic Variation/Evolution and Differential Host Responses Resulting from In-Patient Adaptation ofMycobacterium avium

Abstract

Members of the Mycobacterium avium complex (MAC) are characterized as nontuberculosis mycobacteria and are pathogenic mainly in immunocompromised individuals. MAC strains show a wide genetic variability, and there is growing evidence suggesting that genetic differences may contribute to a varied immune response that may impact the infection outcome. The current study aimed to characterize the genomic changes within M. avium isolates collected from single patients over time and test the host immune responses to these clinical isolates. Pulsed-field gel electrophoresis and whole-genome sequencing were performed on 40 MAC isolates isolated from 15 patients at the Department of Medical Microbiology at St. Olavs Hospital in Trondheim, Norway. Isolates from patients (patients 4, 9, and 13) for whom more than two isolates were available were selected for further analysis. These isolates exhibited extensive sequence variation in the form of single-nucleotide polymorphisms (SNPs), suggesting that M. avium accumulates mutations at higher rates during persistent infections than other mycobacteria. Infection of murine macrophages and mice with sequential isolates from patients showed a tendency toward increased persistence and the downregulation of inflammatory cytokines by host-adapted M. avium strains. The study revealed the rapid genetic evolution of M. avium in chronically infected patients, accompanied by changes in the virulence properties of the sequential mycobacterial isolates.

A Clofazimine-Containing Regimen Confers Improved Treatment Outcomes in Macrophages and in a Murine Model of Chronic Progressive Pulmonary Infection Caused by the Mycobacterium avium Complex

“…In addition, CFZ had better synergistic effects with CLR than with RIF on growth inhibition of all strains except M. avium SMC #7 in macrophages. Indeed, many previous studies have reported variation in virulence among MAC strains and different host responses in macrophages and mice ( Amaral et al, 2011 ; Agdestein et al, 2014 ; Bruffaerts et al, 2017 ; Abdissa et al, 2018 ; Rindi et al, 2018 ; Kannan et al, 2019 ). Moreover, antibiotics are well known to be associated with immune responses ( Labro and Abdelghaffar, 2001 ; Tamaoki, 2004 ; Yuhas et al, 2007 ; Yuhas et al, 2011 ; Singh et al, 2014 ).…”

“…However, the main limitation of in vivo studies is that chronic infection with MAC strains via aerosolization is not easily achieved in mice. Accordingly, the majority of experimental studies of MAC infection in vivo have employed intraperitoneal, intratracheal or intranasal injection rather than aerosol infection ( Amaral et al, 2011 ; Bruffaerts et al, 2017 ; Abdissa et al, 2018 ; Kannan et al, 2019 ). Our previous study mimicked chronic infection with different MAC strains via aerosolization to investigate the possibility of reactivation of MAC infection, and it revealed that the different MAC strains in the mice exhibited different growth rates, which might be associated with differences in host-pathogen interactions ( Cha et al, 2015 ).…”

Global Assessment of Mycobacterium avium subsp. hominissuis Genetic Requirement for Growth and Virulence

“…Mav isolates exhibit high genetic variation (14, 43, 69, 70). In accordance, we registered several large-scale insertions and deletions when we compared the genomic sequence of MAH 11 to the genomic sequence of MAH 104.…”

Nontuberculous Mycobacteria Prevalence in Bats’ Guano from Caves and Attics of Buildings Studied by Culture and qPCR Examinations

“…This is a cosmopolitan ssp. that is able to colonize both various environmental niches and humans [36,85,89,90].…”