Notice of Special Interest: Emerging Viral Infections and their Impact on the Male and Female Reproductive Tract
Notice Number:
NOT-HD-20-021

Key Dates

Release Date:

September 1

First Available Due Date:
October 05, 2020
Expiration Date:
July 16, 2023

Related Announcements

None

Issued by

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers. The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Office of Research on Women's Health (ORWH)

Purpose

Purpose

The purpose of this Notice is to invite applications proposing cutting-edge research on emerging viral infections that are thought to primarily impact non-reproductive sites, at least at initial presentation, but may also affect the male and/or female reproductive tract. The recent global outbreak of the novel coronavirus, SARS-CoV-2, is not an anomaly and will most likely not be the last virus occurrence. Today, infectious diseases are emerging and reemerging more quickly than ever before. In the last four-five years alone, two viral infections, one caused by the Zika virus (ZIKV) and the other caused by a SARS-CoV-2 (Covid19), have spread world-wide, resulting in death, severe disease with yet, unknown, long-term morbidities., or severe birth defects to the new-born. Both ZIKV and SARS-CoV-2 infections may affect male and/or female reproductive systems in addition to other non-reproductive sites. Therefore, it becomes essential to investigate possible effects of emerging viruses on reproductive tissues and cells to better understand potential impacts on fertility that may be sex specific.

Background:

The Zika virus, a flavivirus, is primarily transmitted by Aedes mosquitos; more recently it has been found to be transmitted sexually, unlike other flaviviruses. To date, more than 80 countries and territories have reported evidence of mosquito-transmitted Zika infection. While most people with Zika virus infection are asymptomatic, those that do develop symptoms can experience fever, rash, muscle and joint pain or headaches. More seriously, Zika virus infection during pregnancy can cause infants to be born with microcephaly and other congenital malformations, Congenital Zika Syndrome. Pregnant women can also experience preterm birth and miscarriage.

Evidence of sexual transmission prompted the investigation of male and female reproductive tracts as ZIKV reservoirs. Several groups have demonstrated that ZIKV exhibits tropism for the male reproductive tract. The virus infects Sertoli cells in the testis and causes inflammation leading to structural damage and breakdown of the blood-testis barrier (BTB) in mice. It has been suggested that infection can lead to oligospermia. Interestingly, ZIKV RNA can be detected in semen up to 370 days post the onset of symptoms.

In females, ZIKV RNA has been detected in cervical mucus and vaginal secretions after its clearance from blood. However, in comparison with the male genital tract, the consequences of ZIKV infection on the female genital tract have not been extensively evaluated. Rather, most studies evaluated ZIKV infections in the genital tract of pregnant women due to the relationship between ZIKV and congenital abnormalities of the offspring.

The recent COVID-19 pandemic is caused by a novel coronavirus called SARS-CoV-2. Human infectivity with coronaviruses has occurred previously with MERS-CoV and SARS-CoV. Similar to those infected with ZIKV, people with SARS-CoV-2 infection can be asymptomatic, exhibit a wide range of mild symptoms (cough, chills, fever, loss of taste or smell) or present with severe illness (severe difficulty in breathing, kidney failure, stroke) and death. The virus is extremely transmissible from person-to-person.

Data points to binding of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2), a component of the renin-angiotensin system. Receptors for ACE2 are plentiful in the lungs, the gastrointestinal tract, the kidney, and the heart, all organs affected by SARS-CoV-2 infection. The receptor is also expressed at high levels in the human testis, where it is found in both Sertoli and Leydig cells. One hypothesis is that the testes may harbor SARS-CoV-2 in men, providing it sanctuary from the immune system, beyond the BTB. There are precedents for a pathogen taking up residence in a quiet niche to elude the body’s immune defenses, e.g., the Ebola virus was found to hide in the pigment cells human retina, leaving even recovered patients with lingering virus. Angiotensin-converting enzyme 2 is also localized in the clear cells of the cauda epididymis that are postulated to have an important immune function. Similar to the ZIKA virus, less is known about the presence and effect of SARS-CoV-2 in the female reproductive tract. However, it has been reported that ACE2 is expressed in the ovary, uterus, vagina and placenta. Recently, evidence of vertical transmission of the novel coronavirus from mother to child during pregnancy was also reported. It is possible that transmission may be related to the timing of the pregnancy, i.e., 1st, 2nd, 3rd trimester) or the timing in the menstrual cycle, i.e., proliferative vs. secretory phase).

Scope

Currently, knowledge gaps exist in our understanding of viral infections of both male and female reproductive tract tissues. This NOSI is interested in the recently emergent ZIKA and novel corona viruses, as well as other yet unidentified viruses which may significantly impact public health. Areas of interest of this NOSI include, but are not limited to:

  • Consequences of infection, e.g., cells affected and outcomes of infection – infertility, miscarriage, live births, orchitis, epididymitis, pelvic pain;
  • Mechanism of action for infectivity of reproductive tract tissues;
  • Mechanism of sexual transmission;
  • Whether the reproductive tract acts as a reservoir for viruses;
  • Sex-specific differences in infection as they may relate to reproductive tract tissues and cells;
  • The impact of race and ethnicity on reproductive system impacts of viruses;
  • Impact of nutrition, e.g., Vitamin D sufficiency and the understanding of mechanisms that explain the impact of obesity;
  • Development of model systems to study infections in reproductive tract tissues, e.g., organoids (for R21 applications only)

Non-responsive applications:

  • Infections exclusively localized to the reproductive tract, e.g., urinary tract infections, chlamydia, HPV, HSV, hepatitis B;
  • Epidemiological analysis of a particular infection.

Application and Submission Information

This notice applies to due dates on or after October 5, 2020 and subsequent receipt dates through July 16, 2023. 

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

  • PA-20-185- NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-18-482 - NICHD Exploratory/Developmental Research Grant (R21 - Clinical Trial Optional)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-HD-20-021” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the Scientific/Research, Peer Review, and Financial/Grants Management contacts in Section VII of the listed funding opportunity announcements.

Scientific/Research Contact(s)

Stuart B. Moss, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6979
Email: mossstua@mail.nih.gov


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