Download 2. Immunity to malaria

Immunity to malaria:
more questions than answers
Jean Langhorne, Francis M Ndungu, Anne-Marit Sponaas & Kevin Marsh
Nature Immunology, July 2008
12th January 2009
Overview
1.
Introduction to malaria
2.
Immunity to malaria
•
•
•
mechanisms of immunity
immune response
Immune memory
2
Malaria

Vector-borne infectious disease

Caused by protozoan parasites of the genus plasmodium

Human malaria
 P. falciparum
 P. vivax
 P. ovale
 P. malariae

common & severe
rare & mild
all persons become ill on the first exposure



Causes flu-like illness anemia, fever, chills
followed by control of parasitemia
in severe cases coma and death
Center of disease control and
prevention, Atlanta, USA.
3
Malaria




Wide spread in tropical and subtropical regions
400 million cases per year
3 million death
Majority 2-5 years
© DPDx: CDC's web site for laboratory
identification of parasites
4
Life cycle of Plasmodium falcipare
Involves two hosts
-
Anopheles mosquito
Human host
three distinct cycles
-
Sporogonic cycle (mosquito)
Exo-erythrocytic cycle
Erytrocytic cycle
© DPDx: CDC's web site for laboratory
identification of parasites
5
Life cycle of Plasmodium falcipare
Exo-erythrocytic cycle

infected (female anopheles)
mosquito bites through the skin

sporozoites travel from dermis to
the liver/hepatocytes
undergo an amplification phase
lasting between 2 and 9 days
(asymptomatic stage)


parasite reenters the bloodstream
by rupture of hepatocytes
(Merozoites)
© DPDx: CDC's web site for laboratory
identification of parasites
Life cycle of Plasmodium falcipare
Erythrocytic cycle


merozoites invade red blood cells
(RBC) and initiate the asexual
cycle in RBCs
exponential expansion of parasite
populations leads to febrile illness

sexual stages (male and female
gametocytes) are formed during
the erythrocytic cycle

this stage continues the life cycle
in the mosquito after a blood meal
© DPDx: CDC's web site for laboratory
identification of parasites
7
Life cycle of Plasmodium falcipare
Sporogonic cycle




While in the mosquito's stomach,
the microgametes penetrate the
macrogametes generating
zygotes
zygotes become motile and
elongated (ookinetes)
invade the midgut wall of the
mosquito to develop into oocysts
oocysts grow, rupture, and
release sporozoites which make
their way to the mosquito's
salivary glands.
© DPDx: CDC's web site for laboratory
identification of parasites
8
2. Immunity to malaria
•
•
•
mechanisms of immunity
immune response
Immune memory
9
Immunity to malaria
naturally acquired immunity (NAI) to malaria

Immunity to malaria is seen as
asymptomatic infection




more resistant to new
infections
limits parasitemia
reduces the frequency and
severity of illness
human studies showed that
immunity to malaria is


relatively slow to develop
and incomplete
immunity to death is
acquired more quickly
Langhorne et al., 2008
Mechanisms of Immunity

Picture of human immunity to malaria has been provided
by two main sources:


Deliberately induced malaria in non immune persons
Natural history studies in endemic populations

Immune attack could be directed at any point in the life
cycle of plasmodium

Pre-erythrocytic cycle (asymptomatic stage)


Probably has limited involvement
Erythrocytic cycle
Mechanisms of Immunity
Pre-erythrocytic cycle

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targets are free sporocytes and infected
hepatocytes
Requires mainly CD8+effector cells
producing interferon-γ
Need the help of CD4+ T cells
Antibodies to sporozoites are thought to
have a lesser function
Kill parasites in infected hepatocytes
1
2
1.
Antibodies to sporocyte neutralize sprozoites
and/or block invasion of hepatocytes
2.
IFN-γ and CD8+ T, NK, NKT, and γδT cells kill
intrahepatic parasites
Langhorne et al., 2008
Mechanisms of Immunity
Erythrocytic cycle


targets are free merozoites or
intraerythrocytic parasites (Schizont)
Humoral responses are the key to blood
stage immunity (protective antibody
response)
3.
Antibodies to merozoites opsonize merozites for
uptake and/or inhibit invasion of RBCs
4.
Antibodies to
•
block infection of RBCs by merozoites
•
Antibody-dependent cellular killing mediated
by cytophilic antibodies
•
Block adhesion of infected RBCs to
endothelium
•
Neutralize parasite toxins and prevent the
induction of excessive inflammation
4
3
Langhorne et al., 2008
Mechanisms of Immunity
Erythrocytic cycle


targets are free gametocytes
Humoral responses are the key to blood
stage immunity (protective antibody
response)
6
5
5.
Antibodies prevent sequestration and maturation
of gametocytes
6.
Antibody and complement mediate lysis of
gametocytes and prevent further development
Langhorne et al., 2008
Immune response to plasmodium

Many features are similar to those of sepsis, over-vigorous or
disordered immune responses are central

CD4+ and CD8+ T cells are chief participants in acute
pathology

Enhanced amounts of cytokine responses
 TNF
 IL-1 β, IL-6, IL-10
 IFN-γ
 CCL3 (MIP-1α), CCL4 (MIP-1β)
Immune response to plasmodium

Specific cytokine profiles associated with different syndromes
 Relatively low IL-10 in severe malaria anaemia
 Large amounts of IL-10 in respiratory distress
 Low amounts of CCL5 in severe disease and mortality

Polymorphism in host genes is associated with susceptibility
 IFN-γ
 Interferon regulatory factors
 TNF
 IL-10, IL-4

Balance in the regulation of pro- and anti-inflammatory
cytokines may be critical in determining the extent of
pathology
Trigger for cytokine production

Depends on interaction of host cells and parasite via
pattern-recognition receptors (PRR)

Can be induced by infected RBCs or parasite products
with several Toll-like receptors (erythrocytic cycle)




Plasmodium falciparum erythrocyte membrane protein 1
(PfEMP1)
Glycosylphosphatidylinositol anchors (GPI)
Hemazoin
Ds DNA
Trigger for cytokine production
Trigger for cytokine production

MyD88



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Intracellular adaptor for several TLRs
Important for the induction of some but not all of the
pathology
Also required for controlling acute-stage parasitemia
Immune response via several PRR
Quantity of inflammatory cytokines?
Qualitiy of a person’s response to a particular clone?
Difficult to distinguish pathological from
protective responses
Immune memory in malaria
Immunity to malaria develops


Relatively slow
Is not sterile

Continued exposure to malarial antigens is needed for
 Generation of memory and effector cells
 Persistence or memory and effector cells
 Maintenance of immunity

It is still unclear what components of immunity is lost without
exposure
 Short lived immunity
 Longlived immunity
Immune memory in malaria

Rapid boosting of antibody responses indicate the
presence of memory B cells

Accumulation of memory B cell specific for malaria
indicates the presence of memory B cells

anti-P. falciparum memory B cells


present in adults for over 8 years without evident re-exposure
a subsequent study in children


in contrast presence of anti-P. falciparum serum antibody
only very low frequencies of malaria-specific memory B cells
Immune memory in malaria
Pre-Erythrocytic cycle


To be protective specific CD4+ and CD8+ T cells

must be maintained as effector cells to differentiate very
rapidly into effector-killer cells

Population shift between mostly protective effector
phenotype to the less protective memory phenotype
This could explain why immunological memory is not
always correlated with immunity
Immune memory in malaria
Erythrocytic cycle

CD4+ T cells are induced by natural infection


lower concentrations of malaria-specific antibodies in
malaria-infected people positive for HIV


Frequencies of responding cells and the prevalence of
exposed people with measurable malaria-specific CD4+ T
cells are often low
suggests that CD4+ T cell help is necessary for the induction
and also for the maintenance of protective antibody
Requirment for memory CD4+ T cells in immunity has
still to be elucidated
Immune memory in malaria
1.
Inhibition of DC maturation
2.
Hemozoin can inhibit macrophage
monoyte function
3.
IL-10 from DCs and macrophages
modulated by infect RBCs inhibit
CD4+ T cell activation
4.
CD4+ T cells produce IL-10 and
transforming growth factor-β, which
inhibts the generation of central
and memory-effector cells
Immune memory in malaria
5. Infected RBCs induce apoptosis
and/or depletion of memory B cells
6. The niche for plasma cells of many
different specificities may be
limiting
7. Acceleration of the catabolism of
immunoglobulin molecules
8. Antigenic variation for immune
escape
9. Circulating immune complexes and
low-affinity immunoglobulin
molecules can trigger apoptosis of
long-lived plasma cells
Conclusions more questions than answers
Advanced understanding the host response to
plasmodium
But many questions remain:
 What to measure as a correlate for immunity?
 What mechanisms regulate immune pathology in semiimmune people?
 What defects contribute to the relatively ineffective
immunity in children?
 Why immunity to plasmodium infection can be shortlived?
Thank you for your attention!
Complete life cycle
Trigger for cytokine production

Plasmodium falciparum erythrocyte membrane protein 1
(PfEMP1)
 Adhesive molecules
 sequestration in the post-capillary venules

Glycosylphosphatidylinositol anchors (GPI)
 Anchor on many plamodium membrane proteins
 induction of proinflammatory responses

Hemazoin
 disposal product formed from the digestion of erythrocytes