Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement.
BACKGROUND
Vascular leakage and shock are the major causes of death in patients with dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Thirty years ago, complement activation was proposed to be a key underlying event, but the cause of complement activation has remained unknown.


METHODS
The major nonstructural dengue virus (DV) protein NS1 was tested for its capacity to activate human complement in its membrane-associated and soluble forms. Plasma samples from 163 patients with DV infection and from 19 patients with other febrile illnesses were prospectively analyzed for viral load and for levels of NS1 and complement-activation products. Blood and pleural fluids from 9 patients with DSS were also analyzed.


RESULTS
Soluble NS1 activated complement to completion, and activation was enhanced by polyclonal and monoclonal antibodies against NS1. Complement was also activated by cell-associated NS1 in the presence of specific antibodies. Plasma levels of NS1 and terminal SC5b-9 complexes correlated with disease severity. Large amounts of NS1, complement anaphylatoxin C5a, and the terminal complement complex SC5b-9 were present in pleural fluids from patients with DSS.


CONCLUSIONS
Complement activation mediated by NS1 leads to local and systemic generation of anaphylatoxins and SC5b-9, which may contribute to the pathogenesis of the vascular leakage that occurs in patients with DHF/DSS.
Avirutnan
Panisadee
P
Medical Molecular Biology Unit, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Punyadee
Nuntaya
N
Noisakran
Sansanee
S
Komoltri
Chulaluk
C
Thiemmeca
Somchai
S
Auethavornanan
Kusuma
K
Jairungsri
Aroonroong
A
Kanlaya
Rattiyaporn
R
Tangthawornchaikul
Nattaya
N
Puttikhunt
Chunya
C
Pattanakitsakul
Sa-Nga
SN
Yenchitsomanus
Pa-Thai
PT
Mongkolsapaya
Juthathip
J
Kasinrerk
Watchara
W
Sittisombut
Nopporn
N
Husmann
Matthias
M
Blettner
Maria
M
Vasanawathana
Sirijitt
S
Bhakdi
Sucharit
S
Malasit
Prida
P
D000293:Adolescent; D000914:Antibodies, Viral / Q000276:immunology; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D015936:Complement C5a / Q000032:analysis; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins / Q000032:analysis / Q000502:physiology*; D003715:Dengue / Q000503:physiopathology*; D003716:Dengue Virus / Q000502:physiology*; D005260:Female; D006023:Glycoproteins / Q000032:analysis / Q000502:physiology; D006801:Humans; D008297:Male; D035422:Pleural Cavity / Q000737:chemistry; D012367:RNA, Viral / Q000032:analysis; D014652:Vascular Diseases / Q000821:virology*; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000032:analysis / Q000502:physiology*
D000914:Antibodies, Viral; D015938:Complement Membrane Attack Complex; D006023:Glycoproteins; D012367:RNA, Viral; C047610:SC5b-9 protein complex; D017361:Viral Nonstructural Proteins; D015936:Complement C5a; D003165:Complement System Proteins