Emerging roles of the complement system in host–pathogen interactions

The complement system has historically been entertained as a fluid-phase, hepatically derived system which protects the intravascular space from encapsulated bacteria. However, there has been an increasing appreciation for its role in protection against non-encapsulated pathogens. Specifically, we have an improved understanding of how pathogens are recognized by specific complement proteins, as well as how they trigger and evade them. Additionally, we have an improved understanding of locally derived complement proteins, many of which promote host defense. Moreover, intracellular complement proteins have been identified that facilitate local protection and barrier function despite pathogen invasion. Our review aims to summarize these advances in the field as well as provide an insight into the pathophysiological changes occurring when the system is dysregulated in infection. Novel pattern-recognition molecules trigger the complement cascade and, in certain cases, may downregulate components of the system with the goal of evading the host immune response.Genetic and acquired deficiencies of certain complement components are associated with a higher risk of bacterial infections.Extrahepatic complement proteins modulate host defense, especially in the context of intracellular bacteria.Intracellular complement proteins, derived from both biosynthesis and uptake, play critical roles in cellular survival, pathogen burden, and effector function.Structural proteins on the surface of viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), contribute to increased complement activation, which is associated with a hyperinflammatory response and worse outcomes.