Complement and complement regulatory proteins are upregulated in lungs of COVID-19 patients.

We explored the pathological changes and the activation of local complement system in COVID-19 pneumonia. Lung paraffin sections of COVID-19 infected patients were analyzed by HE (hematoxylin-eosin) staining. The deposition of complement C3, the deposition of C3b/iC3b/C3d and C5b-9, and the expression of complement regulatory proteins, CD59, CD46 and CD55 were detected by immunohistochemistry. In COVID-19 patients' lung tissues, fibrin exudation, mixed with erythrocyte, alveolar macrophage and shed pneumocyte are usually observed in the alveoli. The formation of an "alveolar emboli" structure may contribute to thrombosis and consolidation in lung tissue. In addition, we also found that compared to normal tissue, the lung tissues of COVID-19 patients displayed the hyper-activation of complement that is represented by extensive deposition of C3, C3b/iC3b/C3d and C5b-9, and the increased expression level of complement regulatory proteins CD55, and especially CD59 but not CD46. The thrombosis and consolidation in lung tissues may contribute to the pathogenesis of COVID-19. The increased expression of CD55 and CD59 may reflect a feedback of self-protection on the complement hyper-activation. Further, the increased C3 deposition and the strongly activated complement system in lung tissues may suggest the rationale of complement-targeted therapeutics in conquering COVID-19.

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

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 the NA-dependent DAF removal of sialic acids 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.