Distinct T and NK cell populations may serve as immune correlates of protection against symptomatic pandemic influenza A(H1N1) virus infection during pregnancy.

Balaji Manicassamy,Miloje Savic,Fredrik Oftung,Olav Hungnes,Siri Mjaaland,Lill Trogstad,Rebecca Cox,Ida Laake,Jennifer L. Dembinski

doi:10.1371/journal.pone.0188055

Balaji Manicassamy, Miloje Savic + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0188055

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Abstract

Maternal influenza infection during pregnancy is associated with increased risk of morbidity and mortality. However, the link between the anti-influenza immune responses and health-related risks during infection is not well understood. We have analyzed memory T and NK cell mediated immunity (CMI) responses in pandemic influenza A(H1N1)pdm09 (pdm09) virus infected non-vaccinated pregnant women participating in the Norwegian Influenza Pregnancy Cohort (NorFlu). The cohort includes information on immunization, self-reported health and disease status, and biological samples (plasma and PBMC). Infected cases (N = 75) were defined by having a serum hemagglutination inhibition (HI) titer > = 20 to influenza pdm09 virus at the time of delivery, while controls (N = 75) were randomly selected among non-infected pregnant women (HI titer <10). In ELISpot assays cases had higher frequencies of IFNγ+ CD8+ T cells responding to pdm09 virus or conserved CD8 T cell-restricted influenza A virus epitopes, compared to controls. Within this T cell population, frequencies of CD95+ late effector (CD45RA+CCR7-) and naive (CD45RA+CCR7+) CD8+ memory T cells correlated inversely with self-reported influenza illness (ILI) symptoms. ILI symptoms in infected women were also associated with lower numbers of poly-functional (IFNγ+TNFα+, IL2+IFNγ+, IL2+IFNγ+TNFα+) CD4+ T cells and increased frequencies of IFNγ+CD3-CD7+ NK cells compared to asymptomatic cases, or controls, after stimulation with the pdm09 virus. Taken together, virus specific and functionally distinct T and NK cell populations may serve as cellular immune correlates of clinical outcomes of pandemic influenza disease in pregnant women. Our results may provide information important for future universal influenza vaccine design.

Highlights

During the 2009 influenza pandemic, pregnant women had an increased risk of severe influenza illness and adverse pregnancy outcomes [1,2,3], and 12% of pregnancy-related deaths were attributed to pandemic infection [4].The mechanisms behind influenza infection-related mortality and morbidity in pregnancy are still poorly understood, it is speculated that immune modulation required for fetal tolerance may be one of the major contributing factors [5,6,7]
We analyzed the relationship between T and natural killer (NK) cell-mediated immunity and disease severity in pregnant women infected with influenza A(H1N1)pdm09 virus during the 2009 pandemic in Norway
Influenza infected women without influenza illness (ILI) symptoms had a higher magnitude of IFNγ producing CD8+ T cells, compared to those reporting symptoms, as measured in enzyme-linked IFNγ/Granzyme B immunospot assay (ELISpot) assays after stimulation with the pdm09 virus or peptides representing conserved CD8+ T cell epitopes

Summary

Introduction

During the 2009 influenza pandemic, pregnant women had an increased risk of severe influenza illness and adverse pregnancy outcomes [1,2,3], and 12% of pregnancy-related deaths were attributed to pandemic infection [4]. The mechanisms behind influenza infection-related mortality and morbidity in pregnancy are still poorly understood, it is speculated that immune modulation required for fetal tolerance may be one of the major contributing factors [5,6,7]. CD8+ effector cells and T regulatory cells (Tregs) at the fetal-maternal interface were implicated as modulators of fetal-immune tolerance and antiviral immunity [12,13,14]

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