Inflammation induced by influenza virus impairs innate control of human pneumococcal carriage

Simon P. Jochems; Fernando Marcon; Beatriz F. Carniel; Mark Holloway; Elena Mitsi; Emma Smith; Jenna F. Gritzfeld; Carla Solórzano; Jesús Reiné; Sherin Pojar; Elissavet Nikolaou; Esther L. German; Angie Hyder-Wright; Helen Hill; Caz Hales; Wouter A.A de Steenhuijsen Piters; Debby Bogaert; Hugh Adler; Seher Zaidi; Victoria Connor; Jamie Rylance; Helder I. Nakaya; Daniela M. Ferreira

In murine models of pneumococcal carriage, Th17-dependent recruitment of neutrophils and . We collected a series of nasal micro-biopsies and nasal lining fluid throughout the study to 80 assess ongoing cellular and cytokine responses. Participants were grouped in those who did not 81 become colonized following Spn challenge (carriage-) and those who did (carriage+), as 82 determined by classical microbiology (Fig 1a) . To investigate whether LAIV-induced immune 83 responses were associated with a predisposition to pneumococcal carriage, we measured levels of 84 30 cytokines in nasal lining fluid (Fig 1b) . At day 0, directly prior to Spn inoculation, LAIV 85 significantly increased levels of twenty cytokines after multiple testing correction, including IP-10, 86 TNF-α, IL-10, IFN-and IL-15 (Fig 1b and Table S1 ). In contrast, the control group did not show 87 any significant increase in cytokine response at day 0. Following Spn inoculation, Spn carriage in 88 the absence of LAIV was associated with increased levels of EGF at day 2 (p = 0.023) and 89 decreased levels of IL-1RA at day 9 post Spn inoculation (p = 0.027) compared to baseline, neither 90 of which remained significant after multiple testing correction. No other cytokines, including IL-17A 91 or MCP-1, were significantly altered by carriage alone (Fig 1b) . 5 become carriers (2.4-fold increase, p = 0.0008) than in those who remained carriage-negative (1.5-98 fold increase, p = 0.051). Moreover, subjects with increased levels of IP-10 before inoculation 99 displayed higher pneumococcal density following Spn inoculation (Fig 1d) . This suggests that 100 differences in the response to influenza virus are associated with secondary susceptibility to Spn.