Fungal colonization with Pneumocystis correlates to increasing chloride channel accessory 1 (hCLCA1) suggesting a pathway for up-regulation of airway mucus responses, in infant lungs

Abstract

Fungal colonization with Pneumocystis is associated with increased airway mucus in infants during their primary Pneumocystis infection, and to severity of COPD in adults. The pathogenic mechanisms are under investigation. Interestingly, increased levels of hCLCA1 – a member of the calcium-sensitive chloride conductance family of proteins that drives mucus hypersecretion – have been associated with increased mucus production in patients diagnosed with COPD and in immunocompetent rodents with Pneumocystis infection. Pneumocystis is highly prevalent in infants; therefore, the contribution of Pneumocystis to hCLCA1 expression was examined in autopsied infant lungs. Respiratory viruses that may potentially increase mucus, were also examined. hCLCA1 expression was measured using actin-normalized Western-blot, and the burden of Pneumocystis organisms was quantified by qPCR in 55 autopsied lungs from apparently healthy infants who died in the community. Respiratory viruses were diagnosed using RT-PCR for RSV, metapneumovirus, influenza, and parainfluenza viruses; and by PCR for adenovirus. hCLCA1 levels in virus positive samples were comparable to those in virus-negative samples. An association between Pneumocystis and increased hCLCA1 expression was documented (P=0.028). Additionally, increasing Pneumocystis burden correlated with increasing hCLCA1 protein expression levels (P=0.017). Results strengthen the evidence of Pneumocystis-associated up-regulation of mucus-related airway responses in infant lungs. Further characterization of this immunocompetent host-Pneumocystis-interaction, including assessment of potential clinical significance, is warranted.

A Novel CD4+ T Cell–Dependent Murine Model of Pneumocystis-driven Asthma-like Pathology

“…Furthermore, colonization of live PC within the lung may occur as a transitional state of low PC burden, with the specific host-pathogen interactions (e.g., immunosuppression) ultimately determining the differences between disease, colonization, and clearance (23). Indeed, asymptomatic infection with PC may have immunologic ramifications, as infants with detectable PC in the lungs were previously found to have increased mucus production (21,41), consistent with the findings in our murine model. The ubiquity of human exposure to PC and the specific nature of the immune response to PC beg the question of how this pathogen and the subsequent host response may impact asthma.…”

Pneumocystis -Driven Inducible Bronchus-Associated Lymphoid Tissue Formation Requires Th2 and Th17 Immunity

“…Importantly, colonization of Pneumocystis in all of these populations has been documented. Infants are nearly ubiquitously colonized with Pneumocystis by the age of 4 months; furthermore, Pneumocystis colonization in young children correlates with the increase in a mucus-associated gene, suggestive of a pathologic immune response (Eddens et al, 2016; Pérez et al, 2014; Vargas et al, 2013). Likewise, patients with COPD and Pneumocystis have more severe disease and increases in proteases and inflammatory markers (Fitzpatrick et al, 2014; Morris et al, 2004b; Norris and Morris, 2011).…”

“…demonstrated that nearly all infants by the age of three months had Pneumocystis present in their lungs (Vargas et al, 2013). Colonization with Pneumocystis in these infants was associated with increases in a chloride channel associated with mucus release, suggestive of potential pathologic response to the fungus (Pérez et al, 2014). Likewise, we have previously demonstrated that Pneumocystis exposure in mice led to asthma-like pathology, and that a subset of patients with severe asthma had increased antibody responses against Pneumocystis (Eddens et al, 2016).…”

The Role of Lung and Gut Microbiota in the Pathology of Asthma

“…These differences included increases in the relative abundance of Pneumocystis in the lungs of patients with severe asthma (Goldman et al, 2018), a microbe whose presence within the lungs has been linked to the induction of host type 2 immune responses in humans and animal models (Eddens et al, 2016). Subclinical colonization of the lungs with Pneumocystis at 2-5 months of age has been suggested to be one of the most common infections in infancy (Vargas et al, 2001(Vargas et al, , 2005 and is associated with increased mucin gene expression (Pé rez et al, 2014;Vargas et al, 2001Vargas et al, , 2005Vargas et al, , 2013Rojas et al, 2019). Early lung colonization with Pneumocystis may therefore represent a risk factor for the induction of Th2 cell-skewed immune responses in the lung and predispose infants to asthma (Rojas et al, 2019).…”