Abstract
In 2009, the H1N1 swine flu pandemic highlighted the vulnerability of pregnant women to influenza viral infection. Pregnant women infected with influenza A virus were at increased risk of hospitalization and severe acute respiratory distress syndrome (ARDS), which is associated with high mortality, while their newborns had an increased risk of pre-term birth or low birth weight. Pregnant women have a unique immunological profile modulated by the sex hormones required to maintain pregnancy, namely progesterone and estrogens. The role of these hormones in coordinating maternal immunotolerance in uterine tissue and cellular subsets has been well researched; however, these hormones have wide-ranging effects outside the uterus in modulating the immune response to disease. In this review, we compile research findings in the clinic and in animal models that elaborate on the unique features of H1N1 influenza A viral pathogenesis during pregnancy, the crosstalk between innate immune signaling and hormonal regulation during pregnancy, and the role of pregnancy hormones in modulating cellular responses to influenza A viral infection at mid-gestation. We highlight the ways in which lung architecture and function is stressed by pregnancy, increasing baseline inflammation prior to infection. We demonstrate that infection disrupts progesterone production and upregulates inflammatory mediators, such as cyclooxygenase-2 (COX-2) and prostaglandins, resulting in pre-term labor and spontaneous abortions. Lastly, we profile the ways in which pregnancy alters innate and adaptive cellular immune responses to H1N1 influenza viral infection, and the ways in which these protect fetal development at the expense of effective long-term immune memory. Thus, we highlight advancements in the field of reproductive immunology in response to viral infection and illustrate how that knowledge might be used to develop more effective post-infection therapies and vaccination strategies.
Highlights
Influenza viruses are segmented, negative-stranded enveloped RNA viruses that cause respiratory infections, fever, malaise, coughing, and mucus production
Influenza viral infection and subsequent oxidative stress may interfere with the unique lung and mucosal physiology tightly regulated by sex hormones toward successful pregnancy and fetal development
While most research focused on the consequences of influenza A (H1N1) virus infection during pregnancy, there is evidence that influenza B virus can cause significant maternal and fetal complications following mid-gestation infection [137, 138]
Summary
Negative-stranded enveloped RNA viruses that cause respiratory infections, fever, malaise, coughing, and mucus production. Through a process unique to influenza and other segmented genome viruses, coinfection of different viral subtypes in human, swine, avian or other animal hosts can result in reassortment leading to antigenically unique novel viruses that may take advantage of an immunologically naïve host species [4] This process of reassortment resulted in the emergence of the four major influenza virus strains causing pandemics; the 1918 H1N1 Spanish influenza, the 1957 H2N2 Asian influenza, the 1968 H3N2 Hong Kong influenza, and the 2009 H1N1/09 swine influenza, that infected up to 50% of the global population and caused a significant increase in mortality [2, 3]. Seasonal influenza infections during the second and third trimester of gestation increase the morbidity of pregnant women with higher hospitalization rates than the general population and mortality [6]. This review will discuss how H1N1 influenza virus infection disrupts maternal lung and placental function as well as the role of pregnancy hormones in shaping the innate and cellular immune responses to H1N1 influenza virus infection
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