Alteration of Flt3-Ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to respiratory bacterial superinfection

Abstract

Secondary bacterial infections contribute to the excess morbidity and mortality of influenza A virus (IAV) infection. Disruption of lung integrity and impaired antibacterial immunity during IAV infection participate in colonization and dissemination of the bacteria out of the lungs. One key feature of IAV infection is the profound alteration of lung myeloid cells, characterized by the recruitment of deleterious inflammatory monocytes. We herein report that IAV infection causes a transient decrease of lung conventional dendritic cells (cDCs) (both cDC1 and cDC2) peaking at day 7 post-infection. While triggering emergency monopoiesis, IAV transiently altered the differentiation of cDCs in the bone marrow, the cDC1-biaised pre-DCs being particularly affected. The impaired cDC differentiation during IAV infection was independent of type I interferons (IFNs), IFN-γ, TNFα and IL-6 and was not due to an intrinsic dysfunction of cDC precursors. The alteration of cDC differentiation was associated with a drop of local and systemic production of Fms-like tyrosine kinase 3 ligand (Flt3-L), a critical cDC differentiation factor. Overexpression of Flt3-L during IAV infection boosted the cDC progenitors’ production in the BM, replenished cDCs in the lungs, decreased inflammatory monocytes’ infiltration and lowered lung damages. This was associated with partial protection against secondary pneumococcal infection, as reflected by reduced bacterial dissemination and prolonged survival. These findings highlight the impact of distal viral infection on cDC genesis in the BM and suggest that Flt3-L may have potential applications in the control of secondary infections.

Assessment of enhanced influenza vaccination finds that FluAd conveys an advantage in mice and older adults

“…Vaccine‐mediated protection was further assessed by lethal H3N2‐1968 challenge at long‐term (6 months) and short‐term (21 days) memory time points post‐vaccination. Consistent with our vaccine immunogenicity results, A‐eIIV showed superiority during infection by reducing lung inflammation and increasing Th1 and Th2 cytokines that are key for viral clearance . The H3N2‐1968 HA‐specific antibody response from A‐eIIV, most importantly lung IgA, was recalled at a higher magnitude and avidity compared with other vaccine groups.…”

“…Consistent with our vaccine immunogenicity results, A-eIIV showed superiority during infection by reducing lung inflammation and increasing Th1 and Th2 cytokines that are key for viral clearance. 37,38 The H3N2-1968 HA-specific antibody response from A-eIIV, most importantly lung IgA, was recalled at a higher magnitude and avidity compared with other vaccine groups. Influenza-specific polyfunctional CD8 + T cells and B cells were also selectively recalled by the A-eIIV long-term memory response, unlike other vaccine groups.…”

Viral strategies predisposing to respiratory bacterial superinfections

“…69 Moreover, partial protection against secondary pneumococcal infection was observed, suggesting a potential mitigating role for FLT3-L on secondary bacterial superinfections. 69…”

Antibiotic-related gut dysbiosis induces lung immunodepression and worsens lung infection in mice.

“…Administration of human Flt3-Ligand into mice increases DC-marker positive cells in the bone marrow, liver, Peyer's patches, thymus, peritoneum, and lung [15]. In a murine model of in uenza A virus infection, Beshara et al showed that Flt3-L overexpression reduced the dissemination of S. pneumoniae instilled into the lungs by enhancing bone-marrow cDC progenitors and restoring lung cDCs [16]. These results suggest that its protective effect is not limited to P. aeruginosa.…”