Androgens inhibit protective CD8+ T cell responses against pre-erythrocytic malaria parasites in mice

Caroline J. Duncombe, Nilasha Sen, Felicia N. Watson, Alen S. Poehlman, Erik D. Layton, Kenneth Boey, Ethan N. Conrad, Anya C. Kalata, A. Mariko Seilie, Kimberly A. Dill-McFarland, Chetan Seshadri, Melanie J. Shears and Sean C. Murphy ()
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Caroline J. Duncombe: University of Washington
Nilasha Sen: University of Washington
Felicia N. Watson: University of Washington
Alen S. Poehlman: University of Washington
Erik D. Layton: University of Washington
Kenneth Boey: University of Washington
Ethan N. Conrad: University of Washington
Anya C. Kalata: University of Washington
A. Mariko Seilie: University of Washington
Kimberly A. Dill-McFarland: University of Washington
Chetan Seshadri: University of Washington
Melanie J. Shears: University of Washington
Sean C. Murphy: University of Washington

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Attenuated whole organism vaccines targeting the malaria liver stage reliably confer sterile immunity. These vaccines completely protect female mice from infection, but protection in male mice remains unproven. We discover that male mice vaccinated with prime-and-trap, a whole organism-based vaccine strategy, exhibit poorer protection against Plasmodium sporozoite challenge than females. We investigate this sex difference, and identify vaccinated males have fewer hepatic memory CD8+ T cells than females when scaling for liver biomass, and reduced inflammatory responses post-vaccination. Surgical hormone manipulation clarifies that the presence of testicular hormones hinders protection in male mice. The presence of androgens does not affect memory CD8+ T cell quantity nor quality, but reduces recruitment of CD8+ T cells in male liver tissues via a restricted inflammatory response. Here, we show both males and females form functional memory responses following prime-and-trap vaccination, but the presence of androgens during sporozoite challenge impair protection in male mice.

Date: 2025
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DOI: 10.1038/s41467-025-60193-7

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