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，多次观察到孕妇的高发病率和死亡率。我们先前已经在妊娠小鼠中建立了流感病毒感染模型，该模型再现了在具有严重病程的妊娠妇女中观察到的临床特征。在KFO 296的第一个资助期内获得的该小鼠模型的见解显示，与非妊娠宿主相比，妊娠小鼠的抗病毒免疫应答显著受限。这包括I型干扰素反应降低以及CD8+ T细胞向肺中的迁移受损。在同种异体妊娠小鼠中建立抗病毒应答的多方面失败导致了不太严格的选择性环境，这促进了2009年H1N1病毒变异体的出现，这些变异体特异性地抵消I型干扰素应答并介导增加的病毒致病性。因此，为了继续这个项目，我们现在寻求一种翻译方法，在这种方法中，我们将从孕妇中分离出流感病毒，以检测致病性增加的先天免疫逃逸变体的存在。有趣的是，我们应用类固醇激素孕酮以反映非妊娠小鼠中的妊娠样内分泌环境，显示死亡率增加，表明孕酮参与抑制宿主对大流行性H1N1病毒的免疫应答。因此，另一个重点将是了解孕酮如何影响抗病毒的先天性和适应性免疫反应。此外，我们将分析母体微嵌合体作为一个潜在的因素，以调节后代的健康对流感病毒感染的长期。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。从这一提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.