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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 8
• Main Authors: Pandey, Pratikshya, Al Rumaih, Zahrah, Kels, Ma Junaliah Tuazon, Ng, Esther, Kc, Rajendra, Chaudhri, Geeta, Karupiah, Gunasegaran
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.02.2022
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Antiviral agents; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Biological Sciences; Cell Line; Chemokines; Chlorocebus aethiops; Cidofovir; Cidofovir - pharmacology; Cidofovir - therapeutic use; Combined treatment; Coronaviruses; Cytokines; Cytokines - metabolism; Drug Evaluation, Preclinical; Drug Therapy, Combination; Ectromelia virus - drug effects; Etanercept; Etanercept - administration & dosage; Female; Health services; IL-1β; Infections; Inflammation; Influenza A; Interleukin 12; Interleukin 6; Lung - drug effects; Lung - metabolism; Lung diseases; Lungs; Mice; Mice, Inbred C57BL; Morbidity; NF-kappa B - metabolism; NF-κB protein; Pandemics; Pathology; Pneumonia; Pneumonia, Viral - drug therapy; Pneumonia, Viral - metabolism; Public health; Respiratory diseases; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signal transduction; Signal Transduction - drug effects; Signaling; Signs and symptoms; Stat3 protein; STAT3 Transcription Factor - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor necrosis factor-TNF; Viral diseases; Viral Load - drug effects; Viruses; TNF/NF-κB and STAT3 signaling pathways; combined antiviral and anti-inflammatory drug treatment; respiratory ectromelia virus infection; dysregulated inflammatory cytokine response; viral pneumonia
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2112725119

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.