Influenza A Virus Exacerbates Group A Streptococcus Infection and Thwarts Anti-Bacterial Inflammatory Responses in Murine Macrophages

Abstract

Seasonal influenza epidemics pose a considerable hazard for global health. In the past decades, accumulating evidence revealed that influenza A virus (IAV) renders the host vulnerable to bacterial superinfections which in turn are a major cause for morbidity and mortality. However, whether the impact of influenza on anti-bacterial innate immunity is restricted to the vicinity of the lung or systemically extends to remote sites is underexplored. We therefore sought to investigate intranasal infection of adult C57BL/6J mice with IAV H1N1 in combination with bacteremia elicited by intravenous application of Group A Streptococcus (GAS). Co-infection in vivo was supplemented in vitro by challenging murine bone marrow derived macrophages and exploring gene expression and cytokine secretion. Our results show that viral infection of mice caused mild disease and induced the depletion of CCL2 in the periphery. Influenza preceding GAS infection promoted the occurrence of paw edemas and was accompanied by exacerbated disease scores. In vitro co-infection of macrophages led to significantly elevated expression of TLR2 and CD80 compared to bacterial mono-infection, whereas CD163 and CD206 were downregulated. The GAS-inducible upregulation of inflammatory genes, such as Nos2, as well as the secretion of TNFα and IL-1β were notably reduced or even abrogated following co-infection. Our results indicate that IAV primes an innate immune layout that is inadequately equipped for bacterial clearance.

CRISPR arrays as high-resolution markers to track microbial transmission during influenza infection

“…Among the bacterial species enriched in the infection households, we identified species of the potentially pathogenic genus Rothia [ 28 ]. We also observe various Streptococcus species enriched in both the infection and control households, although some species of Streptococcus are known to associate with viral-bacterial co-infections [ 29 – 31 ]. Similarly enriched in the no infection households was Corynebacterium , which was previously found to be negatively associated with influenza infection [ 3 ].…”

Influenza enhances host susceptibility to non-pulmonary invasive Streptococcus pyogenes infections

“…also demonstrated increased morbidity (paw inflammation) and mortality in superinfected mice by using a model of pulmonary IAV infection followed by intravenous GAS superinfection [ 38 ]. Importantly, they reported that an IAV infection elicited after intravenous GAS infection did not increase disease severity, but that decreased CCL2 (a monocyte chemokine) in plasma at 2 and 4 d following IAV likely alters an otherwise competent anti-bacterial immune response [ 38 ]. This is consistent with our data.…”

“…In addition to the murine superinfection studies, Aleith et al . detected altered expression in superinfected bone marrow derived macrophages compared to macrophages infected with only GAS [ 38 ]. Together, these studies support the model that prior pulmonary virus infection modifies anti-streptococcal immunity.…”