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
Affiliations
Naveen Yadav
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Chaitra Parthiban
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Zachary P. Billman
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Brad C. Stone
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Felicia N. Watson
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Kevin Zhou
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Tayla M. Olsen
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Irene Cruz Talavera
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Annette Mariko Seilie
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Anya C. Kalata
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Jokichi Matsubara
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Melanie J. Shears
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Rebekah A. Reynolds
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA
Sean C. Murphy
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA, USA; Department of Microbiology, University of Washington, Seattle, WA, USA; Corresponding author
Summary: 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.
