Caspase-8 regulates cell death and inflammatory responses in complex respiratory infection 2259631

Abstract Introduction Lung infections represent a major global health burden, with pneumonia remaining one of the leading causes of death in the United States. Secondary bacterial pneumonia following infection with influenza A virus (IAV) significantly increases disease severity and mortality, largely due to disruption of host resistance and tolerance mechanisms. Among bacterial pathogens, Streptococcus pneumoniae (S.p) is most commonly associated with influenza co-infection, a condition characterized by excessive inflammation, tissue damage, and poor therapeutic outcomes. Macrophages, as key orchestrators of pulmonary immune responses, regulate both pathogen clearance and inflammation through tightly controlled cell death pathways. Indeed, the progression of infection relies on the ability of host cells to trigger the appropriate programmed cell death response, which is usually inflammatory (pyroptosis and necroptosis). Pathogens redirect host cell death signaling towards cell death modalities that favor their adaptation, usually anti-inflammatory (apoptosis). These mechanisms lead to the occurrence of PANoptosis, a programmed cell death that incorporates elements of pyroptosis, apoptosis, and necroptosis and where caspase-8 serves as a central regulator. Methods To study the role of caspase-8 in co-infection by IAV and S.p, we infected macrophages derived from mouse bone marrow and human macrophages (THP1 cells) with a specific deletion of caspase-8 obtained using the lox cre and CRISPR methods, respectively. Results We found that the loss of caspase-8 led to a reduction in bacterial growth but an increase in necroptotic cell death, in a manner dependent on RIPK3 and MLKL. Furthermore, caspase-8-deficient macrophages showed reduced production of IL-1β and pro-inflammatory cytokines. Conclusion These results indicate that caspase-8 plays a protective and regulatory role during co-infection by IAV and S.p. by coordinating macrophage PANoptosis through the control of inflammation and pathogen replication. Funding Source n/a Topic Categories Viral Immunology (VIR)