Women’s Health Research Advances – FY 2018

NIAID conducts and supports research to prevent, diagnose, and treat infectious and immunological diseases that affect the health of women and girls.

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HIV/AIDS

Anti-HIV Therapy Strategies Virtually Eliminate HIV Transmission for Duration of Breastfeeding

Previous studies have shown that providing HIV-infected mothers or their uninfected infants with antiretroviral therapy (ART) during breastfeeding is safe and associated with very low transmission of HIV from mother to child for up to 6–12 months of breastfeeding. However, until now, no study has compared these strategies beyond 12 months of breastfeeding. This is important because breastfeeding of HIV-exposed infants beyond the first year of life, particularly in resource-limited settings, is associated with decreased illness and improved survival of the infant.

As part of the NIAID-funded, multinational Promoting Maternal and Infant Survival Everywhere (PROMISE) study, researchers followed 2,431 mother-infant pairs in sub-Saharan Africa and India throughout the duration of breastfeeding and into the second year of the infant’s life. On average, the women in the study did not have symptoms of HIV/AIDS and had relatively high CD4+ cell levels—a marker of good immune system health.

Of the 2,431 mother-infant pairs, 1,220 were randomly assigned to maternal ART, in which the mother received a three-drug ART regimen, and 1,211 were randomly assigned to infant nevirapine, in which the infant received daily doses of the antiretroviral drug nevirapine.

The study found that maternal and infant ART strategies were equally safe and effective at preventing transmission of HIV to the infant for up to 24 months of breastfeeding. Under both treatment strategies, only 0.6% and 0.9% of infants became HIV-infected at 12 and 24 months, respectively, after the baby was born. These results show that while the preferred strategy of treating the mother as part of lifelong ART is highly effective at reducing mother-to-child HIV transmission, infant nevirapine is an effective and safe alternative. This alternative may be needed for infants of mothers who cannot or do not adhere to ART, who temporarily stop ART due to serious side effects, or who have persistent HIV infections that do not respond to ART. However, some of the same barriers may also apply to infant nevirapine.

Reference: Flynn PM et al. Prevention of HIV-1 transmission through breastfeeding: efficacy and safety of maternal antiretroviral therapy versus infant nevirapine prophylaxis for duration of breastfeeding in HIV-1-infected women with high CD4 cell count (IMPAACT PROMISE): a randomized, open-label, clinical trial. J Acquir Immune Defic Syndr. 2018 Apr 1;77(4):383–392.

Chronic Hepatitis C Infection in Women May Affect Response to Anti-HIV Therapy

In the United States, one in four people living with HIV is also infected with hepatitis C virus (HCV). Suppressing HIV levels through antiretroviral therapy (ART) improves long-term health and reduces transmission of HIV to uninfected sexual partners. Yet the effects of chronic HCV co-infection on the effectiveness of ART for HIV infection are unclear, especially among women.

To estimate the effects of chronic HCV on the ability of ART to control HIV in women for up to 15 years, researchers analyzed data from the NIAID-funded Women’s Interagency HIV Study (WIHS). The WIHS follows a large group of U.S. women living with or at risk for HIV infection, with follow-up visits every 6 months. The researchers studied 441 HIV-infected women in the WIHS study who started on ART on or after January 1, 2000, 114 of whom were also co-infected with HCV.

The investigators compared the proportion of study visits at which detectable blood levels of HIV were found among women with and without chronic HCV infection. Higher HIV levels mean an increased risk of disease complications and of HIV transmission. Overall, HCV-infected and HCV-uninfected women with HIV were equally likely to have detectable HIV. However, women with chronic HCV were more likely to have detectable HIV (a sign that ART is not effective) for the first 2 years after starting ART compared with women not infected with HCV. However, by 6 years there was no difference between the two groups. This finding suggests that chronic HCV infection may negatively affect early HIV viral response to ART.

The association between chronic HCV and detectable HIV levels in this study was not fully explained by differences in behaviors, such as poorer adherence to ART or more frequent injection drug use. Therefore, the researchers concluded, biological interactions between HIV and HCV are possible and could reduce the effectiveness of ART in the first few years after starting treatment.

Although the association between chronic HCV and detectable HIV levels may not generalize to all U.S. women with HIV who are on ART, the findings highlight the need to test HIV-infected individuals for HCV infection and to carefully monitor HIV care and facilitate access to HCV treatment among people with HIV/HCV co-infection.

Reference: Willis SJ et al. Chronic hepatitis C virus infection and subsequent HIV viral load among women with HIV initiating antiretroviral therapy. AIDS. 2018 Mar 13;32(5):653–661.

Two Studies Shed More Light on Adverse Pregnancy Outcomes of Antiretroviral Therapy

Women with HIV are at risk of infecting their children during pregnancy, during birth, or shortly thereafter. US and World Health Organization (WHO) guidelines recommend the use of a three-drug regimen of antiretroviral therapy (ART) during pregnancy to reduce the risk of mother-to-child transmission to less than 1%. This recommendation was based on numerous observational studies showing that the use of a three-drug cocktail including the anti-HIV drugs tenofovir and emtricitabine during pregnancy was safe. However, recent results from the NIAID-sponsored Promoting Maternal and Infant Survival Everywhere (PROMISE) trial identified potential safety concerns. Women randomly assigned to receive tenofovir, emtricitabine, and lopinavir had infants at greater risk of very premature birth or death within 14 days of delivery.

To better understand the safety of exposure to various ART regimens during pregnancy, NIAID-funded researchers analyzed data on pregnant HIV-infected women collected from two US-based studies. The women received one of three common three-drug ART regimens: tenofovir, emtricitabine, and lopinavir; tenofovir, emtricitabine and atazanavir; or zidovudine, lamivudine, and lopinavir. Overall, women in the three groups had similar risks of having infants born prematurely or with low birthweight. An analysis of the women who started treatment before conception suggested that those who were treated with tenofovir, emtricitabine, and lopinavir/ritonavir had an increased risk of preterm birth compared to the other two ART regimens.

A few other studies have suggested that becoming pregnant while on ART may lead to similar harmful outcomes. An increasing number of women are conceiving while on ART, as the treatment guidelines now recommend starting treatment immediately after diagnosis of HIV infection.

To examine this issue, NIAID-supported investigators reviewed data from a large clinical trial in which HIV-infected women who were treated during pregnancy were randomly assigned to either continue or stop ART after giving birth. The investigators examined the effects on the outcomes of a subsequent pregnancy, including spontaneous abortion and stillbirth. The women assigned to continue ART had higher rates of spontaneous abortion and stillbirth. However, these results did not hold up when comparing women who actually were or were not on ART, as not all women adhered to the prescribed regimen. Previous studies have provided conflicting data regarding whether ART affects the rate of stillbirths. Further studies are needed to explore pregnancy outcomes among women who conceive on ART, particularly with newer drug regimens. Such studies will inform decisions on how to balance the relatively low risks of adverse pregnancy outcomes against the benefits of lifelong, uninterrupted ART.

References:

Rough K et al. Birth Outcomes for Pregnant Women with HIV Using Tenofovir-Emtricitabine. New England Journal of Medicine. 2018 Apr 26; 378:1593–1603.

Hoffman RM et al. Adverse Pregnancy Outcomes Among Women Who Conceive on Antiretroviral Therapy. Clinical Infectious Diseases. 2019 Jan 7; 68:273–279.

Risk of Acquiring HIV Increases During and After Pregnancy

A new HIV infection during pregnancy or after childbirth (postpartum) not only has negative consequences for the woman’s health but also carries the risk of HIV transmission to the fetus or to the newborn through breastfeeding. Numerous behavioral, cultural, and societal factors around the world potentially could increase a woman’s risk of acquiring HIV during pregnancy.

Some, but not all, previous studies have suggested that pregnant women may have a higher risk of HIV infection compared to non-pregnant women. To provide detailed information about this risk, NIAID-supported researchers compared the probabilities of male-to-female HIV transmission per sex act among non-pregnant, pregnant, and postpartum women.

The study involved 2,751 couples enrolled in either of two HIV prevention clinical trials conducted in eastern and southern Africa. Women underwent HIV and pregnancy testing either monthly or quarterly, depending on which trial they were enrolled in. Each month, couples reported how frequently they had sex and whether they used condoms. Overall, 686 pregnancies and 82 HIV transmissions occurred within the study population.

The researchers found that a woman’s risk of acquiring HIV through sex with a male partner living with HIV increases during pregnancy and is highest during the first 6 months after childbirth. Researchers observed this trend of increased risk of HIV transmission per sex act even after considering behavioral factors, such as use of condoms or pre-exposure prophylaxis (PrEP).

The findings underscore the importance of expanding HIV prevention and testing services for pregnant and postpartum women living in areas with high HIV prevalence. They support current World Health Organization recommendations to include HIV testing as a routine component of prenatal, childbirth, and postpartum care and to offer HIV testing services to couples and partners.

In addition, the results suggest that the physiological changes that a woman’s body undergoes during and after pregnancy contribute to an increased risk of acquiring HIV. While additional research is needed to understand this biologic susceptibility, this observation stresses the importance of testing new HIV prevention strategies in pregnant women to ensure that they are safe and effective during pregnancy.

Note: This summary was adapted from a NIAID Now blog post, which provides more details on the study and its results.

Reference: KA Thomson et al. Increased risk of female HIV-1 acquisition throughout pregnancy and postpartum: a prospective per-coital act analysis among women with HIV-1 infected partners. Journal of Infectious Diseases. 2018 Jun 5;218(1):16–25.

Immunology

Study Reveals Effects of Rituximab Therapy on Antibody Responses in Systemic Sclerosis Patients with Pulmonary Arterial Hypertension

Systemic sclerosis (SSc), also known as scleroderma, is a severe and often fatal autoimmune disease marked by hardening of the skin and the connective tissue of internal organs. Women are about four times more likely than men to develop the disease. Patients with SSc often develop difficult-to-treat complications such as a type of increased blood pressure in the lungs known as pulmonary arterial hypertension (PAH).

A diagnostic feature in people with SSc is the presence of autoantibodies, which are antibodies that target the body’s own proteins and may underlie many features of the disease. Autoantibodies are produced by immune cells known as self-reactive B cells, which escape normal immune regulation. Rituximab, a drug that depletes the body’s B cells, has emerged as a potential treatment for SSc and has shown early promise in a few patients with PAH.

As part of an ongoing NIAID-supported clinical trial that is testing the potential benefits of rituximab in people with SSc who develop PAH (SSc-PAH), researchers asked how rituximab might affect the body’s B cells and antibodies during and following treatment. To answer this question, they examined blood samples from 11 female SSc-PAH patients in the clinical trial who had received infusions of either rituximab or a placebo at the start of therapy and again two weeks later. The researchers collected blood samples from the study participants before starting treatment, at weeks 2 and 4, and then at 12-week intervals following treatment, for about two years. They analyzed the genetic sequences that encode antibodies, assessing the representation and mutation rates of characteristic antibodies produced by specific B-cell subtypes in these patient samples.

The researchers found that SSc-PAH is associated at baseline with abnormalities in B-cell development, particularly in the diversity of antibodies and in the proportions of specific B-cell subtypes. When the researchers examined the dynamics of B-cell depletion during and after rituximab treatment, they found different patterns of B-cell replenishment among the study participants. They also concluded that the time to replenishment after treatment may be predicted from the antibody diversity before treatment (baseline), which could help identify patients who would benefit most from rituximab treatment. These findings prompt further examination into whether differences in B-cell responses might affect clinical outcomes in SSc-PAH patients, which can be pursued when the clinical trial is completed.

Reference: de Bourcy CFA et al. Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis. Sci Immunol. 2017 Sep 29;2(15). eaan8289.

Discovering How Distinct Populations of Immune Cells Silence Inflammation May Help Us Understand Lupus

Systemic lupus erythematosus (SLE, or lupus) is a chronic autoimmune disorder that can affect multiple organs and often causes skin rashes, joint inflammation, and pain. Women, particularly women of color and women of child-bearing age, are much more likely than men to develop lupus.

Programmed cell death, termed apoptosis, is a normal process occurring throughout the body that maintains a healthy balance of cells. Although the causes of lupus are complex and only partially understood, abnormalities in the clearance of apoptotic cells are thought to be key contributors to the disease. Immune cells called macrophages are responsible for safely eliminating apoptotic cells and preventing tissue damage by silencing their inflammatory signals. By contrast, when macrophages eliminate infectious microbes, they trigger a protective immune response that usually promotes inflammation. How macrophages are cued to silence their pro-inflammatory signals has been poorly understood until now.

To investigate how macrophages normally function during clearance of apoptotic cells, NIAID-supported researchers first identified in mice the specific populations of macrophages in certain tissues that are responsible for such “immunologically silent” (non-inflammatory) clearance of apoptotic cells. They demonstrated that these tissue-resident macrophages had on their surface high levels of receptors that specifically recognize apoptotic cells, and low levels, or a complete lack, of receptors that are activated by different types of apoptotic cell debris, particularly nucleic acids.

Further experiments showed that the tissue microenvironment—the cells, molecules, and structures that surround other cells—is crucial for programming these macrophages to clear apoptotic cells without promoting inflammation. Previous experiments had shown that macrophages, when removed from tissues and placed in culture, changed their expression of receptors and instead generated inflammatory responses to apoptotic cells. By comparing genes expressed in tissue-resident versus deprogrammed macrophages, the researchers identified two transcription factors (proteins that turn genes on or off), KLF2 and KLF4, and showed that they are essential mediators of signals that silence the inflammatory response to apoptotic cells. Further research is needed to elucidate exactly how the tissue microenvironment programs macrophages to silence inflammation, and how this process might be dysregulated in disease.

Together, these results provide insight into a mechanism used by the immune system to avoid harmful inflammation and thereby maintain normal conditions in the body’s tissues. Ultimately, improved understanding of these factors may lead to novel therapeutic strategies in disorders with aberrant cell clearance and inflammation, such as lupus.

Reference: Roberts AW et al. Tissue-resident macrophages are locally programmed for silent clearance of apoptotic cells Immunity. 2017 Nov 21;47(5):913-927.e6.

Study Suggests a Link Between the Fetal Immune System and Premature Birth

Premature or preterm birth is the most common cause of infant death in the developed world and can cause short-term and long-term health problems in babies who survive. The most frequent causes of spontaneous premature labor are infection and inflammation. However, researchers don’t yet understand the detailed processes that lead to early labor.

In a healthy pregnancy, the mother’s immune system accepts, or tolerates, the presence of the developing fetus. Similarly, the fetal immune system does not react against cells from the mother that cross the placenta. While research has shown that maternal immune responses against the fetus can lead to pregnancy complications, not much is known about the role of the fetal immune system in causing complications.

To investigate the potential role of the fetal immune system in premature birth, NIAID-funded researchers studied 89 women with healthy pregnancies and 70 women who went into early labor due to premature rupture of the amniotic sac—a membrane that encloses the developing fetus.

The researchers collected blood from the mothers and umbilical cord blood after birth, which provides a glimpse into the fetal immune system. When they compared cord blood from full-term infants and premature infants, they found several differences. Cord blood from premature infants had elevated levels of inflammation-promoting molecules and a greater activation of immune response–boosting cells called dendritic cells. It also contained immune cells known as T-helper cells, primed to react against molecules from the mother. Finally, cord blood from premature infants also contained many more maternal cells than cord blood from infants not born prematurely.

In experiments with uterine cells grown in the lab, the researchers showed that these T-helper cells from premature infants stimulated increased contraction of uterine cells, due to enhanced production of two proteins associated with inflammation, called TNF-alpha and IFN-gamma.

The study findings suggest that an interplay between inflammation, maternal cells that cross the placenta, and aberrant activation of the fetal immune system may play a role in some premature births. Future studies to better understand these processes could ultimately lead to new strategies to predict and prevent premature labor.

Reference: Frascoli M et al. Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-γ and TNF-α. Science Translational Medicine. 2018 Apr 25;10(438). pii: eaan2263.

Immune Response of Pregnant Women to Influenza Vaccination Declines as Pregnancy Progresses

The seasonal influenza (flu) vaccine is recommended for all pregnant women to protect them and their newborn infants from illness. It also reduces the risk of pregnancy complications such as premature birth and low birthweight that can result in short- and long-term health problems for the child.

Influenza is more likely to cause severe illness or death in pregnant women than in women of the same age who are not pregnant, especially during the later stages of pregnancy, suggesting that pregnancy dampens the immune response to the flu virus. Researchers therefore wondered whether a woman’s immune response to seasonal influenza vaccination also declines during pregnancy, potentially reducing the vaccine’s effectiveness.

To help answer this question, a research team funded in part by NIAID studied the antibody response to influenza vaccination throughout pregnancy. The researchers collected blood samples before and after vaccination from 71 healthy pregnant women ages 18–39 and 67 healthy women of the same age range who were not pregnant. They evaluated the blood levels of several types of anti-hemagglutinin (HA) antibodies, which are thought to provide protective immunity against the virus by targeting the HA protein on its surface. At the time of vaccination, 13 of the 71 pregnant women in the study were in their first trimester of pregnancy, 43 were in the second trimester, and 15 were in the third trimester. Most study participants had been previously vaccinated against influenza.

Overall, the team found that anti-HA antibody levels were lower in pregnant women compared to non-pregnant women and these antibody responses decreased as women were vaccinated later in pregnancy. The findings suggest that pregnant women produce a weaker antibody response to some forms of the HA protein when vaccinated in the later stages of pregnancy, correlating with the increased rate of influenza hospitalizations and complications seen as delivery approaches. According to the researchers, these results suggest a need to reconsider the timing of administering the influenza vaccine to pregnant women. Earlier vaccination may lead to better antibody responses to the vaccine and improved protection against influenza.

Reference: Schlaudecker E et al. Declining responsiveness to influenza vaccination with progression of human pregnancy. Vaccine. 2018 Jul 25;36(31):4734-4741.

Infectious Diseases (Other than HIV/AIDS)

Novel Mechanism Identified for Cancer-Promoting Effects of HPV Infection

Certain types of sexually transmitted human papillomaviruses (HPVs), known as high-risk HPVs, cause virtually all cases of cervical cancer. High-risk HPV types can also cause several other cancers, including anal, head and neck, vaginal, and vulvar cancers. Two of these high-risk viruses, HPV16 and HPV18, are responsible for most HPV-caused cancers. A better understanding of how HPV infection can cause cells to become cancerous would help in creating new therapies.

HPV infects epithelial cells, which cover the inside and outside surfaces of the body, including the skin, throat, and genital tract. During persistent infection with high-risk HPVs, the viral genome can become integrated into the genome of an infected cell. This integration into the host-cell genome is a key step in the development of many HPV-associated cancers. Integration can result in dysregulated expression of the viral genes that produce two proteins, E6 and E7. These proteins promote uncontrolled cell division and an accumulation of mutations in infected cells, ultimately leading to cancer.

Using laboratory-grown 20861 cells, which are derived from human cervical epithelial cells, NIAID researchers and their colleagues showed previously that multiple copies of the HPV16 genome were integrated into one region of the genome of 20861 cells. This formed a “super-enhancer-like element”—a stretch of DNA that drives increased E6/E7 gene expression.

In a follow-up study, the NIAID-led team characterized in detail the integration site in 20861 cells to gain insights on the mechanisms that result in high levels of E6/E7. For comparison, they also looked at an HPV-infected human cervical epithelial cell line that harbors multiple copies of HPV16 that are not integrated into the host-cell genome.

The team found that 20861 cells contained more than two dozen copies of both the integrated HPV16 genome and a large section of the host-cell genome adjacent to the integration site. This region of host-cell DNA includes a cellular enhancer element that can alter gene expression. The combination of viral and host-cell DNA sequences creates a super-enhancer that drives high E6/E7 levels. This “hijacking” of a cellular enhancer resulting in formation of a viral-cellular super-enhancer is a novel mechanism by which HPV integration can transform normal cells into cancer cells. These findings suggest that cancer cells that harbor integrated HPV could ultimately be targeted by therapies that disrupt super-enhancer function.

Reference: Warburton A et al. HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression. PLoS Genet. 2018 Jan 24;14(1):e1007179.

Anti-Malaria Antibodies From Mother Protect Infants From Severe Malaria

Malaria caused by infection with Plasmodium falciparum (P. falciparum) parasites kills up to 300,000 children in sub-Saharan Africa each year. In areas where malaria is widespread, children suffer the most from the disease, particularly when they are more than 6 months old. Researchers have known for decades that newborns and young infants in these areas are relatively resistant to malaria infection and to severe malaria, and they have speculated that this resistance is due to antibodies from the mother.

Following up on earlier findings, NIAID-funded researchers and their colleagues in NIAID’s Laboratory of Malaria Immunology and Vaccinology investigated whether antibodies that target a P. falciparum protein called PfSEA-1 are transferred from mother to child during pregnancy, and whether these antibodies are associated with a reduced severity of malaria in the infants.

The researchers studied 647 mother-child pairs in northeastern Tanzania. They collected umbilical cord blood samples from the infants when they were born and followed the children every 2 weeks from birth until they were 1 year old. In the 583 infants with complete follow-up data, the researchers found that anti-PfSEA-1 antibodies in cord blood, but not antibodies to several other P. falciparum proteins, were associated with a reduced risk of severe malaria at ages 9 and 12 months. Infants with the highest levels of anti-PfSEA-1 antibodies had 51.4 percent fewer cases of severe malaria in their first year of life than infants with lower levels of these antibodies.

The team also looked at whether anti-SEA-1 antibodies can protect newborns from malaria in an experimental mouse model of malaria. They vaccinated female mice with SEA-1A from a malaria parasite that infects rodents to generate anti-SEA-1 antibodies, mated the mice, and exposed the newborn mice (pups) to malaria. Pups born to SEA-1–vaccinated mothers had significantly lower blood levels of malaria parasites and survived longer than pups born to non-vaccinated mothers. Furthermore, several of the pups born to vaccinated mothers appeared to be cured of malaria after becoming infected.

Together, these study findings are the first demonstration that antibodies to a malaria protein, SEA-1, from the mother can confer resistance to severe malaria or death in the offspring. The results also suggest that vaccinating pregnant women with PfSEA-1 could help their infants survive malaria infection.

Reference: Maternally derived antibodies to schizont egress antigen-1 and protection of infants from severe malaria. Kurtis JD et al. Clinical Infectious Diseases. 2018 Aug 25. [published online ahead of print]

New Clues to Why Influenza Illness Is More Severe in Women than Men

Differences in disease severity between females and males have been described for several pulmonary (lung) infections, including influenza (flu). In influenza infections, studies have shown that females have more inflammation in the lungs and overall have a more severe outcome compared to males, despite having comparable levels of flu virus in the body. This suggests that the worse outcome in females may result from an inability to resolve inflammation rather than a failure in controlling viral replication.

To help understand the disparate outcomes between males and females following influenza infection, NIAID-funded researchers looked for possible sex-based differences in production of a growth factor called amphiregulin (AREG). This growth factor helps control tissue repair of membranes that line body cavities, such as in the respiratory tract. In response to damage from inflammation, cells that line the nasal cavities and airways release AREG and other factors that help repair and restore the integrity of tissues damaged during infection.

The researchers found that AREG production was greater in lung tissue and laboratory-grown cells derived from males (both human and mouse) than from females. They further showed that this difference, along with the presence of the male sex hormone testosterone, contributed to the faster recovery of males as compared to females following influenza infection. This finding suggests that AREG and testosterone both contribute to limiting tissue damage from inflammation and mediate faster repair of damaged lung tissue.

Results from this study contribute to our understanding of the differences between males and females following influenza infection. Damage from inflammation contributes to more severe outcomes in several types of infection, including HIV, influenza, and Staphylococcus aureus. This study suggests that males may better tolerate influenza infections and have improved repair and recovery of damaged tissue, and that this sex-based difference is mediated by elevated levels of both AREG and testosterone, either independently or in combination.

Reference: Vermillion MS et al. Production of amphiregulin and recovery from influenza is greater in males than females. Biology of Sex Differences. 2018 July 17; 9(1):24.

Lung Function of Pregnant Mice Is Unaffected Following Influenza Virus Infection

Pregnant women are known to be more susceptible to infectious and non-infectious respiratory disease compared to non-pregnant women. Infection with influenza A (flu) viruses (IAV) in pregnant women results in more severe disease, especially in the third trimester of pregnancy, when pregnant women are more likely to be hospitalized and twice as likely to die from influenza-associated disease. Pregnancy is known to induce both anatomic and functional changes in pulmonary (lung) physiology, but little is known about how these changes affect the course of respiratory diseases.

NIAID-funded investigators used a mouse model to investigate how pregnancy affects the response to IAV infection. They examined the changes in pulmonary structure and function in pregnant and nonpregnant mice following IAV infection. Healthy pregnant mice had several features of enhanced pulmonary function compared with healthy nonpregnant mice. After IAV infection, both pregnant and nonpregnant mice showed reduced levels of the hormone progesterone. These lower progesterone levels were associated with features of reduced pulmonary function in nonpregnant mice. However, in pregnant mice the lower progesterone levels were associated with adverse pregnancy outcomes but did not significantly alter pulmonary function.

The mechanisms responsible for increased disease severity in pregnant women following IAV infection are unknown. This study showed that while pregnant mice display significant illness and death following IAV infection, there is no associated reduction in pulmonary function. Further, pregnant mice maintained the ability to mount sufficient antiviral responses to clear IAV infection. The findings suggest that lung-specific physiological and immune responses to IAV are not a major contributor to the increased disease severity seen during pregnancy.

Reference: Vermillion MS et al. Pregnancy preserves pulmonary function following influenza virus infection in C57BL/6 mice. American Journal of Physiology–Lung Cellular and Molecular Physiology. 2018 Oct 1;315(4):L517–L525.

Estrogen Reduces Lung Inflammation and Protects Female Mice From Severe Influenza

Estrogens are reproductive hormones that influence a range of processes in both females and males. Estriol (E3), one of three forms of estrogen that females produce, has wide-ranging activity in diverse tissue types. Because E3 has relatively weak effects on breast and uterine tissues, treating women with E3 is associated with a lower risk of breast and uterine cancer compared with other forms of estrogen. E3 also has anti-inflammatory effects and can reduce the severity of autoimmune diseases such as multiple sclerosis. Despite these properties, little is known about the role of E3 in infectious diseases.

Since influenza A virus (IAV) infection causes excessive inflammation in the lungs, NIAD-funded researchers investigated the effects of E3 treatment on influenza infection in mice. Treating female mice with E3 reduced total lung inflammation and improved disease outcome following infection with nonlethal doses of IAV. Further, E3 treatment reduced the activity of genes in the lungs that code for inflammatory molecules. These changes in gene expression resulted in reduced movement of immune cells into the lungs and other immune changes associated with reduced disease severity. Despite these alterations in immune responses, viral replication and clearance from the body did not change with E3 treatment, suggesting that E3-treated mice maintained enough antiviral immunity despite reduced overall inflammation.

Increasing evidence suggests that the activity of estrogens may contribute to some of the differences in disease severity observed between males and females. Although the mechanisms of estrogen-modulated impacts on the course of disease are complex and vary between tissues, overall evidence indicates that estrogen-dependent effects can impact immune responses. Specifically, results from this study suggest that treatment with E3 is protective during IAV infection, and that E3 may have broad potential as a therapy for both infectious and noninfectious inflammatory diseases.

Reference: Vermillion MS. et al. Estriol Reduces Pulmonary Immune Cell Recruitment and Inflammation to Protect Female Mice From Severe Influenza. Endocrinology. 2018 Sep 1;159(9):3306–3320.

Pregnancy Loss Associated with Zika Virus Infection May Be More Common than Thought

Zika virus can be passed from an infected pregnant woman to her fetus and cause a range of birth defects collectively known as congenital Zika syndrome. Although Zika virus was first discovered in 1947, Zika-related birth defects were not reported until 2015, during a large outbreak of Zika in the Americas.

The incidence of miscarriage and stillbirth in women infected with Zika virus during pregnancy is unknown and may depend on a number of factors. Research published in 2018 in the New England Journal of Medicine showed a 5.8 percent miscarriage rate and a 1.8 percent stillbirth rate in a group of pregnant women with Zika virus infection. However, these rates could be an underestimate because this and other human studies of Zika-associated fetal loss included only pregnant women who displayed signs or symptoms of Zika infection, whereas many people with Zika infection do not have symptoms (are asymptomatic).

In a recent analysis, a large team of experts funded in part by NIAID combined data on Zika-infected nonhuman primates (NHPs) from six National Primate Research Centers in the United States. The physiology of NHPs and their clinical course of Zika virus infection is similar to that of humans. And, as in humans, many Zika virus infections in NHPs do not show substantial clinical signs.

For the analysis, researchers combined published and unpublished data from various studies of pregnant macaques infected with Zika virus. Fetal death (miscarriage or stillbirth) occurred in 13 of 50 (26 percent) of the animals studied. Macaques infected early in pregnancy had significantly higher rates of fetal death than those infected after 55 days of pregnancy. The results track with human data showing more severe fetal outcomes in women infected with Zika in their first trimester compared to those infected later in pregnancy.

The findings raise the concern that Zika virus-associated pregnancy loss in humans may be more common than currently thought, according to the study authors. In addition, they conclude, the rates of fetal death in macaques underscore the need for careful monitoring of fetal loss and stillbirth in Zika-affected human pregnancies.

Reference: Dudley DM et al. Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates. Nature Medicine. 2018 Aug;24(8):1104–1107.

The above summary was adapted from a NIAID news release.

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