Abstract
Understanding of pathogenesis and protection mechanisms underlying influenza-Streptococcus pneumoniae co-infection may provide potential strategies for decreasing its high morbidity and mortality. Interleukin-6 (IL-6) is an important cytokine that acts to limit infection-related inflammation; however, its role in co-infected pneumonia remains unclear. Here we show that the clinically relevant co-infected mice displayed dramatically elevated IL-6 levels; which was also observed in patients with co-infected pneumonia. IL-6−/− mice presented with increased bacterial burden, early dissemination of bacteria to extrapulmonary sites accompanied by aggravated pulmonary lesions and high mortality when co-infection. This protective function of IL-6 is associated with cellular death and macrophage function. Importantly, therapeutic administration of recombinant IL-6 protein reduced cells death in BALF, and enhanced macrophage phagocytosis through increased MARCO expression. This protective immune mechanism furthers our understanding of the potential impact of immune components during infection and provides potential therapeutic avenues for influenza-Streptococcus pneumoniae co-infected pneumonia.
Highlights
Influenza A virus (IAV) and Streptococcus pneumoniae (S. pneumoniae) are two of the major causes of respiratory infections in humans
To identify the kinetics of the nature, strength and timing of interactions between IAV and S. pneumonia, secondary S. pneumoniae infection was established by administration of the bacteria at day 0 (4 h), 1, 2, 3, 4, 5, and 6 post IAV infection (Figure 1A)
This study evaluated whether IL-6 had an important role in resisting secondary bacterial infections post influenza infection
Summary
Influenza A virus (IAV) and Streptococcus pneumoniae (S. pneumoniae) are two of the major causes of respiratory infections in humans. In the 1918 influenza pandemic, more than 50 million individuals died from pneumonia exacerbated by bacterial superinfection [1, 4]. This death toll was higher than the total number of deaths in World War I. Supporting this concern numerous studies in co-infected pneumonia mouse models have reported complex interactions between virus, bacteria and host, leading to failed barrier function in the lungs [5], dysregulated immune responses [2, 6, 7] and unbalanced homeostasis [3]. Past studies have started to explore the mechanisms underlying influenza-induced morbidity and mortality, they remain poorly understood, and a better understanding of secondary infection is a priority
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