Abstract
Viral-bacterial coinfections, such as with influenza A virus and Streptococcus pneumoniae (S.p.), are known to cause severe pneumonia. It is well known that the host response has an important role in disease. Interleukin-1β (IL-1β) is an important immune signaling cytokine responsible for inflammation and has been previously shown to contribute to disease severity in numerous infections. Other studies in mice indicate that IL-1β levels are dramatically elevated during IAV-S.p. coinfection. However, the regulation of IL-1β during coinfection is unknown. Here, we report the NLRP3 inflammasome is the major inflammasome regulating IL-1β activation during coinfection. Furthermore, elevated IL-1β mRNA expression is due to enhanced TLR2-MYD88 signaling, which increases the amount of pro-IL-1β substrate for the inflammasome to process. Finally, NLRP3 and high IL-1β levels were associated with increased bacterial load in the brain. Our results show the NLRP3 inflammasome is not protective during IAV-S.p. coinfection.
Highlights
Secondary bacterial infections during influenza A virus (IAV) infection contribute to disease severity and mortality [1,2,3]
We found that only CD3ε- CD19- CD11b+ CD11c- Gr1, CD3ε- CD19- CD11b+ CD11c+ Gr1- (Dendritic cells), and CD3ε- CD19-CD11b+ CD11c- Gr1+ produced pro-IL-1β on day 2 post-coinfection (Fig 1A–1C)
The invasion of bacteria like S.p. in IAV infected hosts is linked to increased death rates during pandemic outbreaks, such as the 1918 “Spanish Flu”, where pneumococcus was found in samples collected from infected individuals [53,54,55,56]
Summary
Secondary bacterial infections during influenza A virus (IAV) infection contribute to disease severity and mortality [1,2,3]. Streptococcus pneumoniae (S.p.) and Staphylococcus aureus (S.a.) are the dominant pathogens associated with IAV coinfection [1,2,3]. The coinfection of IAV and S.p. results in pneumonia due to multiple factors [4,5,6,7,8]. After IAV exposure, S.p. causes a severe infection requiring only a low inoculum size compared to a single infection [9]. IAV can alter host immunological responses or lung homeostasis that can subsequently impede bacterial clearance [8, 10,11,12,13].
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