Respiratory viral infections cause significant mortality. Pre-existing atopy has demonstrated protection from virus-induced death. Atopic mice with house dust mite (HDM) extract survive normally lethal parainfluenza (Sendai virus, SeV) and influenza A (IAV) infection. Neuregulin-1 (NRG1), markedly elevated in airways of atopic mice, has been shown to significantly attenuate mortality to SeV and IAV in non-atopic mice. Hypothesizing that atopy and NRG1 mediate protection from death through similar mechanisms, we anazlyed single-cell RNA sequencing data from CD45+ (hematopoietic) and CD45- (structural) lung cells prior to infection. Both treatments reduced alveolar macrophages, lymphatic endothelial cells, airway smooth muscle cells, and pericytes, while increasing alveolar type 2 cells. However, atopy led to increased fibroblasts with reduced club cells compared to NRG1 treatment. Further, in the hematopoietic cell compartment, atopy drove an increase in more inflammatory cells than NRG1 and associated with significant upregulation of immune cell signaling pathways, something not seen with NRG1 administration. Moreover, NRG1 knockdown did not reverse the protection from virus-induced death in mice with pre-existing atopy. Taken together, these data strongly suggest that atopy and NRG1 mediate increased survival from a respiratory viral infection through disparate mechanisms.

Respiratory infections with RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen, Sendai virus (SeV), which is similar to RSV, mice made atopic with house dust mite survived a normally lethal SeV infection. One protein that we found markedly elevated in the lungs and bronchoalveolar lavage fluid of atopic mice was neuregulin-1 (NRG1). Administration of NRG1 protected naïve (non-atopic) mice from death with both SeV and mouse adapted influenza A virus (IAV). Survival was associated with reduced alveolar epithelium permeability and reduced phosphorylation of mixed lineage kinase domain-like (MLKL) protein indicating inhibition of necroptosis. In vitro, treatment of mouse lung epithelial cells with NRG1 inhibited SeV induced necroptosis, and NRG1 administration to differentiated human bronchial epithelial cells infected with RSV reduced transepithelial fluid leak and expression of necroptosis associated genes RIPK3 and MLKL, while regulating genes associated with homeostatic maintenance, suggesting stabilized epithelial integrity. In conclusion, our data demonstrate a unique function of NRG1 in respiratory viral infections by reducing alveolar leak, inhibiting epithelial necroptosis, and promoting homeostatic regulation of airway epithelium, all of which associate with markedly reduced mortality to the respiratory viral insult.

Recurrent wheeze and asthma are major health problems, especially in children. Respiratory viral infections are known to induce recurrent wheeze and asthma. Two respiratory viruses associated with most recurrent wheeze and asthma development are respiratory syncytial virus (RSV) and rhinovirus (RV). This review evaluates the roles these 2 viruses play in the development of wheeze and asthma. RSV tends to drive recurrent wheeze in those infants who have a severe infection in the first 2 to 6 months of life and do not have preexisting atopy. This is in contrast with RV, which tends to drive wheeze and asthma in those with preexisting atopy. In the review, the mechanisms that have been proposed to drive the development of asthma and wheeze are explored. Finally, newer developments, such as vaccines, are discussed. In particular, vaccines and treatment for RSV have the potential to alter the development of recurrent wheezing, although vaccines and treatment for RV remain elusive. Both RSV and RV remain a major source of recurrent wheezing in young children.

We demonstrate that proteases produced by the oro-pharyngeal bacterial colonizer Porphyromonas gingivalis (Pg) reduce viral burden and modulate host interferon responses during respiratory syncytial virus (RSV) infection. Several oral bacteria, including Pg , have been shown to translocate to the upper airways through sub-clinical micro-aspiration. Our findings reveal that Pg , upon translocating to this new niche, significantly attenuated lung damage by reducing viral loads during respiratory viral infections in the lungs of wild-type mice. This protective effect was attributed to the activity of gingipains, cysteine endopeptidases produced by Pg , which cleaved envelope glycoproteins on RSV as well as on related murine-specific Sendai virus (SeV), thereby impairing their infectious capacity. Notably, the reduction in viral loads was independent of interferon lambda (IFN-λ) signaling, which is actively suppressed by Pg in airway epithelial cells. However, the complete absence of IFN-λ signaling resulted in a stronger inflammatory response despite a low viral load. Thus, we show a previously undescribed role for the oro-respiratory bacterial colonizer Pg in creating bottlenecks to viral infection by the activity of its proteases. SIGNIFICANCE STATEMENT:Reciprocal interactions between microbial colonizers and host epithelial cells are critical for providing initial defense against viral infections. However, our understanding of this phenomenon has been limited to microbiota-derived ligands that activate host pattern recognition receptors (PRRs), inducing basal interferon expression and downstream antiviral genes. Here, we present a novel mechanism that relies on microbial proteases to directly reduce viral load. Specifically, we discovered that the infectious capacity of the Respiratory Syncytial Virus (RSV) was significantly inhibited upon contact with the proteases (gingipains) produced by the oropharyngeal colonizer Porphyromonas gingivalis . Gingipains caused proteolytic degradation of the RSV envelope and attachment proteins, rendering them inactive. This preemptive reduction in viral infectious capacity consequently diminished the severity of respiratory viral infections in an IFN-independent manner.

The field of allergy and immunology (A/I) has transformed modern medicine with the development of diagnostic and therapeutic advances in all areas of health. This Work Group Report from the Division Directors Committee of the American Academy of Allergy, Asthma & Immunology describes the current state of 5 mission areas (clinical, educational, research, equity, and advocacy) within the A/I divisions/subdivisions of academic medical centers (AMCs) in the United States. The current states of the clinical and educational mission areas in AMCs in A/I are strong, with an increasing prevalence of atopic/immunologic disorders and novel therapeutics, solid trainee interest, and tremendous potential for research, equity, and advocacy efforts. The interest in the field of A/I has outpaced the creation of new positions, leading to an increase in unmatched applicants yearly. Weaknesses and threats include decreasing federal research and educational funding, changing health care insurance policies, the dynamic legislative environment, and the negative impact of the business focus in academic institutions. The future of A/I will depend on the preservation of a strong academic foundation with improved recruitment to academic positions, increased training positions, and greater incentives for development of career opportunities in research and education, utilizing artificial intelligence tools and strong advocacy strategies.

Rationale: Approximately 5-10% of asthmatics have been diagnosed with severe asthma, which is characterized by inflammation that is insensitive to corticosteroids. Cluster of differentiation 38 (CD38) has been shown to regulate immune cell activation and airway smooth muscle hypercontractility in asthma. Previous studies have shown that loss of CD38 does not affect immune cell lung infiltration in mouse models of acute allergen and cytokine exposure. However, the role of CD38 in the context of severe asthma remains unknown. In this study, we chronically challenged wild-type and CD38 knockout mice in a corticosteroid-insensitive mixed allergen model. Methods: CD38 wild-type (CD38+/+) and homozygous knockout (CD38-/-) mice were intranasally exposed to phosphate buffered saline (PBS) or mixed-allergen (Alternaria alternata, Aspergillus fumigatus, house dust mite, and ovalbumin; 10 µg each) and 0.5 µg cyclic-dimeric guanosine monophosphate (MA+GMP) 3 times a week for 4 weeks. The day after the last allergen challenge, airway hyperresponsiveness (AHR) was measured by methacholine challenge using the SCIREQ flexiVent. Lungs were lavaged with PBS and dissociated. Single cell suspensions were antibody stained for cellular phenotyping via flow cytometry. Results: Upon MA+GMP exposure, CD38-/- mice had greater AHR compared to challenged CD38+/+ mice. CD38-/- mice also had increased total CD45+ immune cells in the lung tissue but not in the airways compared to CD38+/+ mice. Specifically, there was a significant increase in total dendritic cells (CD45+ CD11c+ SiglecF-Ly6G-), macrophages (CD45+ CD11c+ SiglecF+ Ly6G-), and eosinophils (CD45+ CD11c- SiglecF+ Ly6G-) in lung tissue of MA+GMP exposed CD38-/- mice compared to CD38+/+ mice. However, there were no significant differences in these populations in the bronchoalveolar lavage. While there were no differences of MA+GMP-induced lung tissue populations of total lymphocytes, helper T cells (CD45+ CD3+ CD4+ CD8-), and innate lymphoid type 2 cells (CD45+ Ly6G- CD11b- CD90+ CD3- KLRG1+) between CD38-/- and CD38+/+ mice, total natural killer (NK) cells (CD45+ CD3- NK1.1+) and interferon gamma-producing NK cells (CD45+ CD3- NK1.1+ CD160+) were significantly lower in the lung tissue of CD38-/- mice compared to CD38+/+ mice. Conclusions: Our data show that upon MA+GMP exposure, loss of CD38 leads to increased AHR and total lung tissue immune cell populations except for NK cells, which were reduced. These data suggest that CD38 may be protective for MA+GMP-induced AHR. This study highlights a novel role for CD38 in severe asthma and highlights the need for further understanding its role in immune cell infiltration during severe allergic airway inflammation.