Hormonal Regulation of Physiology, Innate Immunity and Antibody Response to H1N1 Influenza Virus Infection During Pregnancy

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.

Estrogen Reverses HDAC Inhibitor-Mediated Repression of Aicda and Class-Switching in Antibody and Autoantibody Responses by Downregulation of miR-26a

“…Estrogen plays an important role in the generation of classswitched and mutated antibodies and autoantibodies, thereby contributing to the greater response to microbial vaccines as well as the greater incidence of antibody-mediated autoimmunity, such as in systemic lupus erythematosus, in females (4,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)28). Indeed, we have shown that estrogen enhances AID expression by activating the HOXC4/HoxC4 promoter and inducing HoxC4, which is a critical Aicda promoter activator together with NF-κB (27,28).…”

“…Estrogen plays an important role in boosting the production of mature antibodies and autoantibodies (1,2). This provides an explanation for the greater antibody response to microbial vaccines and infections as well as the greater incidence of antibody-mediated autoimmunity, such as systemic lupus erythematosus, in females (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Like protective antibodies against pathogenic microorganisms, pathogenic autoantibodies in humans and mice with systemic autoimmunity are generally class-switched and hypermutated, strongly suggest a role for estrogen in modulation of immunoglobulin (Ig) class switch DNA recombination (CSR) and somatic hypermutation (SHM).…”

Pregnancy Downregulates Plasmablast Metabolic Gene Expression Following Influenza Without Altering Long-Term Antibody Function

“…Successful pregnancies require expression of PIBF, which promotes Th2 cytokine production and inhibition of NK cell activity, resulting in reduced cytolytic activity at the fetal-maternal interface and potentially increases maternal susceptibility to infection (25). This progesterone-responsive immunomodulatory protein has multiple splice variants.…”

Recent Updates on Research Models and Tools to Study Virus–Host Interactions at the Placenta

“…However, this balance can be disrupted by viral pathogens that cross placental barrier. For example, Littauer and colleagues demonstrated that influenza virus infection disrupts progesterone production and upregulates inflammatory mediators such as cyclooxygenase-2 and prostaglandins, resulting in preterm birth and miscarriages [147]. Furthermore, using an animal model, the same group reported that viral load was negatively associated with progesterone concentration, and reduced progesterone expression was correlated with preterm birth in influenza virus-infected pregnant mice [148].…”