Severe Pandemic H1N1 2009 Infection Is Associated with Transient NK and T Deficiency and Aberrant CD8 Responses

Abstract

BackgroundIt is unclear why the severity of influenza varies in healthy adults or why the burden of severe influenza shifts to young adults when pandemic strains emerge. One possibility is that cross-protective T cell responses wane in this age group in the absence of recent infection. We therefore compared the acute cellular immune response in previously healthy adults with severe versus mild pandemic H1N1 infection.Methods and Principal Findings49 previously healthy adults admitted to the National Hospital of Tropical Diseases, Viet Nam with RT-PCR-confirmed 2009 H1N1 infection were prospectively enrolled. 39 recovered quickly whereas 10 developed severe symptoms requiring supplemental oxygen and prolonged hospitalization. Peripheral blood lymphocyte subset counts and activation (HLADR, CD38) and differentiation (CD27, CD28) marker expression were determined on days 0, 2, 5, 10, 14 and 28 by flow cytometry. NK, CD4 and CD8 lymphopenia developed in 100%, 90% and 60% of severe cases versus 13% (p<0.001), 28%, (p = 0.001) and 18% (p = 0.014) of mild cases. CD4 and NK counts normalized following recovery. B cell counts were not significantly associated with severity. CD8 activation peaked 6–8 days after mild influenza onset, when 13% (6–22%) were HLADR+CD38+, and was accompanied by a significant loss of resting/CD27+CD28+ cells without accumulation of CD27+CD28− or CD27−CD28− cells. In severe influenza CD8 activation peaked more than 9 days post-onset, and/or was excessive (30–90% HLADR+CD38+) in association with accumulation of CD27+CD28− cells and maintenance of CD8 counts.ConclusionSevere influenza is associated with transient T and NK cell deficiency. CD8 phenotype changes during mild influenza are consistent with a rapidly resolving memory response whereas in severe influenza activation is either delayed or excessive, and partially differentiated cells accumulate within blood indicating that recruitment of effector cells to the lung could be impaired.

Early Responses of Natural Killer Cells in Pigs Experimentally Infected with 2009 Pandemic H1N1 Influenza A Virus

“…Hence, the reduction of NKp46 + NK cells was not unique, but did differ from NKp46 − NK cells, which increased in numbers. A similar reduction of CD3 − CD56 + NK cells has been observed in humans with influenza, leading to the hypothesis that NK cells are recruited to the lungs to participate in the defence against the influenza virus [6], [7]. In this study, immunofluorescence staining of lung tissue sections from pigs infected with influenza virus demonstrated a clear difference in the numbers of NKp46 + cells in areas infected with virus, compared to uninfected areas from the same animal.…”

“…The more pronounced NK cell response seen in the second study indicates that the type of virus and severity of the disease may influence the NK cell response in pigs. In humans, a more marked reduction of NK cell numbers in blood has been observed in severe cases of influenza when compared to mild cases [6]. Different influenza viruses have also been shown to activate NK cells to varying extents in vitro [43], [44].…”

Generation and Protective Ability of Influenza Virus–Specific Antibody-Dependent Cellular Cytotoxicity in Humans Elicited by Vaccination, Natural Infection, and Experimental Challenge

“…The data suggest that high levels of homologous ADCC-Abs provide some reduction in viral replication and clinical symptoms. The ability of ADCC-Abs to protect is likely influenced by several factors, including concentration of immunoglobulin G in the upper respiratory tract [23], the availability of cells with CD16 receptor [24,25], and licensing of NK cells [26,27]. Further, ADCC-Abs may play a more significant role in lower respiratory tract infection, as seen in severe clinical disease and mouse models, rather than in the upper respiratory tract infection that occurs in influenza experimental challenge studies.…”

Antibody-Dependent Cellular Cytotoxicity Is Associated with Control of Pandemic H1N1 Influenza Virus Infection of Macaques

“…NK cells infiltrate the lungs early during influenza virus infection and aid in direct viral clearance (35)(36)(37). NK cells can mediate effector functions via ADCC, by recognizing whole virus or viral antigens on the surfaces of infected cells.…”