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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Mucosal Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1427842

NET-EN treatment leads to delayed HSV-2 infection, enhanced mucin and T cell functions in the female genital tract when compared to DMPA in a preclinical mouse model

Provisionally accepted
FIROZ MIAN FIROZ MIAN Sydney Pa Sydney Pa Nuzhat Rahman Nuzhat Rahman Amy Gillgrass Amy Gillgrass *Charu Kaushic Charu Kaushic *
  • McMaster Immunology Research Centre, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada

The final, formatted version of the article will be published soon.

    Depot-medroxyprogesterone acetate (DMPA) and Norethisterone Enanthate (NET-EN) are progestinonly injectable contraceptives widely used by women in sub-Sharan Africa, where incidence of HIV-1 and HSV-2 infection remains high. Studies indicate that DMPA usage can increase the risk of HSV-2 infection, but limited data indicate no increased risk with use of NET-EN. We therefore investigated the effects of NET-EN and DMPA on susceptibility to vaginal HSV-2 infection in ovariectomized (OVX) mice and effects on immune responses, particularly in the vaginal tract (VT). OVX mice, when treated with NET-EN and infected intravaginally, had delayed genital pathology, decreased viral shedding, and extended survival compared to DMPA-or untreated OVX mice. CD4+ T cells isolated from VT showed no significant change in frequency with either contraceptive. However, DMPA significantly decreased the total number of VT CD4+ and CD8+ T cells and the number of IFN-γ producing CD4 and CD8 T cells and increased the percentage of CD4 and CD8 T cells producing TNFα compared to untreated mice. In contrast, NET-EN significantly enhanced percentages of CD8+ T cells compared to DMPA treated mice, and frequencies of IFN-γ+ CD4 and CD8 T cells in the VT compared to untreated mice. Comparative analysis of splenic lymphocytes indicated that DMPA treatment resulted in reduction of CD4+ T cell frequency, but enhanced TNF-α+ CD4 T cells compared to untreated mice. NET-EN enhanced the frequency of CD8 T cells, as well as IFN-γ+ and TNF-α+ CD4, and IFN-γ+ CD8 T cells in the spleen compared to untreated mice. Importantly, we found DMPA treatment that significantly reduced mucin production, whereas NET-EN enhanced expression of cellassociated mucin in VT. High levels of mucin in NET-EN mice were associated with lower levels of HSV-2 virus detected in the vaginal tract. This study provides the first evidence that NET-EN treatment can delay HSV-2 infection compared to DMPA.

    Keywords: Net-EN, DMPA, Herpes simplex virus type 2, IFN-γ, TNF-α, mucin, vaginal tract

    Received: 04 May 2024; Accepted: 18 Oct 2024.

    Copyright: © 2024 MIAN, Pa, Rahman, Gillgrass and Kaushic. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Amy Gillgrass, McMaster Immunology Research Centre, Faculty of Health Sciences, McMaster University, Hamilton, L8S 4K1, Ontario, Canada
    Charu Kaushic, McMaster Immunology Research Centre, Faculty of Health Sciences, McMaster University, Hamilton, L8S 4K1, Ontario, Canada

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