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When a virus encounters a susceptible cell, the virus enters it to initiate cytocidal, persistent, latent or abortive cell infection. The influenza virus induces cytocidal infection accompanied by virus production and cell death in several types of cultures such as HeLa and Madin-Darby canine kidney (MDCK) cell lines and human peripheral blood monocytes in vitro, all of which die through the mechanism of apoptosis. 1-4)The human influenza virus usually infects the human respiratory organs. However, influenza virus was isolated from blood, [5][6][7][8] as well as extrapulmonary regions such as lymph node, spleen, liver, kidney, adrenal glands, meninges, 7,[9][10][11] and cerebrospinal fluid.12,13) These findings substantiate the occurrence of viremia in influenza virus infection and the extrapulmonary dissemination of the virus. Furthermore, influenza virus has been isolated from fetal heart, 10) placenta 14) and amniotic fluid, 10,15) suggesting the occurrence of fetal, placental and amniotic fluid infections with this virus.The influenza virus has not so far been isolated from the fetal membranes of a mother who died of influenza virus infection to our knowledge. However, the virus has been isolated from the placenta and amniotic fluid. 14,15) Additionally, organ cultures of human placenta allow influenza virus replication.16) The influenza virus may spread from the placenta to fetal membranes because they are continuous with the placenta. Furthermore, since amniotic fluid fills amniotic cavity formed by fetal membranes, influenza virus in amniotic fluid may influence the membrane cells. However, little is understood about the influence of influenza virus on human fetal membrane cells.We investigated the relationship between the influenza virus and cultured human fetal membrane cells by studying virus production and the apoptotic death of these cells in vitro. We found that the influenza virus induced cytocidal infection in chorion cells, persistent infection accompanied by virus production and cell survival in amnion cells, and that influenza virus-infected chorion cells became degraded through the apoptotic pathway. The present study demonstrates that the host cells make the choice to commit to degradation through this pathway. MATERIALS AND METHODSChemicals Ribavirin (1-b-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was purchased from Sigma (MO, U.S.A.).Influenza Virus Propagation and Plaque-Forming Assay Influenza virus type A (PR/8/34, H1N1) was propagated in the allantoic cavity of 11-d-old embryonal chicken eggs for 48 to 72 h at 35°C as described.2) Plaque-forming capacity was assayed on confluent monolayers of MDCK (NBL-2) cells (Human Science Research Resources Bank, Japan) as described.4) The chorioallantoic fluid contained 8ϫ10 8 plaque-forming units (PFU)/ml and the hemagglutination titer using human erythrocytes was 1 : 256. Cell Cultures and Virus Infection Human fetal membranes were prepared aseptically from placentas obtained by cesarean section in the month of normal parturition. Primary cult...

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Pregnant women are at an increased risk of influenza-associated adverse outcomes, such as premature delivery, based on data from the latest pandemic with a novel influenza A (H1N1) virus in 2009-2010. It has been suggested that the transplacental transmission of influenza viruses is rarely detected in humans. A series of our study has demonstrated that influenza virus infection induced apoptosis in primary cultured human fetal membrane chorion cells, from which a factor with monocyte differentiation-inducing (MDI) activity was secreted. Proinflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-β, were identified as a member of the MDI factor. Influenza virus infection induced the mRNA expression of not only the proinflammatory cytokines but also chemoattractive cytokines, such as monocyte chemoattractant protein (MCP)-1, regulated on activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1β, IL-8, growth-regulated oncogene (GRO)-α, GRO-β, epithelial cell-derived neutrophil-activating protein (ENA)-78, and interferon inducible protein (IP)-10 in cultured chorion cells. These cytokines are postulated to associate with human parturition. This paper, therefore, reviews (1) lessons from pandemic H1N1 2009 in pregnancy, (2) production of proinflammatory and chemoattractive cytokines by human fetal membranes and their functions in gestational tissues, and (3) possible roles of cytokines produced by human fetal membranes in the pathology of adverse pregnancy outcomes associated with influenza virus infection.

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