Deletion of the complement C5a receptor alleviates the severity of acute pneumococcal otitis media following influenza A virus infection in mice.

Hua Hua Tong,Yong Xing Li,Joshua M Thurman,Kelsey Douthitt,Garrett Lambert,Gregory L Stahl,Caitlin Clancy,Yujuan He,Andrew S Bowman,Dennis W Metzger

doi:10.1371/journal.pone.0095160

Abstract

There is considerable evidence that influenza A virus (IAV) promotes adherence, colonization, and superinfection by S. pneumoniae (Spn) and contributes to the pathogenesis of otitis media (OM). The complement system is a critical innate immune defense against both pathogens. To assess the role of the complement system in the host defense and the pathogenesis of acute pneumococcal OM following IAV infection, we employed a well-established transtympanically-induced mouse model of acute pneumococcal OM. We found that antecedent IAV infection enhanced the severity of acute pneumococcal OM. Mice deficient in complement C1qa (C1qa−/−) or factor B (Bf −/−) exhibited delayed viral and bacterial clearance from the middle ear and developed significant mucosal damage in the eustachian tube and middle ear. This indicates that both the classical and alternative complement pathways are critical for the oto-immune defense against acute pneumococcal OM following influenza infection. We also found that Spn increased complement activation following IAV infection. This was characterized by sustained increased levels of anaphylatoxins C3a and C5a in serum and middle ear lavage samples. In contrast, mice deficient in the complement C5a receptor (C5aR) demonstrated enhanced bacterial clearance and reduced severity of OM. Our data support the concept that C5a-C5aR interactions play a significant role in the pathogenesis of acute pneumococcal OM following IAV infection. It is possible that targeting the C5a-C5aR axis might prove useful in attenuating acute pneumococcal OM in patients with influenza infection.

Highlights

Otitis media (OM) is one of the most common diseases among infants and young children worldwide
Antecedent influenza A viral (IAV) infection induced enhanced complement activation We previously demonstrated that the complement alternative pathway and C3 activation in the middle ear account for the local immune response to Streptococcus pneumoniae (Spn) [18]
Deficiency in C5aR reduced severity of acute pneumococcal OM with an antecedent of influenza virus infection To further assess the functional role of the anaphylatoxin C5a in the pathogenesis of acute pneumococcal OM, we investigated its effect on the severity of OM in mice deficient in C5a receptor (C5ar12/2)

Summary

Introduction

Otitis media (OM) is one of the most common diseases among infants and young children worldwide. Children with OM are at an increased risk of secondary bacterial infection following an upper respiratory viral infection [1], [2], [3]. Virus-modulated host immune and inflammatory responses play a significant role in pneumococcal OM [13], [14]. Two recent reports suggest that mice pre-colonized with Spn are more susceptible to IAV [14], [15]. They found that the inflammatory response to IAV infection mediates pneumococcal replication in the middle ear cavity in an infant mouse model of OM [14]. Much more needs to be learned about the interactions between IAV and Spn and their combined role in the host immune response, the host defense, and the pathogenesis of OM

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Conclusion