1. Academic Validation
  2. Sirolimus alters lung pathology and viral load following influenza A virus infection

Sirolimus alters lung pathology and viral load following influenza A virus infection

  • Respir Res. 2017 Jul 11;18(1):136. doi: 10.1186/s12931-017-0618-6.
Ahmed R Alsuwaidi 1 Junu A George 2 Saeeda Almarzooqi 3 Stacey M Hartwig 4 Steven M Varga 4 Abdul-Kader Souid 2
Affiliations

Affiliations

  • 1 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. alsuwaidia@uaeu.ac.ae.
  • 2 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
  • 3 Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
  • 4 Department of Microbiology & Immunology, Department of Pathology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa, USA.
Abstract

Background: Inhibitors of mTOR, such as sirolimus, have been shown to induce thymus involution and inflammatory lung disease in mice. The latter effect supports the role of this serine/threonine kinase in ameliorating lung inflammation. Other studies have shown sirolimus reduces/delays lung disease associated with various strains of influenza A virus (IAV). Thus, the effects of mTOR inhibitors on influenza Infection deserve further studies.

Methods: Here, we examined the changes in lung viral copies, pathology and pulmonary function associated with IAV (A/PR/8/34) Infection in mice treated with sirolimus.

Results: Body weight loss peaked between days 6-11 post-infection and was more severe in IAV-infected mice that were administered sirolimus as compared to mice that received IAV alone (p = 0.030). Natural log viral gene copies, mean ± SD per mg lung tissue, in IAV-infected mice that were administered sirolimus were 17.31 ± 1.27 on day 4, 19.31 ± 7.46 on day 10, and 0 on day 25. The corresponding number of copies in mice that received IAV alone were 18.56 ± 0.95 on day 4 (p = 0.132), 1.52 ± 1.39 on day 10 (p = 0.008), and 0 on day 25. Lung pathology was evident on days 4, 10, and 25 post Infection, with mean ± SD inflammatory score of 9.0 ± 4.5 in IAV-infected mice that were administered sirolimus, as compared to 11.5 ± 4.5 (p = 0.335) in mice received IAV alone (maximum score, 26.0). Impaired lung function was evident in IAV-infected mice on days 4 and 10, as demonstrated by increased airway resistance and decreased compliance.

Conclusions: In this model, the effects of sirolimus on influenza Infection included severe weight loss and modified viral replication, respiratory function and lung inflammation. The adverse events associated with sirolimus treatment are consistent with its potent immunosuppressive activity and, thus, preclude its use in IAV Infection.

Keywords

Inflammatory score; Influenza A virus; Lung function; Rapamycin; Viral replication.

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