Clemente J. Britto

Bactericidal/Permeability-Increasing Protein Fold–Containing Family Member A1 in Airway Host Protection and Respiratory Disease

Bactericidal/permeability-increasing protein fold-containing family member A1 (BPIFA1), formerly known as SPLUNC1, is one of the most abundant proteins in respiratory secretions and has been identified with increasing frequency in studies of pulmonary disease. Its expression is largely restricted to the respiratory tract, being highly concentrated in the upper airways and proximal trachea. BPIFA1 is highly responsive to airborne pathogens, allergens, and irritants. BPIFA1 actively participates in host protection through antimicrobial, surfactant, airway surface liquid regulation, and immunomodulatory properties. Its expression is modulated in multiple lung diseases, including cystic fibrosis, chronic obstructive pulmonary disease, respiratory malignancies, and idiopathic pulmonary fibrosis. However, the role of BPIFA1 in pulmonary pathogenesis remains to be elucidated. This review highlights the versatile properties of BPIFA1 in antimicrobial protection and its roles as a sensor of environmental exposure and regulator of immune cell function. A greater understanding of the contribution of BPIFA1 to disease pathogenesis and activity may clarify if BPIFA1 is a biomarker and potential drug target in pulmonary disease.

Short Palate, Lung, and Nasal Epithelial Clone–1 Is a Tightly Regulated Airway Sensor in Innate and Adaptive Immunity

Short palate, lung, and nasal epithelial clone-1 (SPLUNC1) is a protein abundantly expressed by the respiratory epithelium of the proximal lower respiratory tract, a site of great environmental exposure. Previous studies showed that SPLUNC1 exerts antimicrobial effects, regulates airway surface liquid and mucociliary clearance, and suppresses allergic airway inflammation. We studied SPLUNC1 to gain insights into its role in host defense. In the lower respiratory tract, concentrations of SPLUNC1 are high under basal conditions. In models of pneumonia caused by common respiratory pathogens, and in Th1-induced and Th2-induced airway inflammation, SPLUNC1 secretion is markedly reduced. Pathogen-associated molecular patterns and IFN-γ act directly on airway epithelial cells to inhibit SPLUNC1 mRNA expression. Thus, SPLUNC1 is quickly suppressed during infection, in response to an insult on the epithelial surface. These experiments highlight the finely tuned fluctuations of SPLUNC1 in response to exposures in the respiratory tract, and suggest that the loss of SPLUNC1 is a crucial feature of host defense across air-breathing animal species.

Respiratory Viral Infections in Chronic Lung Diseases

Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF) and interstitial lung diseases (ILD), affect many individuals worldwide. Patients with these chronic lung diseases are susceptible to respiratory lung infections and some of these viral infections can contribute to disease pathogenesis. This review highlights the associations of lung infections and the respective chronic lung diseases and how infection in the different lung diseases affects disease exacerbation and progression.

Cystic Fibrosis Transmembrane Regulator Modulators: Implications for the Management of Depression and Anxiety in Cystic Fibrosis

BACKGROUND Individuals with cystic fibrosis (CF) are at high risk for depression and anxiety, which are associated with worse medical outcomes. Novel therapies for CF hold great promise for improving physical health, but the effects of these therapies on mental health remain poorly understood. OBJECTIVE This review aims to familiarize psychiatrists with the potential effect of novel CF therapies on depression and anxiety. METHODS We discuss novel therapies that directly target the mutant CF protein, the CF transmembrane regulator (CFTR), which are called CFTR modulators. We summarize depression and anxiety screening and treatment guidelines under implementation in accredited CF centers. Case vignettes highlight the complexities of caring for individuals with CF with comorbid depression and anxiety, including patients experiencing worsening depression and anxiety proximate to initiation of CFTR modulator therapy, and management of drug-drug interactions. CONCLUSIONS Although CFTR modulator therapies provide hope for improving clinical outcomes, worsening depression and anxiety occurs in some patients when starting these novel agents. This phenomenon may be multifactorial, with hypothesized contributions from CFTR modulator-psychotropic medication interactions, direct effects of CFTR modulators on central nervous system function, the psychologic effect of starting a potentially life-altering drug, and typical triggers of depression and anxiety such as stress, pain, and inflammation. The medical and psychiatric complexity of many individuals with CF warrants more direct involvement of mental health specialists on the multidisciplinary CF team. Inclusion of mental health variables in patients with CF registries will facilitate further examination at an epidemiologic level.

Multiparameter single cell profiling of airway inflammatory cells.

Airway diseases affect over 7% of the U.S. population and millions of patients worldwide. Asthmatic patients have wide variation in clinical severity with different clinical and physiologic manifestations of disease that may be driven by distinct biologic mechanisms. Further, the immunologic underpinnings of this complex trait disease are heterogeneous and treatment success depends on defining subgroups of asthmatics. Because of the limited availability and number of cells from the lung, the active site, in‐depth investigation has been challenging. Recent advances in technology support transcriptional analysis of cells from induced sputum. Flow cytometry studies have described cells present in the sputum but a detailed analysis of these subsets is lacking. Mass cytometry or CyTOF (Cytometry by Time‐Of‐Flight) offers tremendous opportunities for multiparameter single cell analysis. Experiments can now allow detection of up to ∼40 markers to facilitate unprecedented multidimensional cellular analyses. Here we demonstrate the use of CyTOF on primary airway samples obtained from well‐characterized patients with asthma and cystic fibrosis. Using this technology, we quantify cellular frequency and functional status of defined cell subsets. Our studies provide a blueprint to define the heterogeneity among subjects and underscore the power of this single cell method to characterize airway immune status.

Regulation and Role of Chitotriosidase during Lung Infection with Klebsiella pneumoniae

Chitinases and chitinase-like proteins are an evolutionary conserved group of proteins. In the absence of chitin synthesis in mammals, the conserved presence of chitinases suggests their roles in physiology and immunity, but experimental evidence to prove these roles is scarce. Chitotriosidase (chit1) is one of the two true chitinases present in mammals and the most prevalent chitinase in humans. In this study, we investigated the regulation and the role of chit1 in a mouse model of Klebsiella pneumoniae lung infection. We show that chitinase activity in bronchoalveolar lavage fluid is significantly reduced during K. pneumoniae lung infection. This reduced activity is inversely correlated with the number of neutrophils. Further, instilling neutrophil lysates in lungs decreased chitinase activity. We observed degradation of chit1 by neutrophil proteases. In a mouse model, chit1 deficiency provided a significant advantage to the host during K. pneumoniae lung infection by limiting bacterial dissemination. This phenotype was independent of inflammatory changes in chit1−/− mice as they exerted a similar inflammatory response. The decreased dissemination resulted in improved survival in chit1−/− mice infected with K. pneumoniae in the presence or absence of antibiotic therapy. The beneficial effects of chit1 deficiency were associated with altered Akt activation in the lungs. Chit1−/− mice induced a more robust Akt activation postinfection. The role of the Akt pathway in K. pneumoniae lung infection was confirmed by using an Akt inhibitor, which impaired health and survival. These data suggest a detrimental role of chit1 in K. pneumoniae lung infections.

Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages

Macrophages (MΦs) with mutations in cystic fibrosis transmembrane conductance regulator (CFTR) have blunted induction of PI3K/AKT signaling in response to TLR4 activation, leading to hyperinflammation, a hallmark of cystic fibrosis (CF) disease. Here, we show that Ezrin links CFTR and TLR4 signaling, and is necessary for PI3K/AKT signaling induction in response to MΦ activation. Because PI3K/AKT signaling is critical for immune regulation, Ezrin-deficient MΦs are hyperinflammatory and have impaired Pseudomonas aeruginosa phagocytosis, phenocopying CF MΦs. Importantly, we show that activated CF MΦs have reduced protein levels and altered localization of the remaining Ezrin to filopodia that form during activation. In summary, we have described a direct link from CFTR to Ezrin to PI3K/AKT signaling that is disrupted in CF, and thus promotes hyper-inflammation and weakens phagocytosis.