Patients with cystic fibrosis (CF) experience lifelong respiratory infections which are a significant cause of morbidity and mortality. These infections are polymicrobial in nature wherein the predominant bacterial species changes as patients age. Young patients have populations dominated by pathobionts such as nontypeable Haemophilus influenzae (NTHi), that are eventually supplanted by pathogens such as Pseudomonas aeruginosa (Pa), which are more typical of late-stage CF disease. In this study, we investigated how initial colonization with NTHi impacts colonization and persistence of Pa in the respiratory tract. Analysis of polymicrobial biofilms in vitro by confocal microscopy revealed that NTHi promoted greater levels of Pa biofilm volume and diffusion. However, sequential infection of mice with NTHi followed by Pa showed significant reduction in Pa in the lungs as compared to infection with Pa alone. Coinfected mice also had reduced severity of airway tissue damage and lower levels of inflammatory cytokines as compared mice infected with Pa alone. Similar results were observed using heat-inactivated NTHi bacteria prior to Pa introduction. Based on these results, we conclude that NTHi can significantly reduce susceptibility to subsequent Pa infection, most likely due to immune priming rather than a direct competitive interaction between species. These findings have potential significance with regard to therapeutic management of early life infections in patients with CF.
Despite advances in treatment options for people with CF, complications of bacterial infections remain the greatest driver of morbidity and mortality in this patient population. These infections often involve more than one bacterial pathogen, and our understanding of how interspecies interactions impact disease progression is lacking.
Patients with cystic fibrosis (CF) experience lifelong respiratory infections which are a significant cause of morbidity and mortality. These infections are polymicrobial in nature, and the predominant bacterial species undergo a predictable series of changes as patients age. Young patients have populations dominated by opportunists that are typically found within the microbiome of the human nasopharynx, such as nontypeable Haemophilus influenzae (NTHi); these are eventually supplanted and the population within the CF lung is later dominated by pathogens such as Pseudomonas aeruginosa ( Pa ). In this study, we investigated how initial colonization with NTHi impacts colonization and persistence of Pa in the respiratory tract. Analysis of polymicrobial biofilms in vitro by confocal microscopy revealed that NTHi promoted greater levels of Pa biofilm volume and diffusion. However, sequential respiratory infection of mice with NTHi followed by Pa resulted in significantly lower Pa as compared to infection with Pa alone. Coinfected mice also had reduced airway tissue damage and lower levels of inflammatory cytokines as compared with Pa infected mice. Similar results were observed after instillation of heat-inactivated NTHi bacteria or purified NTHi lipooligosaccharide (LOS) endotoxin prior to Pa introduction. Based on these results, we conclude that NTHi significantly reduces susceptibility to subsequent Pa infection, most likely due to priming of host innate immunity rather than a direct competitive interaction between species. These findings have potential significance with regard to therapeutic management of early life infections in patients with CF.
Cystic fibrosis (CF) is a genetic disorder affecting epithelial ion transport, which among other impacts results in defective mucociliary clearance and innate defenses in the respiratory tract. Consequently, people with CF experience lifelong infections of the respiratory mucosa that are chronic and polymicrobial in nature. Young children with CF are initially colonized by opportunists like nontypeable Haemophilus influenzae (NTHi), which normally resides within the microbiome of the nasopharynx and upper airways and can also cause infections of the respiratory mucosa that include bronchitis and otitis media. NTHi is typically supplanted by other microbes as patients age; for example, people with CF are often chronically infected with mucoid strains of Pseudomonas aeruginosa , which prior work in our laboratory has shown to promote colonization and persistence by other opportunists that include Stenotrophomonas maltophilia . Our previous work has shown that polymicrobial infection impacts host colonization and persistence of incoming microbes via diverse mechanisms that include priming of host immunity that can promote microbial clearance, and cooperativity within polymicrobial biofilms, which can promote persistence. In infection studies with BALB/c Cftrtm1UNC mice, results showed, as previously observed for WT BALB/c mice, preceding infection with NTHi decreased colonization and persistence by P. aeruginosa . Likewise, polymicrobial infection of BALB/c Cftrtm1UNC and C57BL/6 Cftrtm1UncTg(FABPhCFTR)1Jaw/J mice showed correlation between S. maltophilia and P. aeruginosa , with increased bacterial colonization and lung pathology. Based on these results, we conclude that our previous observations regarding polymicrobial infections with CF opportunists in WT mice are also validated using CF mice.
Animal models have been highly informative for understanding the pathogenesis and progression of cystic fibrosis (CF) lung disease. In particular, the CF rat models recently developed have addressed mechanistic causes of the airway mucus defect characteristic of CF, and how these may change when CFTR activity is restored using new modulator therapies. We hypothesized that inflammatory changes to the airway would develop spontaneously and progressively, and that these changes would be resolved with modulator therapy. To test this, we used a humanized-CFTR rat expressing the G551D variant that responds to the CFTR modulator ivacaftor. Markers typically found in the CF lung were assessed, including neutrophil influx, small airway histopathology, and inflammatory cytokine concentration. Young hG551D rats did not express inflammatory cytokines at baseline but did upregulate these in response to inflammatory trigger. As the hG551D rats aged, histopathology worsened, accompanied by neutrophil influx into the airway and increasing concentrations of TNF-α, IL-1α, and IL-6 in the airways. Ivacaftor administration reduced concentrations of these cytokines when administered to the rats at baseline but was less effective in the rats that had also received inflammatory stimulus. Therefore, we conclude that administration of ivacaftor resulted in an incomplete resolution of inflammation when rats received an external trigger, suggesting that CFTR activation may not be enough to resolve inflammation in the lungs of patients with CF.
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