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.
Medical Molecular Biology Unit, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Panisadee
P
Avirutnan
Nuntaya
N
Punyadee
Sansanee
S
Noisakran
Chulaluk
C
Komoltri
Somchai
S
Thiemmeca
Kusuma
K
Auethavornanan
Aroonroong
A
Jairungsri
Rattiyaporn
R
Kanlaya
Nattaya
N
Tangthawornchaikul
Chunya
C
Puttikhunt
Sa-Nga
SN
Pattanakitsakul
Pa-Thai
PT
Yenchitsomanus
Juthathip
J
Mongkolsapaya
Watchara
W
Kasinrerk
Nopporn
N
Sittisombut
Matthias
M
Husmann
Maria
M
Blettner
Sirijitt
S
Vasanawathana
Sucharit
S
Bhakdi
Prida
P
Malasit
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