Enhanced response to pulmonary Streptococcus pneumoniae infection is associated with primary ciliary dyskinesia in mice lacking Pcdp1 and Spef2

Abstract

BackgroundLower airway abnormalities are common in patients with primary ciliary dyskinesia (PCD), a pediatric syndrome that results from structural or functional defects in motile cilia. Patients can suffer from recurrent bacterial infection in the lung, bronchiectasis, and respiratory distress in addition to chronic sinusitis, otitis media, infertility, and laterality defects. However, surprisingly little is known about the pulmonary phenotype of mouse models of this disorder.ResultsThe pulmonary phenotype of two mouse models of PCD, nm1054 and bgh, which lack Pcdp1 and Spef2, respectively, was investigated by histological and immunohistochemical analysis. In addition, both models were challenged with Streptococcus pneumoniae, a common respiratory pathogen found in the lungs of PCD patients. Histopathological analyses reveal no detectable cellular, developmental, or inflammatory abnormalities in the lower airway of either PCD model. However, exposure to S. pneumoniae results in a markedly enhanced inflammatory response in both models. Based on analysis of inflammatory cells in bronchoalveolar lavage fluid and flow cytometric analysis of cytokines in the lung, the bgh model shows a particularly dramatic lymphocytic response by 3 days post-infection compared to the nm1054 model or wild type animals.ConclusionsDefects in ciliary motility result in a severe response to pulmonary infection. The PCD models nm1054 and bgh are distinct and clinically relevant models for future studies investigating the role of mucociliary clearance in host defense.

Strain-dependent brain defects in mouse models of primary ciliary dyskinesia with mutations in Pcdp1 and Spef2

“…The phenotypic differences between these models could be due to a combination of genetic contribution from the background strains and differences in the function of the Pcdp1 and Spef2 proteins. The severity of the bgh phenotype is consistent with a previously published analysis of Streptococcus pneunomiae challenge in the respiratory system that showed a more severe inflammatory response in bgh mutants than nm1054 mutants (McKenzie et al, 2013). Although ciliary beat frequency is decreased by a comparable amount in both models (Lee et al, 2008; Sironen et al, 2011), it is possible that bgh respiratory cilia beat with an altered waveform, which would be consistent with the aberrant direction of ink flow over bgh ependyma in this study.…”

“…Cilia were labeled using anti-acetylated tubulin (Sigma-Aldrich, T7451) (McKenzie et al, 2013) at a 1:6000 dilution. Glia were labeled using anti-GFAP (Dako, Z0334) (Thelen et al, 2012) at a 1:500 dilution, anti-Iba1 (BioCare Medical, CP290) (Woodruff et al, 2008) at a 1:100 dilution, and anti-CD68 (AbD Serotec, MCA1957) (Thelen et al, 2012) at a 1:25 dilution.…”

“…The nm1054 and big giant head ( bgh ) models were previously characterized on both the C57BL/6J (B6) and 129S6/SvEvTac (129) backgrounds (Lee et al, 2008; Sironen et al, 2011). The PCD in both models is characterized by hydrocephalus, male infertility, and respiratory abnormalities that result from cilia with a reduced beat frequency (Lee et al, 2008; McKenzie et al, 2013; Sironen et al, 2011). However, severe gross hydrocephalus was only observed on the B6 background, suggesting the presence of genetic modifiers of the hydrocephalus.…”

Respiratory epithelial cells orchestrate pulmonary innate immunity

“…Bacterial cultures of sputum from patients with PCD often contain S. aureus , Streptococcus pneumoniae , Haemophilus influenzae and non-tubercular myocobacteria, and chronic infection with P. aeruginosa occurs at older ages in patients with PCD than in patients with cystic fibrosis 40 . Increased production of IL-1, IL-6 and tumor-necrosis factor has been observed during pulmonary infection with S. pneumoniae in mouse models of PCD caused by loss of the genes encoding the PCD-related proteins Pcd1 and Spdef2, which links ciliary dyskinesia to innate defense responses 41 . Secondary dysfunction of the cilia is associated with abnormalities in airway hydration and mucus hyperproduction associated with cystic fibrosis, COPD and cigarette smoking that impair ciliary function and mucociliary clearance, which leads to recurrent infections, bronchiectasis and airway obstruction.…”

Control of lung defence by mucins and macrophages: ancient defence mechanisms with modern functions

“…Interestingly, although chronic infection and inflammation were prominent outcomes in Muc5b knockout mice, their pathobiological impacts were stronger than those observed in models of PCD. In cilia-defective Dnaic , Pcdip1 , Spef2 , and Cby knockout mice, although MCC is severely impaired, upper airway pathologies were not reported to be lethal, and they did not carry over to the lower respiratory tract (31–33). Thus, among MCC components in the lungs, Muc5b is a dominant regulator of homeostatic microbial elimination.…”