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The Injectable Contraceptive Medroxyprogesterone Acetate Attenuates Mycobacterium tuberculosis-Specific Host Immunity
Michele Tomasicchio1, Malika Davids1, Anil Pooran1
1Centre for Lung Infection and Immunity, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town.
Background:
The effects of the widely used progestin-only injectable contraceptives, medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A), on host susceptibility to Mycobacterium tuberculosis (Mtb) are unknown.
Methods:
We recruited human immunodeficiency virus-uninfected females, not taking any contraceptives, from Cape Town, South Africa, to evaluate the effect of MPA, NET-A, and dexamethasone on Mtb containment in monocyte-derived macrophages co-incubated with purified protein derivative (PPD)-driven peripheral blood-derived effector cells.
Results:
MPA (P < .005) and dexamethasone (P < .01), but not NET-A, significantly attenuated Mtb containment in Mtb-infected macrophages co-cultured with PPD-driven effector cells at physiologically relevant concentrations and in a dose-dependent manner. Antagonizing the glucocorticoid receptor with mifepristone (RU486) abrogated the reduction in Mtb containment. In PPD-stimulated peripheral blood mononuclear cells, MPA and dexamethasone, but not NET-A, upregulated (median [interquartile range]) regulatory T cells (5.3% [3.1%-18.2%]; P < .05), reduced CD4+ T-cell interferon-γ (21% [0.5%-28%]; P < .05) and granzyme B production (12.6% [7%-13.5%]; P < .05), and reduced CD8+ perforin activity (2.2% [0.1%-7%]; P < .05). RU486 reversed regulatory T-cell up-regulation and the inhibitory effect on Th1 and granzyme/perforin-related pathways.
Conclusions:
MPA, but not NET-A, subverts mycobacterial containment in vitro and downregulates pathways associated with protective CD8+- and CD4+-related host immunity via the glucocorticoid receptor. These data potentially inform the selection and use of injectable contraceptives in tuberculosis-endemic countries.
Insights
Medroxyprogesterone acetate (MPA) injectable contraceptives impair tuberculosis containment by suppressing immune responses via the glucocorticoid receptor. Norethisterone acetate (NET-A) did not show these effects, suggesting differential impacts of progestin-only contraceptives.
Area of Science:
- Immunology
- Endocrinology
- Infectious Diseases
Background:
- Progestin-only injectable contraceptives like medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A) are widely used globally.
- The impact of these contraceptives on susceptibility to Mycobacterium tuberculosis (Mtb) remains largely unknown.
- Understanding these effects is crucial, especially in tuberculosis-endemic regions.
Purpose of the Study:
- To investigate the effects of MPA, NET-A, and dexamethasone on Mtb containment in human macrophages.
- To elucidate the immunological pathways involved in the interaction between these substances and Mtb infection.
- To assess the role of the glucocorticoid receptor in mediating these effects.
Main Methods:
- Recruitment of HIV-uninfected females in Cape Town, South Africa.
- In vitro co-incubation of monocyte-derived macrophages with Mtb and peripheral blood effector cells stimulated by purified protein derivative (PPD).
- Evaluation of Mtb containment, T-cell responses (T regulatory cells, IFN-γ, granzyme B), and CD8+ T-cell activity, with and without mifepristone (RU486) to antagonize the glucocorticoid receptor.
Main Results:
- MPA and dexamethasone, but not NET-A, significantly reduced Mtb containment in macrophages at physiologically relevant concentrations in a dose-dependent manner.
- The effect of MPA and dexamethasone was abrogated by mifepristone (RU486), indicating mediation via the glucocorticoid receptor.
- MPA and dexamethasone upregulated regulatory T cells and suppressed CD4+ T-cell interferon-γ and CD8+ T-cell perforin activity, effects reversed by RU486.
Conclusions:
- MPA, via the glucocorticoid receptor, impairs Mtb containment and downregulates key CD4+ and CD8+ T-cell mediated immune responses.
- NET-A does not appear to affect Mtb containment or these specific immune pathways.
- Findings suggest that MPA use may influence tuberculosis susceptibility, informing contraceptive choices in endemic areas.
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