More time to kill: A longer liver stage increases T cell-mediated protection against pre-erythrocytic malaria

Naveen Yadav; Chaitra Parthiban; Zachary P Billman; Brad C Stone; Felicia N Watson; Kevin Zhou; Tayla M Olsen; Irene Cruz Talavera; Annette Mariko Seilie; Anya C Kalata; Jokichi Matsubara; Melanie J Shears; Rebekah A Reynolds; Sean C Murphy

doi:10.1016/j.isci.2023.108489

More time to kill: A longer liver stage increases T cell-mediated protection against pre-erythrocytic malaria

iScience. 2023 Nov 20;26(12):108489. doi: 10.1016/j.isci.2023.108489. eCollection 2023 Dec 15.

Authors

Naveen Yadav^{1

2}, Chaitra Parthiban^{1

2}, Zachary P Billman^{1

2}, Brad C Stone^{1

2}, Felicia N Watson^{1

2}, Kevin Zhou^{1

2}, Tayla M Olsen^{1

2}, Irene Cruz Talavera^{1

2}, Annette Mariko Seilie^{1

2}, Anya C Kalata^{1

2}, Jokichi Matsubara^{1

2}, Melanie J Shears^{1

2}, Rebekah A Reynolds^{1

2}, Sean C Murphy^{1

2

3}

Affiliations

¹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
² Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA.
³ Department of Microbiology, University of Washington, Seattle, WA, USA.

Abstract

Liver stage (LS) Plasmodia mature in 2-2.5 days in rodents compared to 5-6 days in humans. Plasmodium-specific CD8⁺ T cell expansion differs across these varied timespans. To mimic the kinetics of CD8⁺ T cells of human Plasmodium infection, a two-dose challenge mouse model that achieved 4-5 days of LS antigen exposure was developed. In this model, mice were inoculated with a non-protective, low dose of late-arresting, genetically attenuated sporozoites to initiate T cell activation and then re-inoculated 2-3 days later with wild-type sporozoites. Vaccines that partially protected against traditional challenge completely protected against two-dose challenge. During the challenge period, CD8⁺ T cell frequencies increased in the livers of two-dose challenged mice but not in traditionally challenged mice, further suggesting that this model better recapitulates kinetics of CD8⁺ T cell expansion in humans during the P. falciparum LS. Vaccine development and antigen discovery efforts may be aided by using the two-dose challenge strategy.

Keywords: Biochemistry; Hepatology; Immunology.

Abstract

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