Differential Type I Interferon Signaling Is a Master Regulator of Susceptibility to Postinfluenza Bacterial Superinfection

Abstract

Bacterial superinfections are a primary cause of death during influenza pandemics and epidemics. Type I interferon (IFN) signaling contributes to increased susceptibility of mice to bacterial superinfection around day 7 post-influenza A virus (IAV) infection. Here we demonstrate that the reduced susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) at day 3 post-IAV infection, which we previously reported was due to interleukin-13 (IL-13)/IFN-γ responses, is also dependent on type I IFN signaling and its subsequent requirement for protective IL-13 production. We found, through utilization of blocking antibodies, that reduced susceptibility to MRSA at day 3 post-IAV infection was IFN-β dependent, whereas the increased susceptibility at day 7 was IFN-α dependent. IFN-β signaling early in IAV infection was required for MRSA clearance, whereas IFN-α signaling late in infection was not, though it did mediate increased susceptibility to MRSA at that time. Type I IFN receptor (IFNAR) signaling in CD11c+ and Ly6G+ cells was required for the observed reduced susceptibility at day 3 post-IAV infection. Depletion of Ly6G+ cells in mice in which IFNAR signaling was either blocked or deleted indicated that Ly6G+ cells were responsible for the IFNAR signaling-dependent susceptibility to MRSA superinfection at day 7 post-IAV infection. Thus, during IAV infection, the temporal differences in type I IFN signaling increased bactericidal activity of both CD11c+ and Ly6G+ cells at day 3 and reduced effector function of Ly6G+ cells at day 7. The temporal differential outcomes induced by IFN-β (day 3) and IFN-α (day 7) signaling through the same IFNAR resulted in differential susceptibility to MRSA at 3 and 7 days post-IAV infection.

Host‐pathogen kinetics during influenza infection and coinfection: insights from predictive modeling

“…First, S. aureus, another common coinfecting bacteria, was shown to inhibit IFN signaling in influenza-infected cells, which resulted in increased virus production. 125 Although it is unknown if pneumococci have this same ability and to what extent this occurs in vivo, particularly considering the enhanced IFN levels during coinfection, [86][87][88] it is an intriguing finding and validates the model-generated hypothesis. Second, pneumococcal neuraminidases, NanA and NanB, have been shown to promote virus replication 126,128 presumably through cleavage of viral NA.…”

“…More work is clearly needed to tease apart the effects of IFN during IAV infection. In addition, because type I IFNs are important mediators of viral–bacterial coinfection severity and likely have a role in viral–viral coinfection dynamics, building new IFN models that are calibrated to data are pivotal.…”

A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza

“…For example, subsequent clearance mechanisms (>4 h pbi), such as neutrophils and macrophages, undergo influenza-induced apoptosis, become dysfunctional, and have reduced chemotactic and phagocytic functions153132333435. It is unclear the extent to which the inflated cytokine response (e.g., type I and II interferons (IFN- α, β, γ ), TNF- α , IL-1 β , IL-6, IL-12, and IL-1016333637383940414243444546474849) facilitates these changes. While our coinfection model does not explicitly account for these cytokines, the model’s ability to accurately estimate AM loss with indicates a limited role for cytokine-mediated functional inhibition of AMs.…”

Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin

“…For instance, type I IFNs are considered crucially implicated in the increased susceptibility to post-influenza Staph. aureus respiratory superinfections [61, 62], a tremendous cause of human morbidity and mortality.…”