Lecture 30 - Immunity to Parasites Flashcards
List some types of parasites
- Protozoa
- Nematodes
- Flukes
- Arthropods
Compare general immune responses against intra- and extracellular parasites
Intracellular:
- Cell mediated immunity
Extracellular:
- Cell mediated & humoral
List some intra- and extracellular parasites
Intracellular:
- Plasmodium
- Leishmania
- Toxoplasma
- Trypanosomes
Extracellular (aka free living)
- Plasmodium (certain stages)
- Helminths
- Flukes
- Trapanosomes
State the infection caused by the following protozoans:
- Plasmodium spp
- Toxoplasma gondii
- Leismania spp
- Trypanosoma spp
- Entamoeba histolytica
- Giardia lamblia
- Malaria
- Toxoplasmosis
- Leishmaniasis
- Trypanosomiasis
- Amoebiasis
- Giardiasis
Outline types of nematodes that cause diseases
List a few of each type
- Filarial worms
- Wuscheria bancrofti
-
Lymphatic filariasis
- Blocks lymphatics - lymphoedema
-
Lymphatic filariasis
- Onchocerca volvulus
- Wuscheria bancrofti
-
Tapeworms
- Taenia solium (pork), Taenia saginata (beef)
-
Hookworms
- Ancyclostoma
-
Roundworms
- Ascaris lumbricoides
Describe the main features of Malaria
What are the two main types?
- Blood infection caused by the *Plasmodium *protozoan parasite
- Transmitted by the female *Anopheles *mosquito
- Often fatal if left untreated
- Two main types:
- P. falciparum
- P. vivax
Describe the emergence of Malaria
Malaria is an ancient disease, it has been around for many centuries
Outline the burden of malaria
- Young children and pregnant women are most at risk
- Developing countries and resource poor communities suffer the most
- Impedes economic development
- Compounds poverty
Describe the pathogenesis of malaria
- Mosquito takes blood meal, regurgitating saliva (to prevent blood clotting), which delivers **sporozoite **into human circulation
- Parasite circulates to liver and replicated in hepatocytes
- Release of tens of thousands of merozoites from liver
- Invasion of RBCs
- Replication in RBCs
- Burst out of RBCs, releasing gametocytes
-
Illness:
- Unchecked replication in organs
- Brain
- Placenta
- Destruction of RBCs
- Inflammatory response
- Unchecked replication in organs
- Severe multi-system illness
- Coma
- Severe anaemia
- Acidosis
- Respiratory distress
What are the three ‘types’ of immunity to malaria?
Immunity to:
- Severe malaria
- Symptomatic malaria
- Malaria in pregnancy
Describe in general immunity to malaria
- Many episodes experienced before immunity is generated
- Immunity is generally directed against blood stage parasites
- Both humoral and cellular
Outline the reasons for slow development of immunity to Plasmodium
Parasite factors:
- Multiple antigenic targets
- Antigenic diveristy
- Antigenic variation
Host factors:
- Inadequate response
- Non-functional
- Irrelevant
- Poor development of memory responses
Describe the various components of immunity to Plasmodium
Sporozoites:
- Abs inhibit infection of hepatocytes
Liver stage:
- CD8+ T cells against infected hepatocytes
- CD4+ T cells:
- IFN-γ ⇒TH1 response
Blood stage:
- Abs against merozoites
- Inhibits:
- RBC invasion
- Merozoite gorwth
- Mechanism:
- Direct neutralisation
- Opsonisation
- Inhibits:
- Abs against infected RBCs
- Parasite Ags expressed on RBC surface
- Opsonisation for phagocytosis
- CD8 responses don’t play a major role
- Because RBCs don’t express MHC I
Describe Plasmodium invasion of RBCs
- Merozoite makes contacts with RBC molecules
- RBC membrane pulled around merozoite
- Sealed off, parasite on indside surrounded by two membrane
-
Very quick
- However, Abs can bind and block the process
Describe the presence of Plasmodium Ags on infected RBCs
What is the implication?
- Multiple Ags expressed on the surface
- Mediate adhesion of parasited RBC to the vasculature
- Sequestration from spleen
- Important targets for Abs
- Abs bind Ags
- RBC is now opsonised
- Phagocytosis by PMNs, macrophages and monocytes
Describe cell-mediated immunity against the malaria parasite
Involved in both protection and pathogenesis:
-
CD8+ T cells
- Doesn’t play a role, as RBCs don’t express MHC I
-
Splenic clearance of parasitised RBCs
- Important, but the parasitised RBCs avoid this by adhering to the vasculature
-
CD4+ T cells:
-
IFN-γ production
- ⇒ protection
-
TNF
- ⇒ severe disease
-
IFN-γ production
Describe the role of CD8+ T cell immunity against the blood stage of Plasmodium
- CD8+ T cells do not play a major role
- This is because RBCs do not express MHC I
Describe the role of Ab in Plasmodium immunity
-
Neutralisation of:
- Sporozoite
- Merozoite
- pRBC
-
Opsonisation
- Tagging for phagocytosis by:
- Macropages, PMNs, DCs
- Tagging for phagocytosis by:
Describe Plasmodium adherence to vasculature
- RBCs express proteins on the surface from Plasmodium
- eg Pfemp1
- These molecules bind to others on the host vascular endothelium
- This allows the parasitised RBCs to avoid detection and removal in the spleen
- However, this makes the RBCs a target for immunity
Outline the various approaches for a malaria vaccine
-
Sporozoites / liver stage
- Block entry to liver cells
- Inhibit parasite development
- Prevent parasites exiting into circulation
-
Merozoites / Blood stage
- Block merozoite replication
- Block entry into RBCs
-
Infected RBCs
- Ab clearance of infected RBCs
- Limitation:
- There is enormous antigenic diversity
- The parasite has evolved these strategies to avoid the host response
Describe the RTS,S vaccine
- Composition
- Based on CS protein
- Major antigenic protein of sporozoites
- Presented in a VLP with a HepB antigen
- new potent adjuvants
- Maximises the Ab response
- new potent adjuvants
- Based on CS protein
- Trials:
- Early trials:
- Partial short lived protection
- Phase 2:
- up to 50% efficacy
- Various African countries
- Phase 3:
- 30-50% efficacy demonstrated
- 15,000 children
- Early trials:
- Proposed licencing, probably in 2-3 years
- Important, but not a complete solution
Describe the study into immunity to malaria works
- Enrol 200 PNG children in the study, administer vaccination
- Monitor immunised children over 6 mths
- Some children contracted infection, some didn’t
- 95% became infected
- 39% developed malaria illness
- Comparison:
- Responses in those who did and did not contract malaria
- Identify specific Abs
- Conclusions:
- Abs block invasion of RBCs
Malaria is not just an immunological challenge, but…
- Economic
- Logistic
- Practical
Describe the major features of Leishmania
Outline the pathogenesis
- Transmitted by sandflies, inoculated into skin by bite
- Africa, Middle East, South Asia
- Various animal reservoirs
- Can infect a range of mammals
- This makes eradication a problem
- Animals can not be treated
-
Pathogenesis:
- Taken up by macrophages & DCs
- Opsonisation → taken up by macrophages via Ab-FcR interactions
- Direct interactions between parasite and mφ molecules
- Replicate in host cells
- May remain local, or disseminate
- Cutaneous leishmaniasis
- Visceral leischmaniasis
- Taken up by macrophages & DCs
Describe the clinical features of Leishmaniasis
- There are a variety of clinical syndromes associated with Leishmania
- Visceral leishmaniasis
- L. donovani
- Severe and fatal form
- Parasite disseminates to various organs
- Massive hepatosplenomegaly
- Cutaneous leishmaniasis
- L. major
- Local disease
- Immune resolution
- Mutocutaneous
- Disseminated cutaneous
- Visceral leishmaniasis
Describe immune mechanisms against Leishmania
Antibodies:
- Can enhance infection by promoting uptake of parasite into macrophages (through FcR interactions)
Pro-inflammatory response:
- Effective
- Clears infected cells
Macrophages:
- Major effector cells for clearance
- Need to be activated, usually by DCs
- Killing of parasites by NO
Th1
- Important for clearance
- Release of pro-inflammatory cytokines
- IL-1β
- LT-α
- IFN-γ
**Th2: **
- Less effective
- Associated with persistance and progression of disease
Describe the role of antibody in Leishmania infection
- Abs are not protective, rather play a role in the pathogenesis
- Parasites are resistant to C’
- Ab opsonisation of the parasite helps parasite uptake into macrophages
Describe the importance of DCs in the outcome of Leishmania infection
- Cytokines from the DCs instruct the TH response, which in turn instruct the Macrophage response
- Depending on the macrophage response, the parasite will either be cleared, or persist to cause disease
-
DC releases IL-12
- TH1 response predominates
- TH1 release IFN-γ onto macrophages
- Induction of iNOS in macrophages
- Production of NO
- Intracellular killing and clearance of parasite
-
DC releases IL-4(?)
- TH2 response predominates
- TH2 releases IL-4, IL-5, IL-13
- Induction of arginase in macrophages
- Parasite survives and replicates in the macrophage
- Leishmaniasis
List the major strategies for immune evasion and persistence by parasites
- Complex life cycles
-
Dormancy
- eg Toxoplasma
- P. vivax
-
Sheltered sites
- Malaria: brain, placenta, RBCs
- In the brain and placenta, there cannot be a vigorous immune response, as this would lead to coma or loss of foetus, respectively
- Worms: gut lumen
- Malaria: brain, placenta, RBCs
- Antigenic diversity
- Antigenic variation
- Immune modulation / manipulation
Describe the antigenic diversity & variation of Plasmodium & Trypanosoma
-
Diversity:
- Multiple antigenic variants / polymorphisms exist within the population of parasites
-
Variation:
- Variants of certain antigens with a single parasite
- Switching of antigens that are expressed within a a single infection
- eg. PfEMP1 in Plasmodium
- ~60 genes encoding different versions of the antigens
- A single parasite can switch on different versions of the gene within a single infection
- eg. PfEMP1 in Plasmodium
Describe recrudescent / repeat infections in malaria
Why does this occur?
-
Repeat infection:
- There are many antigenic variants of the parasite
- When an individual is exposed to a certain variant an immune response is launched and memory generated
- Then, the individual is exposed to a new variant
- Previous immunity is not protective
- ⇒** **repeat infection
-
Recrudescent infection
- During a single infection, an individual launches an immune response against a particular Ag
- The parasite is controlled for a period
- Then, the parasite switches the antigen variant
- The previously developed immunity is no longer protective
- ⇒ recrudescent infection
Describe immunopathology of parasitic infections
- Overexuberant immune responses can add to the pathology of parasitic infections
- Malaria
- Mononuclear cells in placenta associated with low birth weight
- Pro-inflammatory cytokines contribute to coma and death
- Schistosomiasis
- Inflammatory response to eggs responsible for the majority of the organ damage
Which parasites can switch antigenic variants during an infection?
- Plasmodium
- Trypanosoma brucei
Which stage of Plasmodium infection causes disease?
The blood stage
Briefly state which kind of immune responses are the most important in the following stages of Plasmodium infection:
- Blood stage
- Liver stage
- Blood stage: Ab responses
- Liver stage: T cell responses
What is the added challenge to Leishmania eradication?
There are multiple animal reservoirs for this parasite, thus complete eradication will be very difficult
Describe the importance of the following cells in immune responses for malaria
- PMNs
- Macrophages
- B cells
- CD4 T cells
- CD8 T cells
- PMNs and macrophages
- Clearance of opsonised merozoites or pRBCs
- B cells
- Neutralisation and opsonisation of:
- Sporozoite
- Merozoite
- pRBCs
- Neutralisation and opsonisation of:
- CD4 T cells
- B cell help
- Cytokine production (IFN-y)
- CD8 T cells
- Direct killing of infected hepatocytes
- Not important in blood stage infection
Compare the Leishmania species that result in the various clinical leishmaniasis syndromes
- *L. major → *cutaneous leishmaniasis
- L. donovani → visceral leishmaniasis
