Binding host proteins to the M protein contributes to the mortality associated with influenza–Streptococcus pyogenes superinfections

Abstract

The mortality associated with influenza A virus (IAV) is often due to the development of secondary bacterial infections known as superinfections. The group A streptococcus (GAS) is a relatively uncommon cause of IAV superinfections, but the mortality of these infections is high. We used a murine model to determine whether the surface-localized GAS M protein contributes to the outcome of IAV-GAS superinfections. A comparison between wild-type GAS and an M protein mutant strain (emm3) showed that the M3 protein was essential to virulence. To determine whether the binding, or recruitment, of host proteins to the bacterial surface contributed to virulence, GAS was suspended with BALF collected from mice that had recovered from a sub-lethal infection with IAV. Following intranasal inoculation of naïve mice, the mortality associated with the wild-type strain, but not the emm3 mutant strain, was greater compared to mice inoculated with GAS suspended with either BALF from uninfected mice or PBS. Further analyses showed that both albumin and fibrinogen (Fg) were more abundant in the respiratory tract 8 days after IAV infection, that M3 bound both proteins to the bacterial surface, and that suspension of GAS with either protein increased GAS virulence in the absence of antecedent IAV infection. Overall, the results showed that M3 is essential to the virulence of GAS in an IAV superinfection and suggested that increased abundance of albumin and Fg in the respiratory tract following IAV infection enhanced host susceptibility to secondary GAS infection.

Contributions of Influenza Virus Hemagglutinin and Host Immune Responses Toward the Severity of Influenza Virus:Streptococcus pyogenesSuperinfections

“…While capable of causing death as a primary viral invader, the majority of influenza virus-related deaths arise from secondary bacterial infections (38,42,67), including pneumonia (14,83). Studies in pigs (31,33,35,56,57), ferrets (7,17,27,40), and mice (9,73) demonstrate that these complex polymicrobial infections require contributions from the virus (37,39), the host (41,63,66,68,70), and the bacteria (8,22,50) to progress to death, with distinct interactions between the virus and an infected host influencing the severity of secondary bacterial infections. Since these secondary bacterial infections can naturally affect both humans and pigs, there is significant interest in understanding the host-pathogen interactions that are associated with severe secondary bacterial infections, including cytokine and host cell contributions (16,21,31,33,58).…”

“…Interestingly, GAS and influenza share a common seasonality, and work with an influenza virus: GAS model of superinfection has shown an association with necrotizing fasciitis (49,51). Our group has been working with an influenza virus-GAS model of superinfection in mice (12) to evaluate the contribution of influenza viruses and bacteria toward the severity of secondary bacterial infections (22,81). Our previous comparison of influenza viruses and bacterial species showed that the virus strain used for primary inoculation can have a profound effect on susceptibility to secondary infection with GAS, Streptococcus pneumoniae, and Staphylococcus aureus (81).…”

Pathogenic mechanisms of invasive group A Streptococcus infections by influenza virus–group A Streptococcus superinfection

“…However, even if GAS is inoculated several days after influenza virus infection, a considerable proportion of mice die from invasive GAS infections , indicating that factors other than HA and other viral surface proteins can also enhance bacterial invasion. M3 protein is an important pathogenic factor for invasive GAS infections in influenza virus–GAS superinfection . According to this study, GAS mutants lacking M3 protein cannot cause invasion.…”

Volatile scents of influenza A and S. pyogenes (co-)infected cells

“…Even though S. pyogenes plays an important role in co-infection processes 9,10 , sparse information is available and only a few articles are focusing on co-infections involving this bacteria in combination with influenza A 9–12 . S. pyogenes is an important pathogen with a large number of situation dependent virulence factors causing angina, toxin mediated shock syndrome, and pneumonia 13–15 .…”

“…During the binding process of influenza A onto cells, sialic acids are removed through the effect of the viral proteins hemagglutinin (HA) and neuraminidase (NA) 16 . In this way, presence of influenza A virus can support bacterial adhesion because bacterial binding to cells without sialic acid is much easier 1,9 . Okamoto et al .…”