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Genetic diversification of persistent Mycobacterium abscessus within cystic fibrosis patients.

ABSTRACT: Mycobacterium (M.) abscessus infections in Cystic Fibrosis (CF) patients cause a deterioration of lung function. Treatment of these multidrug-resistant pathogens is associated with severe side-effects, while frequently unsuccessful. Insight on M. abscessus genomic evolvement during chronic lung infection would be beneficial for improving treatment strategies. A longitudinal study enrolling 42 CF patients was performed at a CF center in Berlin, Germany, to elaborate phylogeny and genomic diversification of in-patient M. abscessus. Eleven of the 42 CF patients were infected with M. abscessus. Five of these 11 patients were infected with global human-transmissible M. abscessus cluster strains. Phylogenetic analysis of 88 genomes from isolates of the 11 patients excluded occurrence of M. abscessus transmission among members of the study group. Genome sequencing and variant analysis of 30 isolates from 11 serial respiratory samples collected over 4.5 years from a chronically infected patient demonstrated accumulation of gene mutations. In total, 53 genes exhibiting non-synonymous variations were identified. Enrichment analysis emphasized genes involved in synthesis of glycopeptidolipids, genes from the embABC (arabinosyltransferase) operon, betA (glucose-methanol-choline oxidoreductase) and choD (cholesterol oxidase). Genetic diversity evolved in a variety of virulence- and resistance-associated genes. The strategy of M. abscessus populations in chronic lung infection is not clonal expansion of dominant variants, but to sustain simultaneously a wide range of genetic variants facilitating adaptation of the population to changing living conditions in the lung. Genomic diversification during chronic infection requires increased attention when new control strategies against M. abscessus infections are explored.

SUBMITTER: Lewin A

PROVIDER: S-EPMC8526041 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Genetic diversification of persistent Mycobacterium abscessus within cystic fibrosis patients.

Lewin Astrid A Kamal Elisabeth E Semmler Torsten T Winter Katja K Kaiser Sandra S Schäfer Hubert H Mao Lei L Eschenhagen Patience P Grehn Claudia C Bender Jennifer J Schwarz Carsten C

Virulence 20211201 1

Mycobacterium (M.) abscessus infections in Cystic Fibrosis (CF) patients cause a deterioration of lung function. Treatment of these multidrug-resistant pathogens is associated with severe side-effects, while frequently unsuccessful. Insight on M. abscessus genomic evolvement during chronic lung infection would be beneficial for improving treatment strategies. A longitudinal study enrolling 42 CF patients was performed at a CF center in Berlin, Germany, to elaborate ph ...[more]

PMID: 34546836

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Project description:Infections due to Mycobacterium abscessus are a major cause of mortality and morbidity in cystic fibrosis (CF) patients. Furthermore, M. abscessus has been suspected to be involved in person-to-person transmissions. In 2016, dominant global clonal complexes (DCCs) that occur worldwide among CF patients have been described. To elucidate the epidemiological situation of M. abscessus among CF patients in Germany and to put these data into a global context, we performed whole-genome sequencing of a set of 154 M. abscessus isolates from 123 German patients treated in 14 CF centers. We used MTBseq pipeline to identify clusters of closely related isolates and correlate those with global findings. Genotypic drug susceptibility for macrolides and aminoglycosides was assessed by characterization of the erm(41), rrl, and rrs genes. By this approach, we could identify representatives of all major DCCs (Absc 1, Absc 2, and Mass 1) in our cohort. Intrapersonal isolates showed higher genetic relatedness than interpersonal isolates (median 3 SNPs versus 16 SNPs; P < 0.001). We further identified four clusters with German patients from same centers clustering with less than 25 SNPs distance (range 3 to 18 SNPs) but did not find any hint for in-hospital person-to-person transmission. This is the largest study investigating phylogenetic relations of M. abscessus isolates in Germany. We identified representatives of all reported DCCs but evidence for nosocomial transmission remained inconclusive. Thus, the occurrence of genetically closely related isolates of M. abscessus has to be interpreted with care, as a direct interhuman transmission cannot be directly deduced. IMPORTANCE Mycobacterium abscessus is a major respiratory pathogen in cystic fibrosis (CF) patients. Recently it has been shown that dominant global clonal complexes (DCCs) have spread worldwide among CF patients. This study investigated the epidemiological situation of M. abscessus among CF patients in Germany by performing whole-genome sequencing (WGS) of a set of 154 M. abscessus from 123 German patients treated in 14 CF centers. This is the largest study investigating the phylogenetic relationship of M. abscessus CF isolates in Germany.

Project description:Cystic fibrosis patients are highly susceptible to infections with non-tuberculous mycobacteria. Especially Mycobacterium abscessus infections are common but reliable diagnosis is hampered by non-specific clinical symptoms and insensitive mycobacterial culture. In the present study we established novel methods for rapid detection and immune characterization of Mycobacterium abscessus infection in cystic fibrosis patients. We performed Mycobacterium abscessus specific DNA-strip- and quantitative PCR-based analyses of non-cultured sputum samples to detect and characterize Mycobacterium abscessus infections. Concomitantly in vitro T-cell reactivation with purified protein derivatives (PPDs) from different mycobacterial species was used to determine Mycobacterium abscessus specific T-cell cytokine expression of infected cystic fibrosis patients. Four of 35 cystic fibrosis patients (11.4%) were Mycobacterium abscessus culture positive and showed concordant DNA-strip-test results. Quantitative PCR revealed marked differences of mycobacterial burden between cystic fibrosis patients and during disease course. Tandem-repeat analysis classified distinct Mycobacterium abscessus strains of infected cystic fibrosis patients and excluded patient-to-patient transmission. Mycobacterium abscessus specific T-cells were detected in the blood of cystic fibrosis patients with confirmed chronic infection and a subgroup of patients without evidence of Mycobacterium abscessus infection. Comparison of cytokine expression and phenotypic markers revealed increased proportions of CD40L positive T-cells that lack Interleukin-2 expression as a marker for chronic Mycobacterium abscessus infections in cystic fibrosis patients. Direct sputum examination enabled rapid diagnosis and quantification of Mycobacterium abscessus in cystic fibrosis patients. T-cell in vitro reactivation and cytokine expression analyses may contribute to diagnosis of chronic Mycobacterium abscessus infection.

Project description:Mycobacterium abscessus is an emerging opportunistic pathogen affecting patients with chronic lung diseases, primarily cystic fibrosis (CF), or those under immunosuppression. Hence, investigations into the epidemiology and transmission of M. abscessus and accurate antibiotic susceptibility data are essential for the effective treatment of infections caused by this pathogen. This retrospective nationwide study included all clinical M. abscessus isolates (n = 59) from 29 patients diagnosed in the Czech Republic and Slovakia between 2018 and 2023. Whole genome sequencing (WGS) was performed to identify clusters and classify isolates into predominant circulating clones (DCC). Subspecies identification of unique isolates showed subspecies abscessus as the most prevalent (69.0%). The results of drug-susceptibility testing showed that 65.5% of all isolates were resistant to at least three antibiotics tested. CF patients under 24 years of age were the most at-risk group for M. abscessus infection. WGS identified seven clusters (including two cross-border) comprising CF and non-CF patients with a total clustering rate of 48.3%. One cluster involved patients infected with subspecies massiliense strains differing by 0 single nucleotide polymorphisms hospitalized in the same center. Furthermore, we identified representatives of all major DCCs. This study revealed predominant Mycobacterium abscessus complex clones circulating in the Czech Republic and Slovakia. The results show the high discriminatory power of WGS in the molecular epidemiology of M. abscessus and provide supporting evidence of direct or indirect cross-transmission of subspecies massiliense among both CF and non-CF patients.ImportanceThis study highlights the importance of understanding Mycobacterium abscessus transmission because it poses a growing threat to vulnerable populations, especially young cystic fibrosis patients. Investigating how it spreads and which antibiotics work best is crucial for effective treatment. This research used whole genome sequencing to track M. abscessus and found evidence of potential transmission between patients, including across borders. The findings suggest that dominant strains are circulating and some patients may be infected through direct or indirect contact. This knowledge can inform infection control and treatment strategies.

Project description:Rationale: Mycobacterium abscessus is a significant threat to individuals with cystic fibrosis (CF) because of innate drug resistance and potential transmission between patients. Recent studies described global dominant circulating clones of M. abscessus, but detailed genomic surveys have not yet been described for the United States. Objectives: We examined the genetic diversity of respiratory M. abscessus isolates from U.S. patients with CF and evaluated the potential for transmission events within CF Care Centers. Methods: Whole-genome sequencing was performed on 558 M. abscessus isolates from 266 patients with CF attending 48 CF Care Centers in 28 U.S. states as part of a nationwide surveillance program. U.S. isolates were also compared with 64 isolate genomes from 13 previous studies to evaluate the prevalence of recently described dominant circulating clones. Results: More than half of study patients with CF and M. abscessus had isolates within four dominant clones; two clones of M. abscessus subspecies (subsp.) abscessus (MAB) and two clones of M. abscessus subsp. massiliense (MMAS). Acquired drug resistance mutations for aminoglycosides and macrolides were rare in the isolate population, and they were not significantly enriched in dominant clones compared with unclustered isolates. For a subset of 55 patients, there was no relationship between dominant clones and diagnosis of active lung disease (P = 1.0). Twenty-nine clusters of genetically similar MAB isolates and eight clusters of genetically similar MMAS isolates were identified. Overall, 28 of 204 (14%) patients with MAB and 15 of 64 (23%) patients with MMAS had genetically isolates similar to those of at least one other patient at the same CF Care Center. Genetically similar isolates were also found between 60 of 204 (29%) patients with MAB and 19 of 64 (30%) patients with MMAS from different geographic locations. Conclusions: Our study reveals the predominant genotypes of M. abscessus and frequency of shared strains between patients in U.S. CF Care Centers. Integrated epidemiological and environmental studies would help to explain the widespread presence of dominant clones in the United States, including the potential for broad distribution in the environment. Single site studies using systematic, evidence-based approaches will be needed to establish the contributions of health care-associated transmission versus shared environmental exposures.

Project description:Mycobacterium abscessus (M. abscessus) is a highly antimicrobial-resistant pathogen that causes refractory pulmonary disease. Recently, the possibility of M. abscessus cross-transmission among cystic fibrosis (CF) patients has been reported. CF is rare in Asia, but M. abscessus pulmonary disease is common. Therefore, we investigated the possibility of M. abscessus cross-transmission in a Japanese hospital setting. Of 104 M. abscessus isolates, 25 isolates from 24 patients were classified into four clusters based on their variable number of tandem repeat profiles and were subjected to whole-genome sequencing (WGS). The epidemiological linkages among our patients were investigated by integrating the WGS data of previously reported nosocomial outbreak-related M. abscessus clinical isolates in the United Kingdom and the United States. Eight transmissible clusters (TCs) were identified. The United Kingdom and United States isolates were assigned to four clusters (TC1, TC2, TC5, and TC8) and one cluster (TC3), respectively. A total of 12 isolates from our hospital belonged to 4 clusters (TC4, TC5, TC6, and TC7). Epidemiological linkage analysis inferred direct or indirect transmission between patients in our hospital in TC4 and TC5 but not in TC6 and TC7. In TC5, the single nucleotide polymorphism distance between isolates from Japanese and United Kingdom patients was less than 21; however, there was no contact. This study revealed that genetically closely related isolates exist, even in non-CF patients. However, the transmission route remains unclear, and further research is warranted to clarify whether cross-transmission is involved. IMPORTANCE Although the possibility of Mycobacterium abscessus (M. abscessus) cross-transmission in cystic fibrosis (CF) patients has often been reported, it is not clear whether similar events have occurred in Asian non-CF patients. Whole-genome sequencing analysis of M. abscessus isolates from Fukujuji Hospital in Japan indicated that genetically closely related M. abscessus isolates exist. In addition, according to epidemiological linkage analysis, some clusters were suspected of direct or indirect transmission between patients within our hospital. However, the transmission route of M. abscessus remains unclear, because interestingly, one cluster showed a single nucleotide polymorphism distance of less than 21 from the United Kingdom isolates, but no epidemiological linkage was identified.

Project description:Mycobacterium abscessus complex (MABC) is a group of emerging, highly antimicrobial-resistant non-tuberculous mycobacteria. Specific MABC clones are spreading globally in patients with cystic fibrosis (CF); however, associated genomic epidemiology is lacking in East Asia, with very few patients with CF. Here, we investigated MABC populations derived from non-CF patients in Japan and Taiwan. Analysis of whole-genome sequencing data of 220 MABC isolates revealed that 112, 105, and 3 were M. abscessus subsp. abscessus (ABS), M. abscessus subsp. massiliense (MAS), and M. abscessus subsp. bolletii (BOL), respectively. Moreover, >50% of ABS and >70% of MAS were related to four predominant clones in the region. Known mutations conferring macrolide resistance were rare (1.4%) and were not enriched in the predominant clones. Conversely, the macrolide-susceptible erm(41) T28C mutation was significantly enriched in one predominant ABS clone. The most predominant ABS clone was genetically related to the previously described dominant circulating clone (DCC)1 in patients with CF, whereas no isolates were related to DCC2; isolates related to DCC3 were not necessarily predominant in our sample set. We found that the erm(41) T28C mutants spread globally, and some of them reacquired the functional erm(41) gene through both point mutation and recombination. This study revealed predominant MABC clones in Japan and Taiwan and their relationship with the globally superadding clones in the patient community with CF. Our study provides insights into the genetic characteristics of globally dominant and area-specific strains isolated from patients with or without CF and differences between globally spread and regionally specific strains. IMPORTANCE Members of Mycobacterium abscessus complex (MABC) are frequently isolated from patients. Studies have reported that predominant clones of MABC (known as dominant circulating clones; DCCs) are distributed worldwide and transmitted from humans to humans in patients with cystic fibrosis (CF). However, associated genomic epidemiology has not yet been conducted in East Asia, including Japan and Taiwan, where there are only a few patients with CF. Using whole-genome sequencing data derived from non-CF patients in Japan and Taiwan, we revealed prevalent clones and the incidence of macrolide resistance-associated mutations in the MABC population in this region. We also clarified the associations between these predominant clones and DCCs in the global CF patient community. Our results would assist further studies in elucidating the genetic characteristics of strains isolated from patients with or without CF, the differences between globally spread and regionally specific strains, and the adaptive evolution of MABC within the host.

Dataset Information

Genetic diversification of persistent Mycobacterium abscessus within cystic fibrosis patients.

Publications

Genetic diversification of persistent <i>Mycobacterium abscessus</i> within cystic fibrosis patients.

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