Schaffer, K. E. | bioRxiv Science

bioRxiv2025

From colonisation to chronicity: adaptation of Mycobacterium abscessus in the cystic fibrosis lung environment

Chronic infection by opportunistic pathogens is a major contributor to mortality in people with cystic fibrosis (CF). These infections are caused by antimicrobial resistant (AMR) pathogens such as the emerging pathogen, Mycobacterium abscessus, a nontuberculous mycobacteria (NTM) which causes recalcitrant infections with high resistance to antibiotics. M. abscessus adapts over time of colonisation to the conditions in the CF lung, hampering effective treatment. The mechanisms underlying this pathoadaptation are poorly understood and are critical for the development of future therapies. Sequential isolate pairs of M. abscessus from three people with CF were examined for adaptive changes over time of infection. Genomic analysis confirmed that these isolate pairs were clonal. The late infection isolates showed increased host cell attachment to CF bronchial epithelial cells and increased intracellular survival in macrophages, indicative of adaptation to the CF lung environment. Late isolates also showed changes in their proteomes, including changes in abundance of proteins with roles in intracellular survival and antibiotic resistance. Overall, it is clear that M. abscessus can adapt to the CF lung environment and improve its ability to interact with host cells. Impact StatementChronic infection by antimicrobial resistant bacteria impacts both the quality of life and mortality in people with CF. We explored the process of adaptation in the emerging pathogen, Mycobacterium abscessus, over the course of a chronic infection in the CF lung. While this process has been well-documented in other opportunistic pathogens which colonise the CF lung, limited data exist on this process in M. abscessus. Phenotype and proteome changes were assessed in sequential longitudinal clinical isolates of M. abscessus obtained from Saint Vincents University Hospital (SVUH), Dublin, Ireland. Significant changes in the interactions with human cells were observed in late infection isolates after as little as 33 days. Understanding these processes may reveal new avenues for clinical exploitation and this study reveals some novel adaptations which could be exploited to aid current therapies.

microbiology↗

bioRxiv2020

A Universal Stress Protein upregulated by hypoxia may contribute to chronic lung colonisation and intramacrophage survival in cystic fibrosis.

Universal stress proteins (USPs) are ubiquitously expressed in bacteria, plants and eukaryotes and play a lead role in adaptation to environmental conditions. In Gram negative bacteria they enable adaption of bacterial pathogens to the conditions encountered in the human niche, including hypoxia, oxidative stress, osmotic stress, nutrient deficiency or acid stress, thereby facilitating colonisation. We previously reported that all six USP proteins encoded within a low-oxygen responsive locus in Burkholderia cenocepacia showed increased abundance during chronic colonisation of the CF lung. However, the role of USPs in chronic infection is not known. Using mutants derived from B. cenocepacia strain, K56-2, we show that USP76 is required for growth and survival in many conditions associated with the CF lung including, hypoxia, acidic conditions, oxidative stress. Moreover, it is involved in attachment to host epithelial cells, but not virulence. It also has a role in survival in macrophages isolated from people with CF. In contrast, another USP encoded in the same locus, USP92 had no effect on host cell attachment or oxidative stress, but was responsible for a 3-fold increase in virulence. Overall this shows that these USPs, both upregulated during chronic infection, have distinct roles in Burkholderia pathogenesis and may support the survival of B. cenocepacia in the CF lung. Specifically, USP76 is involved in its survival within CF macrophages, a hallmark of Burkholderia infection.

microbiology↗