Influenza Transmission in the Mother-Infant Dyad Leads to Severe Disease, Mammary Gland Infection, and Pathogenesis by Regulating Host Responses.
Influenza Transmission in the Mother-Infant Dyad Leads to Severe Disease, Mammary Gland Infection, and Pathogenesis by Regulating Host Responses.
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DOI：
10.1371/journal.ppat.1005173
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发表时间：
2015-10
期刊：
影响因子：
6.7
通讯作者：
Kelvin AA
中科院分区：
文献类型：
--
作者：
Paquette SG;Banner D;Huang SS;Almansa R;Leon A;Xu L;Bartoszko J;Kelvin DJ;Kelvin AA
季节性流感病毒通常局限于人类上呼吸道，而致病潜力更大的流感病毒通常也会以肺外器官为目标。婴儿、孕妇和哺乳母亲很容易感染流感病毒感染后的严重呼吸道疾病，但母婴二元组的疾病严重机制尚不清楚。在这里，我们使用我们开发的婴儿-母亲雪貂流感模型调查了2009年H1N1流感病毒在哺乳母亲和婴儿中的感染和传播。婴儿在感染后得了严重的疾病和死亡率。病毒从婴儿传播给母亲雪貂导致肺部感染和母亲死亡。在乳房组织中也发现了活病毒，并表达了母亲的乳汁，最终导致乳汁停止。组织病理学显示腺体结构破坏，缺乏乳汁。病毒定位于阳性腺体的乳腺上皮细胞。为了了解乳腺感染的分子机制，我们进行了全球转录分析，结果显示催乳素等产奶基因下调，乳腺退化途径增加，信号从STAT5到STAT3的转变表明。与癌症发展相关的基因也显著增加，包括Jun、Fos和M2巨噬细胞标志物。乳腺内的免疫反应以淋巴细胞相关基因CD3e、IL2ra、CD4降低和IL1β上调为特征。将H1N1直接接种到乳腺会导致婴儿呼吸道感染和婴儿死亡，这表明流感病毒能够在乳腺组织中复制，并可能通过母乳喂养传播。对人乳腺细胞的体外感染研究表明，对H1N1病毒感染很敏感。总之，我们已经表明，在母婴二联体中，流感病毒感染的宿主-病原体相互作用启动了乳腺内的免疫和致癌信号级联反应。这些发现表明，乳腺在感染和免疫方面的作用可能比之前认为的更大。流感被认为是一种呼吸道传染病。母乳喂养允许婴儿和母亲之间频繁的微生物交换。尽管婴儿、孕妇和哺乳母亲更容易感染流感病毒感染后的严重呼吸道疾病，但婴儿和母亲的疾病严重机制尚不清楚。我们感兴趣的是了解婴儿-母亲系统中的免疫反应、致病性和传播动力学。为了达到这个目的，我们开发了一种婴儿-母雪貂流感模型。婴儿感染流感导致病毒传播给母亲，导致严重疾病和死亡。出乎意料的是，感染流感的婴儿雪貂将病毒传播到母亲的乳房，导致表达的母乳中出现活的流感病毒。乳腺中的基因调控分析显示，催乳素等产奶量基因减少，与乳房关闭有关的基因增加。与癌症发生相关的基因显著增加，包括Jun、Fos和BRCA2。我们发现人类乳房细胞能够感染流感病毒，这表明我们的研究结果对人类健康的重要性。我们的数据表明，流感传播可以通过乳腺发生，引发免疫和病理事件，导致流感疾病的严重程度，影响婴儿和产妇的健康。
Seasonal influenza viruses are typically restricted to the human upper respiratory tract whereas influenza viruses with greater pathogenic potential often also target extra-pulmonary organs. Infants, pregnant women, and breastfeeding mothers are highly susceptible to severe respiratory disease following influenza virus infection but the mechanisms of disease severity in the mother-infant dyad are poorly understood. Here we investigated 2009 H1N1 influenza virus infection and transmission in breastfeeding mothers and infants utilizing our developed infant-mother ferret influenza model. Infants acquired severe disease and mortality following infection. Transmission of the virus from infants to mother ferrets led to infection in the lungs and mother mortality. Live virus was also found in mammary gland tissue and expressed milk of the mothers which eventually led to milk cessation. Histopathology showed destruction of acini glandular architecture with the absence of milk. The virus was localized in mammary epithelial cells of positive glands. To understand the molecular mechanisms of mammary gland infection, we performed global transcript analysis which showed downregulation of milk production genes such as Prolactin and increased breast involution pathways indicated by a STAT5 to STAT3 signaling shift. Genes associated with cancer development were also significantly increased including JUN, FOS and M2 macrophage markers. Immune responses within the mammary gland were characterized by decreased lymphocyte-associated genes CD3e, IL2Ra, CD4 with IL1β upregulation. Direct inoculation of H1N1 into the mammary gland led to infant respiratory infection and infant mortality suggesting the influenza virus was able to replicate in mammary tissue and transmission is possible through breastfeeding. In vitro infection studies with human breast cells showed susceptibility to H1N1 virus infection. Together, we have shown that the host-pathogen interactions of influenza virus infection in the mother-infant dyad initiate immunological and oncogenic signaling cascades within the mammary gland. These findings suggest the mammary gland may have a greater role in infection and immunity than previously thought. Influenza is known as a respiratory infectious disease. Breastfeeding allows for frequent microbial exchange between infant and mother. Although infants, pregnant women and breastfeeding mothers are more susceptible to severe respiratory disease following influenza virus infection, the mechanisms of disease severity in infants and mothers is poorly understood. We were interested in understanding the immune responses, pathogenicity, and transmission dynamics in the infant-mother system. With this aim we developed an infant-mother ferret influenza model. Influenza infection in infants led to virus transmission to mothers causing severe disease and mortality. Unexpectedly, influenza-infected infant ferrets transmitted the virus to mother mammary glands leading to live influenza virus in expressed breast milk. Gene regulation analysis in the mammary gland showed reduction of milk production genes such as Prolactin and increased genes involved with breast shutdown. Genes associated with cancer development were significantly increased including JUN, FOS and BRCA2. We found human breast cells were able to be infected with the influenza virus suggesting the importance of our results to human health. Our data suggests influenza transmission can occur through the mammary glands initiating immunological and pathological events contributing to influenza disease severity impacting infant and maternal health.