A Plasmodium Parasite with Complete Late Liver Stage Arrest Protects against Preerythrocytic and Erythrocytic Stage Infection in Mice.

Autor:	Vaughan AM; Center for Infectious Disease Research, Seattle, Washington, USA ashley.vaughan@cidresearch.org stefan.kappe@cidresearch.org., Sack BK; Center for Infectious Disease Research, Seattle, Washington, USA., Dankwa D; Center for Infectious Disease Research, Seattle, Washington, USA., Minkah N; Center for Infectious Disease Research, Seattle, Washington, USA., Nguyen T; Center for Infectious Disease Research, Seattle, Washington, USA., Cardamone H; Center for Infectious Disease Research, Seattle, Washington, USA., Kappe SHI; Center for Infectious Disease Research, Seattle, Washington, USA ashley.vaughan@cidresearch.org stefan.kappe@cidresearch.org.; Department of Global Health, University of Washington, Seattle, Washington, USA.
Jazyk:	angličtina
Zdroj:	Infection and immunity [Infect Immun] 2018 Apr 23; Vol. 86 (5). Date of Electronic Publication: 2018 Apr 23 (Print Publication: 2018).
DOI:	10.1128/IAI.00088-18
Abstrakt:	Genetically attenuated malaria parasites (GAP) that arrest during liver stage development are powerful immunogens and afford complete and durable protection against sporozoite infection. Late liver stage-arresting GAP provide superior protection against sporozoite challenge in mice compared to early live stage-arresting attenuated parasites. However, very few late liver stage-arresting GAP have been generated to date. Therefore, identification of additional loci that are critical for late liver stage development and can be used to generate novel late liver stage-arresting GAPs is of importance. We further explored genetic attenuation in Plasmodium yoelii by combining two gene deletions, PlasMei2 and liver-specific protein 2 ( LISP2 ), that each cause late liver stage arrest with various degrees of infrequent breakthrough to blood stage infection. The dual gene deletion resulted in a synthetic lethal phenotype that caused complete attenuation in a highly susceptible mouse strain. P. yoelii plasmei2 - lisp2 - arrested late in liver stage development and did not persist in livers beyond 3 days after infection. Immunization with this GAP elicited robust protective antibody responses in outbred and inbred mice against sporozoites, liver stages, and blood stages as well as eliciting protective liver-resident T cells. The immunization afforded protection against both sporozoite challenge and blood stage challenge. These findings provide evidence that completely attenuated late liver stage-arresting GAP are achievable via the synthetic lethal approach and might enable a path forward for the creation of a completely attenuated late liver stage-arresting P. falciparum GAP. (Copyright © 2018 American Society for Microbiology.)
Databáze:	MEDLINE
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