Influenza during pregnancy: The emergence of highly virulent H1N1 influenza virus strains and consequences for maternal and offspring’s health

与一般人群相比，孕妇更容易患上严重甚至致命的流感。在2009年H1N1流感大流行期间，反复观察到孕妇的高发病率和高死亡率。我们先前建立了妊娠小鼠流感病毒感染模型，该模型再现了在病程严重的孕妇中观察到的临床特征。在KFO296的第一个资助期内获得的小鼠模型的见解显示，与未怀孕的宿主相比，怀孕小鼠的抗病毒免疫反应显着受到限制。这包括I型干扰素反应降低以及CD8+ T细胞向肺的迁移受损。在同种异体妊娠小鼠中产生抗病毒应答的多方面失败导致了不太严格的选择环境，促进了2009年H1N1病毒变体的出现，这些变体特异性地抵消了I型干扰素应答并介导了病毒致病性的增加。因此，在这个项目的延续中，我们现在寻求一种转化方法，在这种方法中，我们将描述从孕妇分离的流感病毒是否存在致病性增加的先天免疫逃逸变异。有趣的是，我们应用类固醇激素黄体酮来反映非怀孕小鼠的妊娠样内分泌环境，结果显示死亡率增加，这表明黄体酮参与抑制宿主对H1N1大流行病毒的免疫反应。因此，另一个重点将是了解黄体酮如何影响抗病毒先天和适应性免疫反应。此外，我们将分析母体微嵌合作为长期调节后代对流感病毒感染的健康的潜在因素。总之，我们的项目将阐明介导孕妇严重流感的潜在机制，并可能影响后代的免疫反应。从这一建议中获得的结果将强调目前孕妇疫苗接种依从性差的重要性，并可能进一步开辟新的治疗途径。

Compared to the general population, pregnant women are more likely to suffer from severe and even fatal influenza. During the 2009 H1N1 influenza pandemic, high morbidity and mortality rates were repeatedly observed among pregnant women. We have previously established an influenza virus infection model in pregnant mice, which reproduces the clinical features observed in pregnant women with severe courses of disease. Insights arising from this mouse model obtained during the first funding period of the KFO296 revealed that the anti-viral immune response in the pregnant mouse was significantly restricted as compared to the non-pregnant host. This included a reduced type I interferon response as well as impaired migration of CD8+ T cells into the lung. The multi-faceted failure to mount an anti-viral response in allogenic pregnant mice resulted in a less stringent selective environment that promoted the emergence of 2009 H1N1 virus variants that specifically counteract type I interferon response and mediate increased viral pathogenicity. Thus, in continuation of this project, we now seek to pursue a translational approach, in which we will characterise influenza virus isolates from pregnant women for the presence of innate immune escape variants with increased pathogenicity. Interestingly, our application of the steroid hormone progesterone in order to mirror a pregnancy-like endocrine milieu in non-pregnant mice, revealed an increased mortality, suggesting that progesterone is involved in dampening the host’s immune response against pandemic H1N1 virus. Thus, another focus will be to understand how progesterone may affect the anti-viral innate and adaptive immune response. Moreover, we will analyse maternal microchimerism as a potential factor to modulate offspring’s health towards influenza virus infections in the long-term. In summary, our project will elucidate underlying mechanisms that mediate severe influenza in pregnant women and potentially affect offspring’s immune response. Results obtained from this proposal will underscore the importance of the currently poor vaccination compliance in pregnant women and might further open novel therapeutic avenues.