The Stereotypic Response of the Pulmonary Vasculature to Respiratory Viral Infections: Findings in Mouse Models of SARS-CoV-2, Influenza A and Gammaherpesvirus Infections

Abstract

The respiratory system is the main target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 19 (COVID-19) where acute respiratory distress syndrome is considered the leading cause of death. Changes in pulmonary blood vessels, among which an endothelialitis/endotheliitis has been particularly emphasized, have been suggested to play a central role in the development of acute lung injury. Similar vascular changes are also observed in animal models of COVID-19. The present study aimed to determine whether the latter are specific for SARS-CoV-2 infection, investigating the vascular response in the lungs of mice infected with SARS-CoV-2 and other respiratory viruses (influenza A and murine gammaherpesvirus) by in situ approaches (histology, immunohistology, morphometry) combined with RNA sequencing and bioinformatic analysis. Non-selective recruitment of monocytes and T and B cells from larger muscular veins and arteries was observed with all viruses, matched by a comparable transcriptional response. There was no evidence of endothelial cell infection in any of the models. Both the morphological investigation and the transcriptomics approach support the interpretation that the lung vasculature in mice mounts a stereotypic response to alveolar and respiratory epithelial damage. This may have implications for the treatment and management of respiratory disease in humans.

The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19

“…To investigate the frequency of genomic changes that occur in SARS-CoV-2 in the immune compromised or competent host in the presence or absence of antiviral drugs, K18-hACE2 transgenic mice were used as a model for severe SARS-CoV-2 infection in humans 44 . We have found that the pathological changes in the lungs in this model in many aspects resemble those in humans who have died of severe COVID-19 26,28,29,32,33 . To mimic a host with compromised immunity, an experimental protocol was developed in which mice were exposed to cyclophosphamide 40 (Fig.…”

“…Consecutive sections (3-5 µm) were either stained with hematoxylin and eosin (HE) or used for immunohistology (IH). IH was performed to detect viral antigen expression using the horseradish peroxidase method and a rabbit anti-SARS-CoV nucleocapsid protein (Rockland, 200-402-A50) as primary antibody, as previously described 26, 32, 33 .…”

Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression

“…The frequency of infected cells in the lung at 4dpi was low and this may reflect the semi-permissive nature of hRSV infection of mice (reviewed in 83 ). Despite the low frequency of infection, RSV induced a similar inflammatory response as seen with other respiratory viruses, such as SARS-CoV-2 and IAV, with clear evidence of leukocyte recruitment and monocyte and T cell driven vasculitis and perivascular/peribronchial infiltration 84 . Daprodustat treatment dampened these inflammatory responses, although the recruitment of neutrophils was maintained, in line with earlier reports on hypoxia driving neutrophilic inflammation 85 .…”

“…A formalin fixed and paraffin embedded RSV infected (MOI 0.2, 48 hpi) Calu-3 pellet served as positive control; tissue sections incubated without the primary antibody served as negative controls. Further sections were stained for Iba1 (monocytes/macrophage marker), CD3 (T cell marker) and Ly6G (neutrophil marker) following previously published protocols 84,88 .…”

COVID-19 Vaccines for Optimizing Immunity in the Upper Respiratory Tract

“…The pathology of LRT infection by SARS-CoV-2, and the consequent severe disease that requires hospital treatment, is complex and involves a central role for dysfunctional immune responses [12,13]. SARS-CoV-2 infection of the lungs can lead to uncontrolled coagulation and inflammation in the lungs, increased permeability of vascular endothelium [15], diffuse alveolar damage where the lungs are unable to maintain adequate oxygen supply, and systemic pathology [12,13]. The primary goal of COVID-19 vaccination to date has been to prevent or minimize the development of severe disease and death, which is closely dependent on averting or rapidly eliminating SARS-CoV-2 infections in the URT.…”