Hyaluronan Ameliorates Viral Pneumonia in Mice and Humans by Inhibiting E2F1 Transcription Factor

Abstract

Rationale: Viral lung infections are a major cause of morbidity and mortality worldwide. Despite significant advances in vaccines and antivirals, there remains a tremendous need for broadly applicable treatments that can be utilized across viral infections. Prior to infecting epithelial cells, viruses interact with the epithelial glycocalyx, which contains high molecular weight hyaluronan (HMWHA), a glycosaminoglycan that has beneficial effects in lung injury.

Objective: To determine the role of HMWHA in viral pneumonia.

Methods: We infected mice with Influenza or SARS-Cov2 and treated with prophylactic or therapeutic doses of HMWHA or saline control. We performed in vitro experiments of infection with viruses of respiratory and non-respiratory human and animal cells and evaluated the effect of HMWHA on infection. We analyzed existing databases for expression of hyaluronan and the transcription factor E2F1. Finally, we performed a clinical trial with HMWHA in patients with severe COVID-19 Measurements and Main Results: Exogenously applied HMWHA improved survival in SARS-CoV2 and influenza infection in mice, by ameliorating inflammation via the inhibition of E2F1. In a clinical study, inhaled HMWHA improved outcomes in patients with severe COVID-19. Furthermore, airway epithelia naturally express HMWHA, which is induced during viral infection and prevents infection via macromolecular crowding of viruses.

Conclusions: Our data provide a mechanistic justification for the use of HMWHA as a broadly effective prophylactic and therapeutic agent in viral airway infection. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: hyaluronan , E2F1 , viral pneumonia , viral infection , treatment.