Complement-Related Proteins Control the Flavivirus Infection of Aedes aegypti by Inducing Antimicrobial Peptides

Abstract

The complement system functions during the early phase of infection and directly mediates pathogen elimination. The recent identification of complement-like factors in arthropods indicates that this system shares common ancestry in vertebrates and invertebrates as an immune defense mechanism. Thioester (TE)-containing proteins (TEPs), which show high similarity to mammalian complement C3, are thought to play a key role in innate immunity in arthropods. Herein, we report that a viral recognition cascade composed of two complement-related proteins limits the flaviviral infection of Aedes aegypti. An A. aegypti macroglobulin complement-related factor (AaMCR), belonging to the insect TEP family, is a crucial effector in opposing the flaviviral infection of A. aegypti. However, AaMCR does not directly interact with DENV, and its antiviral effect requires an A. aegypti homologue of scavenger receptor-C (AaSR-C), which interacts with DENV and AaMCR simultaneously in vitro and in vivo. Furthermore, recognition of DENV by the AaSR-C/AaMCR axis regulates the expression of antimicrobial peptides (AMPs), which exerts potent anti-DENV activity. Our results both demonstrate the existence of a viral recognition pathway that controls the flaviviral infection by inducing AMPs and offer insights into a previously unappreciated antiviral function of the complement-like system in arthropods.

Mosquito Defense Strategies against Viral Infection

“…Hemocytes, which share similarity to mammalian hematogenous cells, are the major cell types in the hemolymph. Although mosquito hemocytes are permissive for the replication of multiple arboviruses [9,67], cellular and humoral immunity in the hemolymph plays an important role in limiting systemic dissemination of arboviruses (Figure 1C) [68]. One of the antiviral mechanisms in the hemolymph is the extracellular phenoloxidase (PO) cascade, which is a humoral immune response that produces cytotoxic intermediates and the formation of melanin following wounding or infection [69,70].…”

“…In addition to PO-mediated humoral immunity in the mosquito hemolymph, a recent study reported an extracellular pattern recognition mechanism mediated by dual complement-like proteins highly expressed in hemocytes that limited flaviviral infection of A. aegypti by inducing AMPs [68] (Figure 1C). The mammalian complement system is activated during the early phase of viral invasion.…”

“…Recently, a role for TEPs in flavivirus infection was elucidated in A. aegypti . A member of the TEPs designated macroglobulin complement-related factor ( AaMCR ) was identified as an immune factor crucial for opposing flavivirus infection in A. aegypti [68,82]. AaMCR is incapable of directly depositing on the flaviviral surface for elimination; instead, it employs a scavenger receptor (AaSR-C) with complement-related domains to capture DENV and subsequently exerts its potent antiviral role by inducing multiple AMPs during the early stage of viral infection [68].…”

“…A member of the TEPs designated macroglobulin complement-related factor ( AaMCR ) was identified as an immune factor crucial for opposing flavivirus infection in A. aegypti [68,82]. AaMCR is incapable of directly depositing on the flaviviral surface for elimination; instead, it employs a scavenger receptor (AaSR-C) with complement-related domains to capture DENV and subsequently exerts its potent antiviral role by inducing multiple AMPs during the early stage of viral infection [68]. In addition to the axis of complement-like factors, other immune signaling cascades in hemocytes (i.e., the Toll, Imd and JAK-STAT pathways) may also play a role in the induction of AMPs or other antiviral effectors [46,53].…”

“…Additionally, multiple immune components belonging to the Imd and Toll signaling pathways were up-regulated following DENV infection of A. aegypti salivary glands, thereby indicating that both the Imd and Toll pathways might participate in innate immunity against DENV infection of the salivary glands and mediate the induction of the cecropin-like effector to restrict viral propagation [45]. The complement-like factors AaMCR and AaSR-C are also expressed at mild levels in A. aegypti salivary glands, suggesting a potential role in viral recognition and AMPs induction [68]. A recent investigation identified more anti-DENV inducible factors in the salivary glands.…”