Download - Session 10: Immunity to Malaria
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IMMUNITY TO MALARIA
Fidel Zavala
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Plasmodium Life Cycle
MOSQUITOES MOSQUITOES
SPOROZOITES
GAMETOCYTES
ASEXUAL BLOOD STAGESLIVER STAGES
RING
TROPHOZOITE
SCHIZONT
MEROZOITES
F. Zavala
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SPOROZOITE LIVER BLOOD MEROZOITES
Plasmodium StagesPlasmodium Stages
(Serum) (Hepatocytes) (Erythrocytes) (Serum)
* SUSCEPTIBLE TO DIFFERENT IMMUNE MECHANISMS
* EXPRESS DIFFERENT ANTIGENS
* LIVE IN DIFFERENT ENVIRONMENTS
F. Zavala
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Immune Responses toPre-Erythrocytic States
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CDC
• Mosquitoes inject dozens of sporozoites into the dermis
• Parasites reach the blood and infect hepatocytes
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Sporozoite-Induced Immune Response
• Normal exposure to parasites does not induce a response strong enough to protect against infection.
• In experimental immunizations, large immunizing doses are required to achieve protection
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Immunization of Humans with P. falciparum-Infected Irradiated Mosquitoes
ANTIGENS?ANTIGENS?PROTECTIVE IMMUNE MECHANISMS???PROTECTIVE IMMUNE MECHANISMS???Bull WHO 1978;57(suppl 1):263
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Antibodies Abolish Sporozoite Infectivity
Photograph courtesy of Masamichi Aikawa
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Antibodies Against The SporozoiteSurface Inhibit
• Parasite Motility
• Hepatocyte Invasion
They can confer sterile immunity…
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Sterile Protection AgainstSporozoite-Induced Infection
• High levels of antibodies
• High binding affinity
• Maintained for a long time
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Immunity To Malaria Liver StagesImmunity To Malaria Liver Stages
α, β CD8+ T cellsα,β CD4+ T cells
γ δ T cells?NK/NKT cells?
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Persistence of the CD8+ T Cell Response After a Immunization with
Sporozoites
0 30 60 90 120 150 180
Days after immunization
IFN
γse
c ret
ing
cells
/ 106
lym
phoc
ytes
LIVER
SPLEEN
0
2500
5000
7500
0
4000
8000
12000
F. Zavala
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Plasmodium Life Cycle
ANTIBODIES T-CELLS
MOSQUITOES MOSQUITOES
SPOROZOITES
GAMETOCYTES
ASEXUAL BLOOD STAGESLIVER STAGES
RING
TROPHOZOITE
SCHIZONT
MEROZOITES
F. Zavala
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Natural Immunity?
• It is difficult to become immune by natural exposure
• Serum titers from natural infected individuals to sporozoite antigen in IFA is in low hundreds in contrast to immunized individuals with titers in thousands
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Identification Of P. Falciparum CD8+T-Cell Epitopes Recognized By Humans
Specific amino acid residues composing epitopes from CSP, SSP2, EXP1, LSA1, and PfS16 proteins
But at very low levelsBut at very low levels……....
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Immunization of Humans with P. falciparum-Infected Irradiated Mosquitoes
This is a vaccine but is impractical…Bull WHO 1978;57(suppl 1):263
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T-CELL EPITOPES T-CELL EPITOPESREPEAT DOMAINB-cell epitopes
Vaccine DevelopmentVaccine DevelopmentThe CS protein is present in The CS protein is present in sporozoitessporozoites and liver stages.and liver stages.
• Induction of specific antibodies
• Induction of anti-liver stage T cells
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Immune Responses toImmune Responses toErythrocyticErythrocytic StagesStages
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Antibodies Inhibit Merozoite Infection of Erythrocytes
F. Zavala
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Antigens Of Asexual Blood Stages Recognized By Protective Immune
Responses• Merozoite surface protein-1• Merozoite surface protein-1 -2• Dense granule-RESA• Microneme- EBA-175
• Rhoptry– AMA-1, rhoptry-associated protein 1 and 2– Rhop-1 and 2
• Red blood cell surface– PfEMP-1 – Pf332– Rosettin
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Immunization with Merozoite surface antigen protected monkeys from
death during course of infection of Plasmodium falciparum (FUP strain)
in vaccinated monkeys (Aotustrivirgatus)
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Monocyte-Antibody Mediated Inhibition of Parasite Growth
MONOCYTE
CYTOKINES?
PHAGOCYTOSIS
F. Zavala
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“Knobs” In P. Falciparum Infected Erythrocyte
D. Sullivan
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Extensive Antigen Polymorphismin Malaria Parasites
F. Zavala
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Immune Responses toSexual Stages
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Plasmodium Life Cycle
MOSQUITOES MOSQUITOES
SPOROZOITES
GAMETOCYTES
ASEXUAL BLOOD STAGESLIVER STAGES
RING
TROPHOZOITE
SCHIZONT
MEROZOITES
F. Zavala
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TBV Concept
Immunize people
Antibodies picked up by the mosquito during blood feed will stop parasite’s development in the mosquito
(NON-INFECTIOUS MOSQUITOES)
No further Malaria Transmission
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ImmunopathologyImmunopathology
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Anti-Parasite Immune Responses May....
* Abolish parasite development
* Attenuate parasite infection
* Be ineffectual or irrelevant
* Exacerbate disease
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CEREBRAL MALARIA: PATHOGENESIS
• adhesion molecules
• nitric oxide?
MalariaMalaria““toxinstoxins””(GPI?)(GPI?)
Infected RBCInfected RBC
Macrophages ?Macrophages ?TT-- cells ?cells ?
SEVEREMALARIA
ENDOTHELIAL CELLS
HYPOGLYCEMIA
CYTOKINESCYTOKINESLT, TNF- α , IFN−γ ...
METABOLIC ACIDOSIS
F. Zavala
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Severe Malaria
CEREBRAL MALARIA:confusion, stupor, delirium, convulsions, paralysis, coma…
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Cerebral Malaria: Obstruction Of Small Capillaries By Parasitized Erytrocytes
SEQUESTRATION OF SEQUESTRATION OF TROPHOZOITES AND SCHIZONTSTROPHOZOITES AND SCHIZONTS
CDC/Dr. Melvin
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Anemia
• Erythrocyte destruction– Release of parasites– Phagocytosis
• Dyserythropoiesis– TNF-α– INF-γ
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Vaccine Targets
MOSQUITOES MOSQUITOES
SPOROZOITES
GAMETOCYTES
ASEXUAL BLOOD STAGESLIVER STAGES
RING
TROPHOZOITE
SCHIZONT
MEROZOITES
F. Zavala
ALL STAGES…
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Immunity Against Immunity Against MalariaMalaria
PARTIAL STERILE
Attenuates AbolishesInfection Infection