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Science Advances—FY 2014

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

HIV/AIDS
Immunology
Infectious Diseases (Other Than HIV/AIDS)

HIV/AIDS

HIV Superinfection in Female Sex Workers

If an HIV-infected individual becomes subsequently infected with a different strain of HIV, they are said to be superinfected. If superinfection occurs, the infected person may progress more rapidly to AIDS and show less sensitivity to therapy. NIAID intramural researchers demonstrated that HIV superinfection occurred at a high rate and was similar to that of primary HIV infection in Ugandan female sex workers. The results of this study differed from a similar study of high-risk female bar workers in Kenya that found the rate of superinfection to be significantly lower than the rate of primary HIV infection. Regardless of the relationship between rates of superinfection and primary infection, however, the findings suggest that individuals who are participating in higher-risk behavior are most likely at increased risk of both primary HIV infection and superinfection. These findings add to the growing evidence that HIV superinfection occurs at a significant rate throughout the world.

Reference: Redd AD, Ssemwanga D, Vandepitte J et al. Rates of HIV-1 superinfection and primary HIV-1 infection are similar in female sex workers in Uganda. AIDS. 2014 Sep 10;28(14):2147-52.

A Protein in Breast Milk Inhibits HIV Transmission From Mothers to Their Infants

To achieve an AIDS-free generation, strategies that prevent the transmission of HIV from mother to child after birth are critical, particularly in developing countries. Surprisingly, more than 90 percent of children breastfed from HIV-infected mothers do not contract HIV. NIAID-funded researchers identified a specific protein in breast milk, called Tenascin-C, which neutralizes HIV. Researchers believe that the anti-HIV properties of Tenascin-C contribute to protecting infants against infection. This knowledge about protective proteins in breast milk could be used to develop new safe and effective treatments to prevent postnatal and other types of HIV transmission.

Reference: Fouda GG, Jaeger FH, Amos JD et al. Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk. Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18220-5.

Social and Cultural Factors Influence Effectiveness of HIV Prevention Strategies in Women

Pre-exposure prophylaxis (PrEP) is a Food and Drug Administration-approved HIV prevention approach for people at high risk of contracting HIV. To prevent infection, healthy individuals take daily doses of antiviral therapy. NIAID-funded researchers evaluated the results from a 2010–2012 clinical study in South Africa, which showed that two PrEP strategies in women were ineffective because of lack of patient adherence to daily treatment regimens. The researchers found that social and cultural factors influenced women’s daily use of antiviral therapy. Misunderstandings about the trial were common, including about the rationale for having healthy individuals take antiviral drugs when not infected with HIV. In addition, women were challenged with physical side effects and negative attributes of the treatments and faced social stigmas associated with being on HIV therapy. These results suggest that social and cultural factors must be considered when designing and implementing future HIV PrEP clinical trials.

Reference: van der Straten A, Stadler J, Montgomery E et al. Women's experiences with oral and vaginal pre-exposure prophylaxis: the VOICE-C qualitative study in Johannesburg, South Africa. PLoS One. 2014 Feb 21;9(2):e89118.

Immunology

Sex Hormones and Other Factors That Affect Asthma Prevalence in Adolescent Girls

Asthma is a severe and chronic disease that causes wheezing, breathlessness, chest tightness, and coughing. Development of asthma is influenced by both genetic and environmental factors. The prevalence of asthma in girls increases after puberty, and previous studies have identified an association between asthma and sex hormones—both those produced by the body and those in medications. In this study, NIAID-supported researchers identified a process by which sex hormones lead to modifications of the gene GATA3, which in turn regulate the so-called T-helper 2 (Th2) immune response associated with asthma. This process was influenced by both oral contraceptive use and a woman’s age at first menstrual cycle, revealing a pathway that may explain how sex hormones in women can increase asthma prevalence after puberty.

To determine the genetic factors and processes that influence asthma incidence in adolescent females, this team of investigators analyzed how the process of DNA methylation of genes in the Th2 pathway affects asthma risk in girls 10 to 18 years of age. DNA methylation is a type of chemical modification that alters gene activity while leaving the underlying genetic code unchanged. The results show that interaction between DNA methylation and genetic sequence variations in genes of the Th2 pathway likely contributes to asthma risk in girls. Furthermore, this effect may vary with age, which may influence asthma during the transition from childhood to adulthood.

References: Guthikonda K, Zhang H, Nolan VG, et al. Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation. Clin Epigenetics. 2014 Sep 19;6(1):17.

Zhang H, Tong X, Holloway JW, et al. The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition. Clin Epigenetics. 2014 Apr 15;6(1):8.

A Genome-Wide Study of Sex-Specific Asthma Risk Genes

Whereas genes on the human sex chromosomes are known to contribute to differences in disease prevalence and risk, the effect of genes from autosomal (non-sex) chromosomes on these differences has not been as well studied. NIAID-funded researchers searched for sex-specific asthma risk genes through a genome-wide scan for interactions between autosomal genes and male or female physiological factors. The researchers studied a group of ethnically diverse individuals of European American, African American, African Caribbean, and Latino ancestries. The study identified six sex-specific chromosome regions, or loci, associated with asthma risk, all of which were connected with specific ancestries. One chromosome region, the interferon regulatory factor 1 (IRF1) locus, contains a gene that has a known role in immune pathways involved in asthma. These findings, along with prior reports of sex-specific differences in interferon responses, suggest that the IRF1 locus is a strong candidate for contributing to male-specific asthma risk.

Reference: Myers RA, Scott NM, Gauderman WJ, et al. Genome-wide interaction studies reveal sex-specific asthma risk alleles. Hum Mol Genet. 2014 Oct 1;23(19):5251-9.

Maternal Diet May Reduce Childhood Allergy and Asthma

In the United States, food allergy and asthma occur in approximately 5 percent and 8.4 percent of people, respectively. Researchers have long suspected that maternal diet during pregnancy plays a role in the development of childhood allergy and asthma but previous study results have been conflicting. Unlike previous analyses that focused on late pregnancy, this NIAID-supported study examined the effect of maternal diet during the first two trimesters of pregnancy on the development of childhood asthma and allergy. The results showed that higher maternal intake of peanut, milk, and wheat during early pregnancy was associated with reduced odds of mid-childhood allergy and asthma, suggesting that eating these foods during pregnancy could help curb the rising incidence of asthma and allergy in the United States.

Reference: Bunyavanich S, Rifas-Shiman SL, Platts-Mills TA, et al. Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children. J Allergy Clin Immunol. 2014 May;133(5):1373-82.

Local Immunological Memory in Vaginal Tissue Leads to Improved Protection From STIs

Long-term immunity to infectious diseases relies on the immune system’s ability to recognize previously encountered pathogens during reinfections. This immunological memory is facilitated in part by specific components of the immune system called memory T cells. Generated during a prior infection, these cells are ever ready to mount a rapid and powerful response to reinfections. Originally thought to reside only in circulatory systems such as blood, recent studies identified resident memory T cells (Trm) that remain in specific tissues where the infection was first encountered. In this NIAID-funded study, vaginal infection of mice with herpes simplex virus (HSV) led to the generation of local Trm that provided better protection against HSV than did circulatory memory T cells. These results suggest that alternative vaccine strategies for STIs may result in improved disease prevention in women.

Reference: Iijima N, Iwasaki A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science. 2014 Oct 3;346(6205):93-8.

New Insights on the Control of Autoimmune Antibody Production and Inflammation in Lupus

Systemic lupus erythematosus (SLE), more commonly known as lupus, is an autoimmune disease. Inflammation caused by lupus can affect many body systems, including the central nervous system, joints, skin, kidneys, blood cells, heart, and lungs. Approximately 322,000 Americans are diagnosed with or suspected of having SLE, and 90 percent of people with lupus are women. People with SLE produce abnormal antibodies (autoantibodies) that target DNA and RNA from the body’s own cells, contributing to inflammation. Autoantibody production is controlled in part via signals transmitted by two different receptor molecules, TLR7 and TLR9, which are found in various types of immune cells. Through genetic manipulation in mouse models of lupus, NIAID-funded investigators found that TLR7- and TLR9-mediated signaling in immune cells called B cells have opposing effects on inflammation and on the types of autoantibodies produced. These findings stress the critical importance of dysregulated TLR signaling in B cells in the development of SLE and could inform efforts to target TLR signals therapeutically in SLE and other disorders characterized by autoantibody production.

Reference: Jackson SW, Scharping NE, Kolhatkar NS et al. Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. J Immunol. 2014 May 15;192(10):4525-32. 2014.

Loss of Estrogen-Mediated Immune Response Makes Females More Susceptible to Crohn’s Disease

Crohn’s disease is a form of inflammatory bowel disease that affects women with increased severity and at a higher rate than men. To investigate possible mechanisms for this disparity, NIAID-funded researchers studied a strain of mice known as SAMP mice that spontaneously develop chronic intestinal inflammation resembling human Crohn’s disease, with a similar disparity between females and males. They found that T regulatory (Treg) cells, which are known to modulate immune responses, were reduced in frequency and activity in female mice compared to male mice. Male SAMP mice treated with estrogen responded by increasing Tregs that reduced Crohn’s-like symptoms, whereas females were resistant to the effect of estrogen. Further studies showed that estrogen signaling at the receptor level in female mice is disrupted and leads to fewer protective Treg cells. These findings suggest that therapies designed to enhance protective estrogen-mediated signaling in Tregs may be beneficial for treating chronic inflammatory disorders such as Crohn’s disease.

Reference: Goodman WA, Garg RR, Reuter BK et al. Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis. Mucosal Immunol. 2014 Sep;7(5):1255-65.

Infectious Diseases (Other Than HIV/AIDS)

Narrowing the Field of Anti-Malaria Targets

Pregnancy-associated malaria (PAM), or placental malaria, is associated with low birth weight, maternal anemia, and gestational hypertension and is a major cause of death and disease for women and their children in sub-Saharan Africa. NIAID intramural investigators recently shed light on acquired immunity to PAM in mothers and their unborn children and infants. Clinical immunity to PAM is attributed to antibodies that recognize the malaria parasite Plasmodium falciparum protein VAR2CSA on the infected red blood cell surface. However, there has been no consensus on which of VAR2CSA’s six Duffy binding-like (DBL) domains would be most effective in eliciting immunity if used in a vaccine. NIAID-funded investigators have provided the first evidence that, in P. falciparum-exposed women who have had multiple pregnancies, the DBL2χ, DBL3χ, and DBL5ε domains are targeted by antibody opsonization. This finding is highly significant, as antibody opsonization is the process by which a pathogen is marked for ingestion and destruction by white blood cells called phagocytes. This discovery reveals key information for developing effective preventive and therapeutic approaches for PAM and potentially other infectious diseases.

Reference: Lambert LH, Bullock JL, Cook ST et al. Antigen reversal identifies targets of opsonizing IgGs against pregnancy-associated malaria. Infect Immun. 2014 Nov;82(11):4842-53.

New Insights on Vaccination Before Conception for Listeria monocytogenes

Pregnant women are unusually vulnerable to infection with the foodborne bacterium Listeria monocytogenes (Lm), with often deadly consequences for the developing fetus. Vaccinating women before conception has been shown to protect pregnant women and their babies from a wide range of infections. This NIAID-funded study examined whether vaccination for Lm before conception protected against subsequent infection by virulent Lm in pregnant mice. The results showed that even though the mice generated protective Lm-specific immune cells, susceptibility to Lm during pregnancy could not be overcome when researchers mated mice of two different genetic strains. By contrast, vaccination was effective when the parent mice (and thus the mother and fetus) were of the same strain. These findings show that maternal-fetal genetic differences dictate the ineffectiveness of pre-conception vaccination against fetal complications and provide new clues on how physiological shifts during pregnancy regulate immune responsiveness.

Reference: Clark DR, Chaturvedi V, Kinder JM et al. Perinatal Listeria monocytogenes susceptibility despite preconceptual priming and maintenance of pathogen-specific CD8(+) T cells during pregnancy. Cell Mol Immunol. 2014 Nov;11(6):595-605.

Testosterone Suppresses Response to Influenza Vaccination

Females often have more robust immune responses than males to infections and vaccination for reasons that scientists do not fully understand. NIAID-funded researchers showed that, after seasonal influenza vaccination, women produced more antibodies that could effectively neutralize the virus compared to men. Gene expression studies showed that men with weak vaccine responses had high expression levels in a cluster of lipid metabolism genes that may be controlled by the male hormone testosterone. Men with high testosterone levels and elevated gene expression of this cluster exhibited a lower immune response to influenza vaccination compared to women or to men with low testosterone. The results suggest that male hormones may suppress immune responses to vaccines by altering expression of specific genes.

Reference: Furman D, Hejblum BP, Simon N et al. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):869-74.

Male Circumcision Does Not Protect Female Partners From Mycoplasma genitalium

Mycoplasma genitalium is a sexually transmitted disease associated with inflammation of the reproductive system. Among women, the worldwide prevalence of M. genitalium infection is approximately 1 to 5 percent. For men, previous studies have shown that circumcision reduced the risk of acquiring M. genitalium. To determine whether circumcision would also protect female partners of circumcised men, NIAID-funded researchers conducted a clinical trial in Uganda and found that male circumcision did not protect female partners from M. genitalium infection. The researchers suggested that multiple factors may have contributed to the study results. For example, female partners may have engaged in outside relationships, or circumcision may not have affected the infected genital areas of men, such as the urethra.

Reference: Tobian AAR, Gaydos C, Gray RH et al. Male circumcision and Mycoplasma genitalium infection in female partners: a randomised trial in Rakai, Uganda. Sex Transm Infect. 2014 Mar;90(2):150-4.

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Last Updated April 29, 2015