Inflammatory and antiviral responses to influenza A virus infection are dysregulated in pregnant mice with allergic airway disease.

Influenza A virus (IAV) infections are increased during pregnancy especially with asthma as a comorbidity, leading to asthma exacerbations, secondary bacterial infections, intensive care unit admissions, and mortality. We aimed to define the processes involved in increased susceptibility and severity of IAV infections during pregnancy, especially with asthma. We sensitized mice to house dust mite (HDM), induced pregnancy, and challenged with HDM to induce allergic airway disease (AAD). At midpregnancy, we induced IAV infection. We assessed viral titers, airway inflammation, lung antiviral responses, mucus hypersecretion, and airway hyperresponsiveness (AHR). During early IAV infection, pregnant mice with AAD had increased mRNA expression of the inflammatory markers Il13 and IL17 and reduced mRNA expression of the neutrophil chemoattractant marker Kc. These mice had increased mucous hyperplasia and increased AHR. miR155, miR574, miR223, and miR1187 were also reduced during early infection, as was mRNA expression of the antiviral ß-defensins, Bd1, Bd2, and Spd and IFNs, Ifnα, Ifnß, and Ifnλ. During late infection, Il17 was still increased as was eosinophil infiltration in the lungs. mRNA expression of Kc was reduced, as was neutrophil infiltration and mRNA expression of the antiviral markers Ifnß, Ifnλ, and Ifnγ and Ip10, Tlr3, Tlr9, Pkr, and Mx1. Mucous hyperplasia was still significantly increased as was AHR. Early phase IAV infection in pregnancy with asthma heightens underlying inflammatory asthmatic phenotype and reduces antiviral responses.NEW & NOTEWORTHY Influenza A virus (IAV) infection during pregnancy with asthma is a major health concern leading to increased morbidity for both mother and baby. Using murine models, we show that IAV infection in pregnancy with allergic airway disease is associated with impaired global antiviral and antimicrobial responses, increased lung inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). Targeting specific ß-defensins or microRNAs (miRNAs) may prove useful in future treatments for IAV infection during pregnancy.

Nasal epithelial cells to assess in vitro immune responses to respiratory virus infection in pregnant women with asthma.

Respiratory virus-induced asthma exacerbations occur frequently during pregnancy and are associated with adverse outcomes for mother and child. Primary nasal epithelial cells (pNECs) provide a useful method to study immune responses in pregnancy. pNECs were obtained by nasal brushings from pregnant and non-pregnant women with and without asthma. pNECS were infected in vitro with major group Rhinovirus 43 (RV43) and seasonal influenza (H3N2). Following infection, pNECs showed measurable quantities of interferon (IFN)-λ, IL-1ß, IL-8, IP-10 and MIP1-α. pNECs provide a safe and effective method for studying respiratory epithelial cell responses during pregnancy.

Maternal Smoke Exposure Impairs the Long-Term Fertility of Female Offspring in a Murine Model.

The theory of fetal origins of adult disease was first proposed in 1989, and in the decades since, a wide range of other diseases from obesity to asthma have been found to originate in early development. Because mammalian oocyte development begins in fetal life it has been suggested that environmental and lifestyle factors of the mother could directly impact the fertility of subsequent generations. Cigarette smoke is a known ovotoxicant in active smokers, yet disturbingly 13% of Australian and 12% of US women continue to smoke throughout pregnancy. The focus of our investigation was to characterize the adverse effects of smoking on ovary and oocyte quality in female offspring exposed in utero. Pregnant mice were nasally exposed to cigarette smoke for 12 wk throughout pregnancy/lactation, and ovary and oocyte quality of the F1 (maternal smoke exposed) generation was examined. Neonatal ovaries displayed abnormal somatic cell proliferation and increased apoptosis, leading to a reduction in follicle numbers. Further investigation found that altered somatic cell proliferation and reduced follicle number continued into adulthood; however, apoptosis did not. This reduction in follicles resulted in decreased oocyte numbers, with these oocytes found to have elevated levels of oxidative stress, altered metaphase II spindle, and reduced sperm-egg interaction. These ovarian and oocyte changes ultimately lead to subfertility, with maternal smoke-exposed animals having smaller litters and also taking longer to conceive. In conclusion, our results demonstrate that in utero and lactational exposure to cigarette smoke can have long-lasting effects on the fertility of the next generation of females.

Plasmacytoid dendritic cells and CD8 T cells from pregnant women show altered phenotype and function following H1N1/09 infection.

BACKGROUND: Pregnant women are a high-risk group during influenza pandemics. In this study we determined whether plasmacytoid dendritic cells (pDCs) and CD8 T cells from pregnant women display altered activity following in vitro infection with 2009 pandemic swine influenza (H1N1/09). METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from pregnant (n = 26) and nonpregnant (n = 28) women. DC subtypes were enumerated from PBMCs. PBMCs were infected with H1N1/09 and CD86, human leukocyte antigen-DR (HLA-DR), and programmed death ligand 1/2 (PDL1/2) measured on pDCs. PD receptor 1 (PD1) was measured on CD8 T cells. Interferon-alpha (IFN-α), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNFα), and IFN-gamma were measured from culture supernatant. RESULTS: pDC (ie, CD303(+)/CD1c(-) PBMCs) percentages were lower in pregnant compared with nonpregnant women (P < .05). Following H1N1/09 infection, pDCs from pregnant women showed higher expression of CD86 (P < .01), HLA-DR (P < .001), and PDL1 (P < .001) compared with nonpregnant women. Expression of PD1 on CD8 T cells was higher during pregnancy (P < .05). Following H1N1/09 infection, PBMCs from pregnant women displayed reduced IFN-α (P < .01), IL-2 (P < .01), and IFN-γ (P < .01) compared with nonpregnant women. Blocking PDL1 during H1N1/09 infection increased these cytokines during pregnancy (P < .05). CONCLUSION: Altered maternal cellular antiviral activity is implicated in the increased morbidity during pregnancy following influenza pandemics.

Alterations in inflammatory, antiviral and regulatory cytokine responses in peripheral blood mononuclear cells from pregnant women with asthma.

BACKGROUND & OBJECTIVE: Severe asthma exacerbations during pregnancy are a common complication leading to poor health outcomes for both the mother and the baby. Asthma exacerbations are caused most frequently by respiratory viruses. A balance between antiviral and inflammatory immune responses is critical during pregnancy; the balance may be altered by asthma and respiratory virus infection. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from (i) non-pregnant healthy controls, (ii) pregnant non-asthmatics, (iii) post-partum non-asthmatics, (iv) non-pregnant asthmatics (v) pregnant asthmatics, and (vi) post-partum asthmatics. Cells were cultured in vitro with the mitogen phytohaemagglutinin or with a strain of the 2009 pandemic swine influenza. Interferon (IFN)-γ, interleukin (IL)-10 and IL-17 protein were measured from culture supernatant. Neutrophil counts were obtained in samples from pregnant and post-partum women. RESULTS: Following the phytohaemagglutinin stimulation of PBMCs, pregnant asthmatics had significantly higher IL-17 and significantly lower IFN-γ responses compared with healthy non-pregnant women. Following infection with influenza, a significant reduction was also observed in IFN-γ and IL-10 production from PBMC of pregnant asthmatics. The IL-17 response to phytohaemagglutinin correlated with the neutrophil percentage. Differences in IFN-γ, IL-10 and IL-17 were found to persist for at least 6 months post-partum. CONCLUSIONS: A reduction in antiviral and regulatory immunity with increased inflammation during pregnancy occurs in PBMC from pregnant women with asthma. This novel information may relate to the increased susceptibility and disease severity to respiratory virus infections observed during pregnancy.

Investigating the Links between Lower Iron Status in Pregnancy and Respiratory Disease in Offspring Using Murine Models.

Maternal iron deficiency occurs in 40-50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.

Maternal complications and the management of asthma in pregnancy.

Pregnancy is a unique state requiring alterations in maternal physiology to accommodate the growing fetus. Whilst the maternal immune system is normally well adept at performing this task, the presence of immune disorders, such as asthma, often lead to pregnancy-related complications affecting both mother and baby. Australia has a high prevalence of asthma; with approximately 12% of pregnant women reported to have current asthma. Poor control of asthma is of far greater risk than the use of asthma medications. Being able to identify complications associated with asthma during pregnancy is of great importance in providing appropriate asthma management and medical care to these pregnant women, which may have lifelong consequences for their offspring.

CD8 T cells and dendritic cells: key players in the attenuated maternal immune response to influenza infection.

Pregnancy provides a unique challenge for maternal immunity, requiring the ability to tolerate the presence of a semi-allogeneic foetus, and yet still being capable of inducing an immune response against invading pathogens. To achieve this, numerous changes must occur in the activity and function of maternal immune cells throughout the course of pregnancy. Respiratory viruses take advantage of these changes, altering the sensitive balance of maternal immunity, leaving the mother with increased susceptibility to viral infections and increased disease severity. Influenza virus is one of the most common respiratory virus infections during pregnancy, leading to an increased risk of ICU hospitalisations, pneumonia, acute respiratory distress syndrome and even death. Whilst much research has been performed to understand the changes that must take place in maternal immunity during pregnancy, considerable work is still needed to fully comprehend this tremendous feat. To date, few studies have focused on the alterations that occur in maternal immunity during respiratory virus infections. This review highlights the role of dendritic cells (DCs) and CD8 T cells during pregnancy, and the changes that occur in these antiviral cells following influenza virus infections.