The Complement System in Flavivirus Infections

Abstract

The incidence of flavivirus infections has increased dramatically in recent decades in tropical and sub-tropical climates worldwide, affecting hundreds of millions of people each year. The Flaviviridae family includes dengue, West Nile, Zika, Japanese encephalitis, and yellow fever viruses that are typically transmitted by mosquitoes or ticks, and cause a wide range of symptoms, such as fever, shock, meningitis, paralysis, birth defects, and death. The flavivirus genome is composed of a single positive-sense RNA molecule encoding a single viral polyprotein. This polyprotein is further processed by viral and host proteases into three structural proteins (C, prM/M, E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) that are involved in viral replication and pathogenicity. The complement system has been described to play an important role in flavivirus infection either by protecting the host and/or by influencing disease pathogenesis. In this mini-review, we will explore the role of complement system inhibition and/or activation against infection by the Flavivirus genus, with an emphasis on dengue and West Nile viruses.

Vero Cell Proteomic Changes Induced by Zika Virus Infection

“…The activation of innate immunity leads to the activation of the complement cascade in response to viral infection. Complement components inhibit flavivirus infections such as Dengue, West Nile, and Yellow Fever at the replication level or by inducing inflammatory responses which lead to increases in the severity of disease . IPA predicted the activation of the complement cascade in our study by 24 hpi.…”

“…IPA predicted the activation of the complement cascade in our study by 24 hpi. During infection, viral NS1, one of the nonstructural proteins produced after cleavage of the viral polyprotein by host and viral proteases, aids viral pathogenesis by interaction with complement proteins and regulators involved in the complement cascade . Complement 4, which plays a role in the alternate and the classical complement pathways, is cleaved by C4‐NSI into two subunits, C4a (an anaphylatoxin) and C4b (opsonin) which aid in elimination of viral particles .…”

Zika virus infection studies with CD34+ hematopoietic and megakaryocyte‐erythroid progenitors, red blood cells and platelets

“…Notably, preliminary experiments indicated that ZIKV infection of CD34 + HSPCs did neither inhibit cell growth nor prevented differentiation of erythroid and megakaryocytic cells (data not shown) as it is reported for other viruses such as DENV. [81][82][83][84] Thus, we speculate that thrombocytopenia and anemia in ZIKV-infected patients might be explained by cell damage due to an overshooting immune response 84,85 or ZIKV-induced impairment of blood vessel integrity or development [86][87][88] rather than by a direct interaction of ZIKV with erythroid and megakaryocytic cells. However, further investigations are crucial to unravel the connection of ZIKV pathogenicity and symptoms manifestation towards the prevention and cure of ZIKV infections.…”

The dengue virus non-structural protein 1 (NS1) use the scavenger receptor B1 as cell receptor in human hepatic and mosquito cells

“…The DENV, soluble circulating NS1 has been involved in several pathogenic mechanisms during the infection process. It has been reported NS1 can affect the complement pathway promoting the degradation of C4 protein, alters the coagulation system inhibiting the activation of prothrombin (reviewed by Conde et al, 2017). NS1 can also disrupts endothelium integrity, promoting an increase in the vascular permeability after internalization by endocytosis, that may be related to plasma leakage (Glasner et al, 2017; Puerta-Guardo et al, 2019; Wang et al, 2019).…”