Complement Decay-Accelerating Factor is a modulator of influenza A virus lung immunopathology

Abstract

Clearance of viral infections, such as SARS-CoV-2 and influenza A virus (IAV), must be fine-tuned to eliminate the pathogen without causing immunopathology. As such, an aggressive initial innate immune response favors the host in contrast to a detrimental prolonged inflammation. The complement pathway bridges innate and adaptive immune system and contributes to the response by directly clearing pathogens or infected cells, as well as recruiting proinflammatory immune cells and regulating inflammation. However, the impact of modulating complement activation in viral infections is still unclear. In this work, we targeted the complement decay-accelerating factor (DAF/CD55), a surface protein that protects cells from non-specific complement attack, and analyzed its role in IAV infections. We found that DAF modulates IAV infection in vivo, via an interplay with the antigenic viral proteins hemagglutinin (HA) and neuraminidase (NA), in a strain specific manner. Our results reveal that, contrary to what could be expected, DAF potentiates complement activation, increasing the recruitment of neutrophils, monocytes and T cells. We also show that viral NA acts on the heavily sialylated DAF and propose that it exacerbates complement activation, leading to lung immunopathology. Remarkably, this mechanism has no impact on viral loads but rather on the host resilience to infection and may have direct implications in zoonotic influenza transmissions.

Altered Signal Transduction in the Immune Response to Influenza Virus and S. pneumoniae or S. aureus Co-Infections

“…The complement system recognizes the aforementioned pathogens in the early stages of infection in the upper and lower respiratory tract and bridges the innate and adaptive immune response [ 31 ]. Signal transduction is induced via specific cleavage of the complement factors C5 and C3, which serve as chemoattractants and recruit immune cells to sites of activation by binding to their anaphylatoxin receptors C5aR (CD88) and C3aR, respectively.…”

“…Binding and cleavage of DAF/CD55 by viral proteins HA and NA results in an overreaction of the complement system and leads to a massive recruitment of innate immune cells. Here, overshooting secretion of cytokines and chemokines induces tissue damage and facilitates the invasion of e.g., S. pneumoniae or S. aureus without affecting viral load [ 31 ].…”