Tissue-localized immune responses in people with cystic fibrosis and respiratory nontuberculous mycobacteria infection

Hayes, Don; Shukla, Rajni; Cheng, Yizi; Gecili, Emrah; Merling, Marlena R; Szczesniak, Rhonda; Ziady, Assem G.; Woods, Jason C.; Hall-Stoodley, Luanne; Liyanage, Namal P. M.; Robinson, Richard

doi:10.1172/jci.insight.157865

Cited by 8 publications

(4 citation statements)

References 56 publications

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“…Indeed, much of the lung damage that occurs in CF results from the deleterious effects of an overexuberant inflammatory response to infection, as the host is incapable of controlling microbial growth due to intrinsic host defense defects related to CFTR dysfunction [ 44 , 45 ]. Our results demonstrating increased immune activity in patients with NTM-PD are consistent with a recent study that compared the bronchoalveolar lavage fluid of CF patients with vs. without NTM infection and found that those with NTM infection had increased immune cells and inflammation [ 46 ]. Moreover, regions of the lung with increased inflammation correlated with greater lung tissue damage based on CT scans [ 46 ].…”

Section: Discussionsupporting

confidence: 92%

“…Our results demonstrating increased immune activity in patients with NTM-PD are consistent with a recent study that compared the bronchoalveolar lavage fluid of CF patients with vs. without NTM infection and found that those with NTM infection had increased immune cells and inflammation [ 46 ]. Moreover, regions of the lung with increased inflammation correlated with greater lung tissue damage based on CT scans [ 46 ].…”

Section: Discussionsupporting

confidence: 92%

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Whole blood RNA-seq demonstrates an increased host immune response in individuals with cystic fibrosis who develop nontuberculous mycobacterial pulmonary disease

et al. 2022

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Background Individuals with cystic fibrosis have an elevated lifetime risk of colonization, infection, and disease caused by nontuberculous mycobacteria. A prior study involving non-cystic fibrosis individuals reported a gene expression signature associated with susceptibility to nontuberculous mycobacteria pulmonary disease (NTM-PD). In this study, we determined whether people living with cystic fibrosis who progress to NTM-PD have a gene expression pattern similar to the one seen in the non-cystic fibrosis population. Methods We evaluated whole blood transcriptomics using bulk RNA-seq in a cohort of cystic fibrosis patients with samples collected closest in timing to the first isolation of nontuberculous mycobacteria. The study population included patients who did (n = 12) and did not (n = 30) develop NTM-PD following the first mycobacterial growth. Progression to NTM-PD was defined by a consensus of two expert clinicians based on reviewing clinical, microbiological, and radiological information. Differential gene expression was determined by DESeq2. Results No differences in demographics or composition of white blood cell populations between groups were identified at baseline. Out of 213 genes associated with NTM-PD in the non-CF population, only two were significantly different in our cystic fibrosis NTM-PD cohort. Gene set enrichment analysis of the differential expression results showed that CF individuals who developed NTM-PD had higher expression levels of genes involved in the interferon (α and γ), tumor necrosis factor, and IL6-STAT3-JAK pathways. Conclusion In contrast to the non-cystic fibrosis population, the gene expression signature of patients with cystic fibrosis who develop NTM-PD is characterized by increased innate immune responses.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Whole blood RNA-seq demonstrates an increased host immune response in individuals with cystic fibrosis who develop nontuberculous mycobacterial pulmonary disease

et al. 2022

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“…These data support the idea that the smooth morphotype may gain a foothold for sustained infection at infection sites that are limited or deficient in complement factors (20,21), and transition to the more virulent rough morphotype occurs under prolonged selective pressure . A recent report of reduced complement levels in the CF lung support this idea (40) The dependence of complement activation on antibodies was unexpected. The plasma donors were healthy, and we previously showed minimal anti-Mab specific antibodies in healthy individuals (41).…”

Section: Discussionmentioning

confidence: 99%

Divergent host innate immune response to the smooth-to-roughM. abscessusadaptation to chronic infection

Wheeler

Lenhart-Pendergrass

Rysavy

et al. 2023

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Mycobacterium abscessus is a nontuberculous mycobacterium emerging as a significant pathogen for individuals with chronic lung disease, including cystic fibrosis and chronic obstructive pulmonary disease. Current therapeutics have poor efficacy. New strategies of bacterial control based on host defenses are appealing, but anti-mycobacterial immune mechanisms are poorly understood and are complicated by the appearance of smooth and rough morphotypes with distinct host responses. We explored the role of the complement system in the clearance of M. abscessus morphotypes by neutrophils, an abundant cell in these infections. M. abscessus opsonized with plasma from healthy individuals promoted greater killing by neutrophils compared to opsonization in heat-inactivated plasma. Rough clinical isolates were more resistant to complement but were still efficiently killed. Complement C3 associated strongly with the smooth morphotype while mannose-binding lectin 2 was associated with the rough morphotype. M. abscessus killing was dependent on C3, but not on C1q or Factor B; furthermore, competition of mannose-binding lectin 2 binding with mannan or N-acetyl-glucosamine during opsonization did not inhibit killing. These data suggest that M. abscessus does not canonically activate complement through the classical, alternative, or lectin pathways. Complement-mediated killing was dependent on IgG and IgM for smooth and on IgG for rough M. abscessus. Both morphotypes were recognized by Complement Receptor 3 (CD11b), but not CR1 (CD35), and in a carbohydrate- and calcium-dependent manner. These data suggest the smooth-to-rough adaptation changes complement recognition of M. abscessus and that complement is an important factor for M. abscessus infection.

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“…Numerous studies have also demonstrated the presence of complement and antibody components in the airway ( 17 , 18 ), although these components are subject to cleavage by proteases in the CF airway that can render them ineffective ( 19 – 23 , 44 , 45 ). Using a proteomics approach, Hayes et al recently demonstrated that complement components were largely absent from bronchoalveolar lavage fluids in pwCF both with and without NTM infection ( 46 ). In the context of our findings that complement is an important component of the neutrophil response to M. avium , this may indicate that local complement deficiency in the lung could be a particular susceptibility factor in NTM infection.…”

Section: Discussionmentioning

confidence: 99%

Deficient Complement Opsonization Impairs Mycobacterium avium Killing by Neutrophils in Cystic Fibrosis

et al. 2023

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Tissue-localized immune responses in people with cystic fibrosis and respiratory nontuberculous mycobacteria infection

Cited by 8 publications

References 56 publications

Whole blood RNA-seq demonstrates an increased host immune response in individuals with cystic fibrosis who develop nontuberculous mycobacterial pulmonary disease

Whole blood RNA-seq demonstrates an increased host immune response in individuals with cystic fibrosis who develop nontuberculous mycobacterial pulmonary disease

Divergent host innate immune response to the smooth-to-roughM. abscessusadaptation to chronic infection

Deficient Complement Opsonization Impairs Mycobacterium avium Killing by Neutrophils in Cystic Fibrosis

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