Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza.
BACKGROUND
Human host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1.


METHODS
We profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene.


RESULTS
Increased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1beta), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-gamma) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-alpha, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients.


CONCLUSIONS
While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness.
Bermejo-Martin
Jesus F
JF
National Centre of Influenza, Hospital Clínico Universitario de Valladolid, Valladolid, Spain. jfbermejo@saludcastillayleon.es
Ortiz de Lejarazu
Raul
R
Pumarola
Tomas
T
Rello
Jordi
J
Almansa
Raquel
R
Ramírez
Paula
P
Martin-Loeches
Ignacio
I
Varillas
David
D
Gallegos
Maria C
MC
Serón
Carlos
C
Micheloud
Dariela
D
Gomez
Jose Manuel
JM
Tenorio-Abreu
Alberto
A
Ramos
María J
MJ
Molina
M Lourdes
ML
Huidobro
Samantha
S
Sanchez
Elia
E
Gordón
Mónica
M
Fernández
Victoria
V
Del Castillo
Alberto
A
Marcos
Ma Angeles
MA
Villanueva
Beatriz
B
López
Carlos Javier
CJ
Rodríguez-Domínguez
Mario
M
Galan
Juan-Carlos
JC
Cantón
Rafael
R
Lietor
Aurora
A
Rojo
Silvia
S
Eiros
Jose M
JM
Hinojosa
Carmen
C
Gonzalez
Isabel
I
Torner
Nuria
N
Banner
David
D
Leon
Alberto
A
Cuesta
Pablo
P
Rowe
Thomas
T
Kelvin
David J
DJ
D000328:Adult; D018925:Chemokines / Q000097:blood*; D016207:Cytokines / Q000097:blood*; D017931:DNA Primers; D005260:Female; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics; D007251:Influenza, Human / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D007362:Intensive Care Units; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D012367:RNA, Viral / Q000302:isolation & purification; D012720:Severity of Illness Index; D018417:Th1 Cells / Q000502:physiology; D019562:Viral Load
D018925:Chemokines; D016207:Cytokines; D017931:DNA Primers; D012367:RNA, Viral