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Exogenous Activation of Invariant Natural Killer T Cells by ?-Galactosylceramide Reduces Pneumococcal Outgrowth and Dissemination Postinfluenza.

ABSTRACT: Influenza 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 ?-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. Intranasal treatment with ?-GalCer during the acute phase (on day 7) of influenza virus H3N2 and H1N1 infection failed to activate (gamma interferon [IFN-?] 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, ?-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 ?-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.

Importance

Despite the application of vaccination programs and antiviral drugs, influenza A virus (IAV) infection is responsible for widespread morbidity and mortality (500,000 deaths/year). Influenza infections can also result in sporadic pandemics that can be devastating: the 1918 pandemic led to the death of 50 million people. Severe bacterial infections are commonly associated with influenza and are significant contributors to the excess morbidity and mortality of influenza. Today's treatments of secondary bacterial (pneumococcal) infections are still not effective enough, and antibiotic resistance is a major issue. Hence, there is an urgent need for novel therapies. In the present study, we set out to evaluate the efficacy of ?-galactosylceramide (?-GalCer)-a potent agonist of invariant NKT cells that is currently in clinical development-in a mouse model of postinfluenza, highly invasive pneumococcal pneumonia. Our data indicate that treatment with ?-GalCer reduces susceptibility to superinfections and, when combined with the corticosteroid dexamethasone, reduces viral-bacterial pneumonia.

SUBMITTER: Barthelemy A

PROVIDER: S-EPMC5090038 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Exogenous Activation of Invariant Natural Killer T Cells by α-Galactosylceramide Reduces Pneumococcal Outgrowth and Dissemination Postinfluenza.

Barthelemy Adeline A Ivanov Stoyan S Hassane Maya M Fontaine Josette J Heurtault Béatrice B Frisch Benoit B Faveeuw Christelle C Paget Christophe C Trottein François F

mBio 20161101 6

Influenza 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 result ...[more]

PMID: 27803187

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Project description:BackgroundHuman CD1d-restricted, invariant natural killer T cells (iNKT) are a unique class of T lymphocytes that recognise glycolipid antigens such as alpha-galactosylceramide (alphaGalCer) and upon T cell receptor (TCR) activation produce both Th1 and Th2 cytokines. iNKT cells expand when cultured in-vitro with alphaGalCer and interleukin 2 (IL-2) in a CD1d-restricted manner. However, the expansion ratio of human iNKT cells varies between individuals and this has implications for attempts to manipulate this pathway therapeutically. We have studied a panel of twenty five healthy human donors to assess the variability in their in-vitro iNKT cell expansion responses to stimulation with CD1d ligands and investigated some of the factors that may influence this phenomenon.ResultsAlthough all donors had comparable numbers of circulating iNKT cells their growth rates in-vitro over 14 days in response to a range of CD1d ligands and IL-2 were highly donor-dependent. Two reproducible donor response patterns of iNKT expansion were seen which we have called 'strong' or 'poor' iNKT responders. Donor response phenotype did not correlate with age, gender, frequency of circulating iNKT, or with the CD1d ligand utilised. Addition of exogenous recombinant human interleukin 4 (IL-4) to 'poor' responder donor cultures significantly increased their iNKT proliferative capacity, but not to levels equivalent to that of 'strong' responder donors. However in 'strong' responder donors, addition of IL-4 to their cultures did not significantly alter the frequency of iNKT cells in the expanded CD3+ population.Conclusion(i) in-vitro expansion of human iNKT cells in response to CD1d ligand activation is highly donor variable, (ii) two reproducible patterns of donor iNKT expansion were observed, which could be classified into 'strong' and 'poor' responder phenotypes, (iii) donor iNKT response phenotypes did not correlate with age, gender, frequency of circulating iNKT cells, or with the CD1d ligand utilised, (iv) addition of IL-4 to 'poor' but not 'strong' responder donor cultures significantly increased their in-vitro iNKT cell expansion to alphaGalCer.