Estradiol May Increase Resistance To Sexually Transmitted Diseases Interview with:

Charu Kaushic. PhD. Professor OHTN Applied HIV Research Chair Department of Pathology and Mol. Medicine McMaster Immunology Research Center, McMaster University

Dr. Charu Kaushic

Charu Kaushic. PhD.
OHTN Applied HIV Research Chair
Department of Pathology and Mol. Medicine
McMaster Immunology Research Center,
McMaster University What is the background for this study? What are the main findings?

Dr. Kaushic: Female sex hormones, estradiol and progesterone have been shown to regulate immune responses in many experimental and clinical studies. We and others have shown previously that these hormones also regulate susceptibility to and outcome of sexually transmitted infections (STIs), including Chlamydia, HSV-2, SIV and HIV-1. Most studies show that progesterone generally increases susceptibility while estradiol generally confers protection against STIs. This has recently gained much more widespread attention because of the controversy surrounding use of injectable hormonal contraceptives in geographical areas where there is high prevalence of HIV-1. The most frequently used injectable contraceptive uses a progestin-based formulation which has been correlated with 2-fold increase in HIV acquisition and transmission in epidemiological studies. Oral contraceptives that contain a combination of estradiol and progesterone do not show similar correlation with increased infection. This is currently a very important women’s health issue, which is being carefully monitored by many public health agencies, including WHO. Many researchers are focusing efforts in understanding how sex hormones can increase or decrease susceptibility of women to STIs.

We have published in this area for more than a decade, including a series of papers showing that in a mouse model, the outcome of genital herpes (HSV-2) infection can depend on which hormone we treat the mice with. A few years ago, we showed for the first time that mice that received an HSV-2 vaccine under the influence of estradiol were much better protected and showed less disease pathology (Bhavanam et al, Vaccine 2008). These results were reproduced a year later by another group, using an actual HSV-2 vaccine formulation. Since then, we have been working to understand at a cellular level, the underlying mechanism of estradiol-mediated enhanced protection. In this PLOS Pathogens paper, we report for the first time a cellular mechanism by which estradiol was seen to enhance immune protection against HSV-2 infection in mice.

The main findings are that estradiol primes dendritic cells in the vaginal tract to induce enhanced anti-viral T cell responses. Dendritic cells are key immune cells that decide what type of immune responses will be mounted against an infection. Under the influence of estradiol, the dendritic cells in the vaginal tract of mice induced Th17 cells which in turn helped enhance anti-viral T cell responses (Th1), resulting in better protection against genital HSV-2. This regulation of anti-viral immunity was seen only in the reproductive tract. What should clinicians and patients take away from your report?

Dr. Kaushic: Once these findings can be confirmed in women, these studies could have important implications in a number of areas, including whether women at a higher risk of acquiring STIs should be on choosing their contraceptives carefully. The clinicians might want to consider their patient’s risk before prescribing specific types of contraceptives. More broadly, understanding how to enhance protection against sexually transmitted viral infection will help in designing better prophylactic strategies, including vaccines. What recommendations do you have for future research as a result of this study?

Dr. Kaushic: One of the immediate lines of research to pursue would be to verify if similar effect of estradiol on anti-viral immunity is seen in women. First evidence to look for would be whether Th17 cells are present in reproductive tract of women and if this population is altered with hormonal changes, for example during menstrual cycle or in women taking hormonal contraceptives. There are already reports that Th17 cells are present in genital tract of women, but it is currently not known whether they are regulated by sex hormones. If so, then next steps would be to measure improvements in anti-viral immunity in women by functional tests. Thank you for your contribution to the community.


Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway

Varun C. Anipindi, Puja Bagri, Kristy Roth, Sara E. Dizzell, Philip V. Nguyen, Christopher R. Shaler, Derek K. Chu, Rodrigo Jiménez-Saiz, Hong Liang, Stephanie Swift, Aisha Nazli, Jessica K. Kafka, Jonathan Bramson, Zhou Xing, Manel Jordana, Yonghong Wan, Denis P. Snider, Martin R. Stampfli, Charu Kaushic. Estradiol Enhances CD4 T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway. PLOS Pathogens, 2016; 12 (5): e1005589 DOI: 10.1371/journal.ppat.1005589

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