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Targeting ectromelia virus and TNF/NF-κB or STAT3 signaling for effective treatment of viral pneumonia

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journal contribution
posted on 2023-05-21, 17:06 authored by Pratikshya PandeyPratikshya Pandey, Al Rumaih, Z, Tuazon Kels, MJ, Ng, E, Rajendra KCRajendra KC, Chaudhri, G, Gunasegaran KarupiahGunasegaran Karupiah
Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1β, IL-12p40, TGF-β, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.

History

Publication title

Proceedings of the National Academy of Sciences of The United States of America

Volume

119

Issue

8

Article number

e2112725119

Number

e2112725119

Pagination

1-12

ISSN

0027-8424

Department/School

Tasmanian School of Medicine

Publisher

National Academy of Sciences

Place of publication

2101 Constitution Ave Nw, Washington, USA, Dc, 20418

Rights statement

© 2022. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License, https://creativecommons.org/licenses/by-nc-nd/4.0/

Repository Status

  • Open

Socio-economic Objectives

Efficacy of medications; Treatment of human diseases and conditions