Antagonism of the complement component C4 by flavivirus nonstructural protein NS1

Abstract

The complement system plays an essential protective role in the initial defense against many microorganisms. Flavivirus NS1 is a secreted nonstructural glycoprotein that accumulates in blood, is displayed on the surface of infected cells, and has been hypothesized to have immune evasion functions. Herein, we demonstrate that dengue virus (DENV), West Nile virus (WNV), and yellow fever virus (YFV) NS1 attenuate classical and lectin pathway activation by directly interacting with C4. Binding of NS1 to C4 reduced C4b deposition and C3 convertase (C4b2a) activity. Although NS1 bound C4b, it lacked intrinsic cofactor activity to degrade C4b, and did not block C3 convertase formation or accelerate decay of the C3 and C5 convertases. Instead, NS1 enhanced C4 cleavage by recruiting and activating the complement-specific protease C1s. By binding C1s and C4 in a complex, NS1 promotes efficient degradation of C4 to C4b. Through this mechanism, NS1 protects DENV from complement-dependent neutralization in solution. These studies define a novel immune evasion mechanism for restricting complement control of microbial infection.

The pathogenesis of dengue

“…80 NS1 promotes efficient degradation of C4 to C4b and by this mechanism, NS1 is suggested to protect DENV from complement-dependent neutralization in solution. 80 The significance of these observations with the independent observation that early NS1 concentrations in blood are positively associated with disease severity are not yet clear, but are consistent with a role for NS1 and complement in pathogenesis . 81,82 Finally, it is plausible that the low levels of complement observed in severe dengue are merely a marker of a severe systemic disease rather than an indicator of their role in capillary permeability.…”

In vitro and in vivo characterization of chimeric duck Tembusu virus based on Japanese encephalitis live vaccine strain SA14-14-2

“…Similar to other known flaviviruses, DTMUV has an approximately 11 kb single-stranded positive-sense RNA genome, which contains a single ORF that encodes three structural proteins (C, prM, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5), flanked by the 5¢ and 3¢ untranslated regions (UTRs). The structural proteins are supposed to be involved in cellular attachment, membrane fusion and virion assembly, and the nonstructural proteins are responsible for genome replication and counteraction of host immunity, in similar mechanisms to other known pathogenic flaviviruses (Avirutnan et al, 2010;Best et al, 2005;Crook et al, 2014;Jones et al, 2005;Munoz-Jordan et al, 2003;Werme et al, 2008). DTMUV is highly pathogenic for ducks, and exhibited neurotropic effects in a mouse model Tang et al, 2013).…”

Pathogenesis of Dengue Haemorrhagic Fever and Its Impact on Case Management

“…Complement activation as well as vascular permeability may be in�uenced by viral products like NS1. Different immune mechanisms in the form of antibody enhanced viral replication leading to an exaggerated cytokine response impacts vascular permeability [12][13][14].…”

“…Certain complement fragments such as C3a and C5a are known to enhance permeability. NS1 antigen in dengue virus has been shown to regulate complement activation and hence could play a role in the pathogenesis of DHF [12,13,[25][26][27]. Clearly immunopathogenic mechanisms are involved in plasma leakage and coagulopathy.…”