GM-CSF shields IAV-infected mice from bacterial superinfection - 20/03/24

Influenza A virus (IAV) infection predisposes to subsequent bacterial superinfection in the lungs. Streptococcus pneumoniae (Sp) is the main bacteria involved in this co-infection process and promotes a greater pneumonia severity. Because alveolar macrophages (AM) are critical in maintaining alveoli homeostasis, we suspect an IAV-induced dysfunction of the lung granulocyte macrophages stimulating colony factor (GM-CSF) production that drives the AM function. The aim of the study is (i) to examine if a defective GM-CSF signaling could be evidenced during IAV infection and, (ii) to assess whether administration of GM-CSF protects mice from Sp superinfection.

We compared GM-CSF production in bronchoalveolar lavage (BAL) from IAV infected mice and human. c57BL/6J mice were infected by a mild inoculum of influenza A virus (IAV, H3N2, 10 PFU) by intranasal route (IN). GM-CSF concentration in human BAL was obtained from patients with PCR-confirmed influenza infection and a BAL performed within the four firth days of ICU admission. Next, we performed a bioinformatic analysis based on publicly available AM transcriptomic datasets collected in IAV-infected mice and Csf2 (colony stimulating factor 2)-/- mice. From Csf2-/- mice, we defined genes that are altered when the GM-CSF instruction is defective. Using the transcriptome dataset of AM from IAV-infected mice (and control) we assessed whether AM presented a GM-CSF defective signature. Finally, IAV-infected mice were treated by GM-CSF (IN, 10μg/mouse) at day 0, 2- and 4-days post-infection (dpi), and superinfected at dpi 7 by Sp (IN, SP1 strain). We monitored weight, survival and AM count.

A lung GM-CSF production was observed in BAL of IAV-infected patient, but not in mice. In AM collected from IAV-infected mice, nearly all the genes whose expression reflect the lack of GM-CSF instruction were up regulated (n=25/28). Moreover, AM count dropped drastically after IAV-infection: AM represented only 35% from baseline AM count in BAL at dpi 7. However, IAV-induced AM depletion was significantly less important in mice treated with GM-CSF (62% from baseline count). Results were similar when studying AM count in BAL or lung homogenate. Finally, GM-CSF administration in IAV-infected mice reduced mortality by 50% of Sp – superinfection (preliminary data).

It is likely that there are alterations of the GM-CSF instruction post-IAV infection that prevents efficient AM immune function, as reveal by the murine models. Consistently, GM-CSF administration prevents mAMs depletion and mortality due to bacterial superinfection in IAV-infected mice. These data underline the potential protective role of GM-CSF during influenza infection.