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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biocatalysis / drug effects
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CHO Cells
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Complement C1 / metabolism
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Complement C1 Inhibitor Protein / metabolism
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Complement C1s / agonists
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Complement C1s / antagonists & inhibitors
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Complement C1s / metabolism
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Complement C3-C5 Convertases / metabolism
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Complement C3b / metabolism
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Complement C4 / antagonists & inhibitors*
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Complement C4 / metabolism
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Complement C4b / metabolism
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Complement Factor I / metabolism
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Complement Hemolytic Activity Assay
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Complement Pathway, Classical / drug effects
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Complement Pathway, Classical / immunology
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Complement Pathway, Mannose-Binding Lectin / drug effects
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Complement Pathway, Mannose-Binding Lectin / immunology
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Cricetinae
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Cricetulus
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Dengue Virus / immunology
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Enzyme Precursors / metabolism
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Guinea Pigs
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Humans
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Kinetics
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Neutralization Tests
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Protein Binding / immunology
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Viral Nonstructural Proteins / metabolism*
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Viral Nonstructural Proteins / pharmacology
Substances
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Complement C1
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Complement C1 Inhibitor Protein
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Complement C4
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Enzyme Precursors
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NS1 protein, Dengue virus type 2
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NS1 protein, Flavivirus
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Viral Nonstructural Proteins
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nonstructural protein 1, West Nile virus
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Complement C3b
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Complement C4b
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Complement C3-C5 Convertases
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Complement C1s
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Complement Factor I