Rapamycin adjuvant and exacerbation of severe influenza in an experimental mouse model

Abstract

Influenza virus infection often causes severe disease and acute respiratory distress syndrome. It is a common belief that overwhelming immune response contributes to the severe illness. Physicians and researchers have put forth immune modulation as salvage therapy for better recovery. However, empiric corticosteroid failed in both humans and animal models. Reported success with Rapamycin in humans prompted a comprehensive animal study and mechanistic dissection. Here we report the effect of Rapamycin alone or in combination with Oseltamivir for severe influenza in BALB/c mice. We found that Rapamycin had no antiviral effect against H1N1, H3N2 and novel-H1N1 influenza viruses in vitro. Rapamycin alone aggravated the severe disease of PR8 H1N1 influenza virus infection in mice. Timely Oseltamivir anti-viral therapy abolished the disease. Delayed Oseltamivir treatment could not prevent severe illness and Rapamycin adjuvant was associated with exacerbated disease. Rapamycin adjuvant suppressed influenza hemagglutinin antigen-specific T cell immunity and impaired virus clearance from the lungs. It also resulted in intensified lung pathology with increased intra-alveolar edema and hyaline deposition. Rapamycin may work as the salvage therapy for severe influenza but it is very difficult to define the appropriate window for such treatment to take effect.

Dynamically Linking Influenza Virus Infection Kinetics, Lung Injury, Inflammation, and Disease Severity

“…The nonlinear relations derived from the histomorphometric analysis further provide a way to interpret and utilize weight loss data, which is the most readily available type of data and commonly used as a measure of disease severity in infection models (Figs 4-5). In our data and others', there is a spike in weight loss, symptom score, and/or inflammation at ∼6 d pi [50,54,70,71] (Fig 4D). Our data suggests that this is due to CD8 E infiltration and activity while the infection continues to spread (Fig 4).…”

Critical care management of adults with community-acquired severe respiratory viral infection

“…Inhibitors of the mTOR pathway like sirolimus combined with oseltamivir have shown inconsistent effects in murine models of severe influenza [32,33]. Sirolimus also can modulate inflammatory responses through its immunosuppressive properties [34].…”

Passive immune therapy and other immunomodulatory agents for the treatment of severe influenza: Systematic review and meta‐analysis

“…In terms of other immunomodulatory agents, despite the apparent mortality benefit with adjunctive mTOR inhibitors observed in the small RCT by Wang et al, subsequent studies have questioned this finding. For example, in an animal study, rapamycin attenuated antigen‐specific immune responses without reducing pulmonary inflammation, but impairing viral clearance . The clinical use of powerful immunosuppressants, including mTOR inhibitors and corticosteroids, needs to be carefully judged to determine whether benefits outweigh risks.…”

“…For example, in an animal study, rapamycin attenuated antigen-specific immune responses without reducing pulmonary inflammation, but impairing viral clearance. 39 The clinical use of powerful immunosuppressants, including mTOR inhibitors and corticosteroids, needs to be carefully judged to determine whether benefits outweigh risks. Which populations are most likely to benefit, and the optimal timing of administration (eg before or after the onset of critical illness) are important factors that are not well understood.…”