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 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.

AhR Activation Leads to Attenuation of Murine Autoimmune Hepatitis: Single-Cell RNA-Seq Analysis Reveals Unique Immune Cell Phenotypes and Gene Expression Changes in the Liver

“…In the current study, the use of scRNA-seq led to some surprising observations such as the changes occurring in the B cell compartment, especially CD55+ B cells, because ConA is a polyclonal T cell mitogen. CD55, also called Decay Accelerating Factor, is a regulatory protein involved in complement activation and has been shown to be modulated in many infections and diseases (66)(67)(68)(69). An increase in the surface expression of CD55 has been associated with inhibition of complement system activation (69).…”

Immunometabolic Signature during Respiratory Viral Infection: A Potential Target for Host-Directed Therapies

“…Viral antigens processed by the complement system also activate the adaptive response [ 243 ], enhancing Th1 response [ 244 ] and B cell memory viability [ 245 ] and modulating Treg and Th17 responses [ 246 ]. The antiviral response triggered by the complement system is essential in the neutralization of respiratory viruses; however, recent data have shown that its hyperactivation is behind severe cases of SARS-CoV-2 [ 247 , 248 , 249 , 250 ] and influenza [ 251 , 252 ] virus infection.…”