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.
Highlights
Members of the Mycobacterium avium complex (MAC) are characterized as nontuberculosis mycobacteria and are pathogenic mainly in immunocompromised individuals
Macrophages release interleukin-12 (IL-12), which aids in the activation of T cells, leading to interferon gamma (IFN-␥)-producing CD4ϩ T helper 1 (Th1) cells, thought to be essential in fighting mycobacterial infections [11]
For patients 4, 9, and 13, for whom more than two consecutive M. avium isolates were recovered from the same patient, we observed that most of the isolates had identical or very similar SnaBI profiles, suggesting the presence of a single strain persisting over time
Summary
Members of the Mycobacterium avium complex (MAC) are characterized as nontuberculosis mycobacteria and are pathogenic mainly in immunocompromised individuals. 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. 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. 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. We investigated genetic changes by sequencing M. avium isolates sampled from individual patients over time and studied the host responses to these sequential isolates in vitro in primary mouse macrophages and in vivo in mice
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