A Plasmodium parasite with complete late liver stage arrest protects against preerythrocytic and erythrocytic stage infection in mice

Ashley M. Vaughan, Brandon Wilder, Dorender Dankwa, Nana Minkah, Thao Nguyen, Hayley Cardamone, Stefan H.I. Kappe

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere00088-18
JournalInfection and Immunity
Volume86
Issue number5
DOIs
StatePublished - May 1 2018
Externally publishedYes

Fingerprint

Plasmodium
Parasites
Liver
Infection
Sporozoites
Plasmodium yoelii
Gene Deletion
Immunization
Malaria
Antibody Formation

Keywords

  • Attenuated
  • GAP
  • Liver stage
  • Malaria
  • Plasmodium
  • Preerythrocytic
  • Protection
  • Sporozoite
  • Vaccine

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

A Plasmodium parasite with complete late liver stage arrest protects against preerythrocytic and erythrocytic stage infection in mice. / Vaughan, Ashley M.; Wilder, Brandon; Dankwa, Dorender; Minkah, Nana; Nguyen, Thao; Cardamone, Hayley; Kappe, Stefan H.I.

In: Infection and Immunity, Vol. 86, No. 5, e00088-18, 01.05.2018.

Research output: Contribution to journalArticle

Vaughan, Ashley M. ; Wilder, Brandon ; Dankwa, Dorender ; Minkah, Nana ; Nguyen, Thao ; Cardamone, Hayley ; Kappe, Stefan H.I. / A Plasmodium parasite with complete late liver stage arrest protects against preerythrocytic and erythrocytic stage infection in mice. In: Infection and Immunity. 2018 ; Vol. 86, No. 5.
@article{55a268cb14604c60ad7ac2107a5f4363,
title = "A Plasmodium parasite with complete late liver stage arrest protects against preerythrocytic and erythrocytic stage infection in mice",
abstract = "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.",
keywords = "Attenuated, GAP, Liver stage, Malaria, Plasmodium, Preerythrocytic, Protection, Sporozoite, Vaccine",
author = "Vaughan, {Ashley M.} and Brandon Wilder and Dorender Dankwa and Nana Minkah and Thao Nguyen and Hayley Cardamone and Kappe, {Stefan H.I.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1128/IAI.00088-18",
language = "English (US)",
volume = "86",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "5",

}

TY - JOUR

T1 - A Plasmodium parasite with complete late liver stage arrest protects against preerythrocytic and erythrocytic stage infection in mice

AU - Vaughan, Ashley M.

AU - Wilder, Brandon

AU - Dankwa, Dorender

AU - Minkah, Nana

AU - Nguyen, Thao

AU - Cardamone, Hayley

AU - Kappe, Stefan H.I.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

KW - Attenuated

KW - GAP

KW - Liver stage

KW - Malaria

KW - Plasmodium

KW - Preerythrocytic

KW - Protection

KW - Sporozoite

KW - Vaccine

UR - http://www.scopus.com/inward/record.url?scp=85045931952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045931952&partnerID=8YFLogxK

U2 - 10.1128/IAI.00088-18

DO - 10.1128/IAI.00088-18

M3 - Article

VL - 86

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 5

M1 - e00088-18

ER -