Savic Miloje, Dembinski Jennifer L, Laake Ida, Hungnes Olav, Cox Rebecca, Oftung Fredrik, Trogstad Lill, Mjaaland Siri
Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
KG Jebsen Centre for Influenza Vaccine Research, Oslo-Bergen, Norway.
PLoS One. 2017 Nov 16;12(11):e0188055. doi: 10.1371/journal.pone.0188055. eCollection 2017.
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.
孕期母体感染流感与发病和死亡风险增加有关。然而，感染期间抗流感免疫反应与健康相关风险之间的联系尚未得到充分理解。我们分析了参与挪威流感妊娠队列（NorFlu）的甲型H1N1流感大流行（pdm09）病毒感染且未接种疫苗的孕妇中记忆性T细胞和自然杀伤（NK）细胞介导的免疫（CMI）反应。该队列包含免疫接种、自我报告的健康和疾病状况以及生物样本（血浆和外周血单核细胞）信息。感染病例（N = 75）定义为分娩时血清血凝抑制（HI）效价≥20针对pdm09流感病毒，而对照（N = 75）是从未感染孕妇（HI效价<10）中随机选取的。在酶联免疫斑点试验中，与对照相比，病例中对pdm09病毒或保守的CD8 T细胞限制性甲型流感病毒表位产生IFNγ + CD8 + T细胞的频率更高。在这个T细胞群体中，CD95 + 晚期效应细胞（CD45RA + CCR7 - ）和初始（CD45RA + CCR7 + ）CD8 + 记忆T细胞的频率与自我报告的流感样疾病（ILI）症状呈负相关。与无症状病例或对照相比，pdm09病毒刺激后，感染女性的ILI症状还与多功能（IFNγ + TNFα + 、IL2 + IFNγ + 、IL2 + IFNγ + TNFα + ）CD4 + T细胞数量减少以及IFNγ + CD3 - CD7 + NK细胞频率增加有关。综上所述，病毒特异性且功能不同的T细胞和NK细胞群体可能作为孕妇大流行性流感疾病临床结局的细胞免疫相关指标。我们的结果可能为未来通用流感疫苗设计提供重要信息。
