Abstract
ABSTRACTInfluenza A virus infection can predispose to potentially devastating secondary bacterial infections. Invariant natural killer T (iNKT) cells are unconventional, lipid-reactive T lymphocytes that exert potent immunostimulatory functions. Using a mouse model of postinfluenza invasive secondary pneumococcal infection, we sought to establish whether α-galactosylceramide (α-GalCer [a potent iNKT cell agonist that is currently in clinical development]) could limit bacterial superinfection. Our results highlighted the presence of a critical time window during which α-GalCer treatment can trigger iNKT cell activation and influence resistance to postinfluenza secondary pneumococcal infection. Intranasal treatment with α-GalCer during the acute phase (on day 7) of influenza virus H3N2 and H1N1 infection failed to activate (gamma interferon [IFN-γ] and interleukin-17A [IL-17A]) iNKT cells; this effect was associated with a strongly reduced number of conventional CD103+ dendritic cells in the respiratory tract. In contrast, α-GalCer treatment during the early phase (on day 4) or during the resolution phase (day 14) of influenza was associated with lower pneumococcal outgrowth and dissemination. Less intense viral-bacterial pneumonia and a lower morbidity rate were observed in superinfected mice treated with both α-GalCer (day 14) and the corticosteroid dexamethasone. Our results open the way to alternative (nonantiviral/nonantibiotic) iNKT-cell-based approaches for limiting postinfluenza secondary bacterial infections.
Highlights
Influenza A virus infection can predispose to potentially devastating secondary bacterial infections
While the dose of inoculated pneumococci was selflimiting as an infection in the absence of influenza A virus (IAV), IAV-experienced mice were susceptible to pneumococcal challenge—as reflected by the presence of bacteria in the lungs and spleen (Fig. 1)
It is noteworthy that mice challenged at 4 dpi were resistant to invasive pneumococcal infection; this finding is in line with maintenance of lung barrier functions at that time point (Fig. 1B and Fig. S1B)
Summary
Influenza A virus infection can predispose to potentially devastating secondary bacterial infections. Using a mouse model of postinfluenza invasive secondary pneumococcal infection, we sought to establish whether ␣-galactosylceramide (␣-GalCer [a potent iNKT cell agonist that is currently in clinical development]) could limit bacterial superinfection. Our results highlighted the presence of a critical time window during which ␣-GalCer treatment can trigger iNKT cell activation and influence resistance to postinfluenza secondary pneumococcal infection. Invariant natural killer T (iNKT) cells constitute a highly conserved subset of innate-like T lymphocytes with potent immunostimulatory properties. These cells recognize lipid antigens presented by the monomorphic major histocompatibilty complex (MHC) class I-like homologue CD1d expressed by antigenpresenting cells [21,22,23,24]. In view of this unique property, iNKT cells are critical for the regulation of innate and adaptive immune responses
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have