Tregs control the development of symptomatic West Nile virus infection in humans and mice.
West Nile virus (WNV) causes asymptomatic infection in most humans, but for undefined reasons, approximately 20% of immunocompetent individuals develop West Nile fever, a potentially debilitating febrile illness, and approximately 1% develop neuroinvasive disease syndromes. Notably, since its emergence in 1999, WNV has become the leading cause of epidemic viral encephalitis in North America. We hypothesized that CD4+ Tregs might be differentially regulated in subjects with symptomatic compared with those with asymptomatic WNV infection. Here, we show that in 32 blood donors with acute WNV infection, Tregs expanded significantly in the 3 months after index (RNA+) donations in all subjects. Symptomatic donors exhibited lower Treg frequencies from 2 weeks through 1 year after index donation yet did not show differences in systemic T cell or generalized inflammatory responses. In parallel prospective experimental studies, symptomatic WNV-infected mice also developed lower Treg frequencies compared with asymptomatic mice at 2 weeks after infection. Moreover, Treg-deficient mice developed lethal WNV infection at a higher rate than controls. Together, these results suggest that higher levels of peripheral Tregs after infection protect against severe WNV disease in immunocompetent animals and humans.
Blood Systems Research Institute, San Francisco, California 94118, USA.
Marion C
MC
Lanteri
Katie M
KM
O'Brien
Whitney E
WE
Purtha
Mark J
MJ
Cameron
Jennifer M
JM
Lund
Rachel E
RE
Owen
John W
JW
Heitman
Brian
B
Custer
Dale F
DF
Hirschkorn
Leslie H
LH
Tobler
Nancy
N
Kiely
Harry E
HE
Prince
Lishomwa C
LC
Ndhlovu
Douglas F
DF
Nixon
Hany T
HT
Kamel
David J
DJ
Kelvin
Michael P
MP
Busch
Alexander Y
AY
Rudensky
Michael S
MS
Diamond
Philip J
PJ
Norris
D000328:Adult; D000368:Aged; D000818:Animals; D001782:Blood Donors; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010641:Phenotype; D012367:RNA, Viral / Q000097:blood; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D013997:Time Factors; D014901:West Nile Fever / Q000276:immunology* / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D014902:West Nile virus / Q000502:physiology; D055815:Young Adult
D012367:RNA, Viral