H1N1 influenza virus infection results in adverse pregnancy outcomes by disrupting tissue-specific hormonal regulation.
H1N1 influenza virus infection results in adverse pregnancy outcomes by disrupting tissue-specific hormonal regulation.
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DOI：
10.1371/journal.ppat.1006757
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发表时间：
2017-11
期刊：
影响因子：
6.7
通讯作者：
Skountzou I
中科院分区：
文献类型：
--
作者：
Littauer EQ;Esser ES;Antao OQ;Vassilieva EV;Compans RW;Skountzou I
怀孕期间对流感病毒感染的易感性增加归因于在怀孕前和怀孕期间发生的免疫学变化，以“耐受”发育中的胎儿。这些全身性变化最常见的特征是细胞介导的免疫抑制和体液免疫反应的升高，称为Th1-Th2转变。然而，孕妇感染流感病毒后增加风险的潜在机制尚未完全阐明。我们使用怀孕中晚期的BALB/c小鼠来确定亚致死性感染A/Brisbane/59/07 H1N1季节性流感病毒对妊娠完成的影响。母亲和胎儿的健康状况受到密切监测，并与受感染的非怀孕小鼠进行比较。妊娠期感染的严重程度与羊膜早破、胎儿存活率和出生时体重、肺部病毒载量以及先天和获得性免疫反应介导的全身和组织炎症程度有关。在此，我们报告流感病毒感染导致炎症反应的失调，从而导致早产、胎儿生长发育障碍、增加胎儿死亡率和孕产妇发病率。我们观察到显著的脑室特异性免疫反应与激素合成和调节的变化相关。孕酮、环氧合酶-2、前列腺素E_2和前列腺素F_2α的表达异常伴随着感染后早期胎盘结构的显著重塑和基质金属蛋白酶-9的上调。总而言之，这些发现证明了季节性流感病毒启动一种强大的促流产机制的潜力，并对胎儿健康造成不利后果。母体免疫学得到了很好的平衡，为发育中的胎儿维持了一个宽容和支持的分子环境，同时继续监测外来微生物的威胁。怀孕期间的流感病毒感染对母亲及其新生儿是一个重大的临床风险，在世界范围内增加了住院、早产、低出生体重以及孕产妇和新生儿死亡。在小鼠怀孕模型中，我们展示了流感病毒感染如何扰乱对呼吸道病原体做出反应的微妙和相互关联的细胞因子和激素信号通路。在我们的研究中，孕妇的肺和胎盘结构因感染而受损，母子的健康受到了影响。流感病毒感染增加了母亲因怀孕已经存在的身体压力，或逆转了建立和维持健康怀孕所需的荷尔蒙环境。通过解剖感染后炎症对整个母亲解剖的影响，我们可以为怀孕人群量身定做抗炎治疗。此外，对免疫反应的透彻了解将有助于为妇女免疫和生殖健康的这一微妙时期量身定做疫苗设计和剂量。
Increased susceptibility to influenza virus infection during pregnancy has been attributed to immunological changes occurring before and during gestation in order to “tolerate” the developing fetus. These systemic changes are most often characterized by a suppression of cell-mediated immunity and elevation of humoral immune responses referred to as the Th1-Th2 shift. However, the underlying mechanisms which increase pregnant mothers’ risk following influenza virus infection have not been fully elucidated. We used pregnant BALB/c mice during mid- to late gestation to determine the impact of a sub-lethal infection with A/Brisbane/59/07 H1N1 seasonal influenza virus on completion of gestation. Maternal and fetal health status was closely monitored and compared to infected non-pregnant mice. Severity of infection during pregnancy was correlated with premature rupture of amniotic membranes (PROM), fetal survival and body weight at birth, lung viral load and degree of systemic and tissue inflammation mediated by innate and adaptive immune responses. Here we report that influenza virus infection resulted in dysregulation of inflammatory responses that led to pre-term labor, impairment of fetal growth, increased fetal mortality and maternal morbidity. We observed significant compartment-specific immune responses correlated with changes in hormonal synthesis and regulation. Dysregulation of progesterone, COX-2, PGE2 and PGF2α expression in infected pregnant mice was accompanied by significant remodeling of placental architecture and upregulation of MMP-9 early after infection. Collectively these findings demonstrate the potential of a seasonal influenza virus to initiate a powerful pro-abortive mechanism with adverse outcomes in fetal health. Maternal immunology is finely balanced to maintain a tolerant and supportive molecular environment for the developing fetus while continuing surveillance against foreign microbial threats. Influenza viral infection during pregnancy is a significant clinical risk for mothers and their newborns, increasing hospitalization, preterm birth, low birth weight, and maternal and neonatal deaths worldwide. In a mouse pregnancy model, we show how influenza virus infection disrupts the delicate and interconnected cytokine and hormonal signaling pathways that respond to respiratory pathogens. The health of mothers and offspring was impacted in our study, after pregnant mothers’ lung and placental architecture was compromised by infection. Influenza virus infection increased the stress on the mother’s body already present due to pregnancy, or reversed the hormonal environment required to establish and maintain healthy pregnancy. By dissecting the effects of inflammation post-infection throughout the mother’s anatomy, we can tailor anti-inflammatory treatments for the pregnant population. Also, thorough knowledge of immune responses will assist in tailoring vaccine design and dosage for this delicate period of women’s immunological and reproductive health.
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影响因子：
17.1
作者：
Beatty, P. Robert;Puerta-Guardo, Henry;Harris, Eva
通讯作者：
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影响因子：
2.6
作者：
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Goepel, Wolfgang
影响因子：
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作者：
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影响因子：
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作者：
Chan KH;Zhang AJ;To KK;Chan CC;Poon VK;Guo K;Ng F;Zhang QW;Leung VH;Cheung AN;Lau CC;Woo PC;Tse H;Wu W;Chen H;Zheng BJ;Yuen KY
通讯作者：
Yuen KY
DOI：
10.1126/science.aad0314
发表时间：
2016-02-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Choi GB;Yim YS;Wong H;Kim S;Kim H;Kim SV;Hoeffer CA;Littman DR;Huh JR
通讯作者：
Huh JR