The long pentraxin PTX3 as a functional ancestor of antibodies in the immune response to Aspergillus fumigatus

Abstract

Invasive aspergillosis (IA) is a life-threatening infection amongst immunocompromised individuals primarily caused by the opportunistic fungus Aspergillus fumigatus (AF). A key role in the early immune response to AF is played by the complement system, an essential component of the humoral arm of innate immunity that includes three distinct activation pathways: classical, lectin and alternative (CP, LP and AP, respectively). Other soluble pattern recognition molecules (PRMs) are known to cooperate with complement in the handling of AF, including collectins, ficolins and pentraxins. In particular, the long pentraxin PTX3 exerts non-redundant protective roles against AF. PTX3 is a functional ancestor of antibodies: it has opsonic activity towards AF, and enhances recognition, phagocytosis and killing of fungal conidia by immune cells, mainly polymorphonuclear neutrophils (PMNs), via complement and Fc receptors (FcRs) pathways. Ptx3-null mice are highly susceptible to IA and treatment with the exogenous protein has therapeutic efficacy in several models of IA in immunocompromised hosts. Furthermore, epidemiologic evidence indicates that variation in the ptx3 gene is associated with the risk of IA in human stem cell transplant recipients and invasive mold infections in acute leukemia patients. Here, I characterized the molecular mechanisms underlying the role of PTX3 in the opsono-phagocytosis and killing of AF conidia by human and murine PMNs, both in vitro and in vivo. I found that PTX3 promotes the selective recruitment of C3b on the wall of AF conidia, by exclusively targeting the AP of complement. Factor H (major inhibitor of the AP) is required for this process, thus pointing to a novel function (activating rather inhibitory) of this complement regulator when combined with PTX3. Also, complement receptor 1 (CR1, primary receptor of C3b), recognizes the PTX3-bound C3b on AF conidia and facilitates their uptake and killing by PMNs. Therefore, I identified a novel functional axis involving factor H, C3b and CR1 that supports the pro-phagocytic and pro-killing activities of PTX3 in antifungal immunity, and opens new vistas on the crosstalk between fundamental humoral components of the innate immune system.