Murine models of SARS-CoV-2 infection are critical for elucidating the biological pathways underlying COVID-19. Because human angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2, mice expressing the human ACE2 gene have shown promise as a potential model for COVID-19. Five mice from the transgenic mouse strain K18-hACE2 were intranasally inoculated with SARS-CoV-2 Hong Kong/VM20001061/2020. Mice were followed twice daily for 5 days and scored for weight loss and clinical symptoms. Infected mice did not exhibit any signs of infection until day 4, when no other obvious clinical symptoms other than weight loss were observed. By day 5, all infected mice had lost around 10% of their original body weight but exhibited variable clinical symptoms. All infected mice showed high viral titers in the lungs as well as altered lung histology associated with proteinaceous debris in the alveolar space, interstitial inflammatory cell infiltration, and alveolar septal thickening. Overall, these results show that the K18-hACE2 transgenic background can be used to establish symptomatic SARS-CoV-2 infection and can be a useful mouse model for COVID-19.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts.In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene and accumulation of the hyaluronan polysaccharide was decreased in the lung. In patients with COVID-19, hyaluronan was increased in the lungs and plasma. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator.Finally, hyaluronan was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.Summary: IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization reduced disease and decreased lung hyaluronan deposition.Administration of IL-13 induced hyaluronan in the lung. Blockade of the hyaluronan receptor CD44 prevented mortality, highlighting a novel mechanism for IL-13-mediated hyaluronan synthesis in pulmonary pathology.

Abstract/SummaryMurine models of SARS-CoV-2 infection are critical for elucidating the biological pathways underlying COVID-19 disease. Because human ACE2 is the receptor for SARS-CoV-2, mice expressing the human ACE2 gene have shown promise as a potential model for COVID-19. Five mice from the transgenic mouse strain K18-hACE2 were intranasally inoculated with SARS-CoV-2 Hong Kong/VM20001061/2020. Mice were followed twice daily for five days and scored for weight loss and clinical symptoms. Infected mice did not exhibit any signs of infection until day four, when weight loss, but no other obvious clinical symptoms were observed. By day five all infected mice had lost around 10% of their original body weight, but exhibited variable clinical symptoms. All infected mice showed high viral titers in the lungs as well as altered lung histology associated with proteinaceous debris in the alveolar space, interstitial inflammatory cell infiltration and alveolar septal thickening. Overall, these results show that symptomatic SARS-CoV-2 infection can be established in the K18-hACE2 transgenic background and should be a useful mouse model for COVID-19 disease.

Here we report on an inpatient cohort of COVID-19 positive patients where plasma cytokines were tested for association with future need for mechanical ventilation. Hierarchical clustering, Kaplan-Meier curves, and odds ratios demonstrated that two cytokines, IL-13 (OR: 1.57) and IL-7 (OR: 1.04) and the growth factor bFGF (OR: 1.04), were predictive for intubation.

Background Based on studies implicating the type 2 cytokine interleukin (IL)-13 as a potential contributor to critical COVID-19, this trial was designed as an early phase II study to assess dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, for treatment of inpatients with COVID-19. Methods We conducted a phase IIa randomized double-blind placebo-controlled trial (NCT04920916) to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Results Forty eligible subjects were enrolled from June to November of 2021. There was no statistically significant difference in adverse events nor in the primary endpoint of ventilator free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, there were two deaths in the dupilumab group compared five deaths in placebo (60-day survival 89.5% vs 76.2%, adjusted HR 0.05, 95% CI: 0.004- 0.72, p = 0.03). Among subjects who were not in the ICU at randomization, three subjects in the dupilumab arm were admitted to the ICU compared to six in the placebo (17.7% vs. 37.5%; adjusted HR 0.44, 95% CI: 0.09-2.09, p = 0.30). Lastly, we found evidence of type 2 signaling blockade in the dupilumab group through analysis of immune biomarkers over time. Conclusions Although the primary outcome of day 28 ventilator-free survival was not reached, adverse events were not observed and survival was higher in the dupilumab group by day 60.