Biology subjects

Grayson, M. H.

Publications and source records attributed to Grayson, M. H..

3 recordsLinked to original sources

bioRxiv2025

Virion stripping: A new role for bacterial proteases

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-{lambda}) signaling, which is actively suppressed by Pg in airway epithelial cells. However, the complete absence of IFN-{lambda} 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 STATEMENTReciprocal 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.

microbiology↗

bioRxiv2023

Neuregulin-1 protects against respiratory viral induced mortality

Respiratory viral infections due to RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen similar to RSV, Sendai virus (SeV), we found that mice made atopic with house dust mite before viral infection all survived a normally lethal SeV infection. Moreover, adoptive transfer of CD11c+ cells from atopic mice delayed viral mortality. Neuregulin-1 (NRG1) message was highly expressed in CD11c+ cells from atopic mice and atopic lungs and bronchoalveolar lavage fluid had elevated levels of NRG1 protein. Administration of NRG1 protected non-atopic mice from death and associated with reduced alveolar epithelium permeability. Utilizing an in vitro system of well-differentiated human bronchial epithelial cells and mouse tracheal epithelial cells NRG1 reduced RSV and SeV titers. Expression of genes that play a role in airway epithelium integrity and stability were altered by NRG1; potentially regulating viral induced dysregulation of the epithelia and suggesting NRG1 mediated maintenance of homeostasis. In conclusion, our studies demonstrate atopy induced NRG1 likely plays a novel role in survival from severe respiratory viral infections and may have therapeutic value to prevent mortality from these infections. SignificanceSevere respiratory viral infections are associated with significant mortality in infants and the elderly; however, allergic disease can protect from these outcomes. This study identified a protein called neuregulin-1 (NRG1), produced by cells of the immune system in allergic mice, that provides a survival advantage against respiratory viral infection. NRG1 pretreatment in non-atopic mice infected with a lethal dose of a rodent RNA virus (Sendai virus), similar to human respiratory syncytial virus, significantly reduced death. Further, NRG1 pretreatment reduced viral replication in human and mouse airway epithelial cell cultures. These studies signify a potential therapeutic role of NRG1 in modulating the severity of respiratory viral infections.

immunology↗

bioRxiv2021

PRMT5 in T cells drives Th17 responses, mixed granulocytic inflammation and severe allergic airway inflammation

Severe asthma is characterized by steroid insensitivity and poor symptom control, and is responsible for the majority of asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding in mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in asthmatic lungs. Here, we show that PRMT5 drives allergic airway inflammation in a mouse model reproducing multiple aspects of human severe asthma. We find that PRMT5 is required in CD4+ T cells for chronic steroid-insensitive severe lung inflammation, with selective T cell deletion of PRMT5 robustly suppressing eosinophilic and neutrophilic lung inflammation, pathology, airway remodeling and hyperresponsiveness. Mechanistically, we observed high pulmonary sterol metabolic activity, ROR-{gamma}t and Th17 responses, with PRMT5-dependent increases in ROR-{gamma}ts agonist desmosterol. Our work demonstrates that T cell PRMT5 drives severe allergic lung inflammation and has potential implications for the pathogenesis and therapeutic targeting of severe asthma.

immunology↗