Schwere Fragen Flashcards
How does Trypanosoma cruzi invade its host cells?
1) has as many ligands as it could possibly have on surface
examples:
- muzines (defense against digestive enzymes)
- fibronectine receptors ⇒ help adherering to the host cell (macrophages or muscle)
2) induces “induced phagocytosis” through PIP3 to get in or directly by recruiting lysosomes (unknown how it survives or get’s out of the macrophage)
Describe the two pathomechanisms that can contribute to the chronic, pathogenic complications elicited by a Trypanosoma cruzi infection.
1) parasite let’s host cells erupt after proliferation⇒ can disturb peristalsis by destroying ganglia of smooth muscles
2. 1) TLR2 immune response ⇒ sialic acid transfered from host cells to parasite surface, but recognized in chronic phase with TLR2 ⇒ recruiting of NK-cells which induces inflammation ⇒ can lead to autoimmune reaction (because an epitope of parasites protein resembles an extracellular receptor in heart muscles)
Which host cells are invaded by Leishmania, and how does host cell invasion occur? Describe the course of infection after transmission by an infected Phlebotomus sandfly.
- neutrophils and macrophages are targeted
⇒ Trojan-horse-theory: neutros are the first ones at biting site, take them up, are prolonged apoptotic by parasite and taken up in disguise by macrophages - has ONE ULTIMATE receptor for host fibronectin, mannose and complement factors ⇒ protease on surface cleaves C3 ⇒ presented to macros complement CR1 and CR2 receptors ⇒ phagocytosis
Which immune factors contribute to: i) recovery of versus ii) chronic cutaneous lesion after inoculation with e.g. Leishmania brasiliensis?
- Recovery: cytokines from TH1 (e.g. IL-12, TNF and IFN-gamma) cause inflammation ⇒ strong T-cell response and IFN-gamma production
- Chronic: immune factors from TH2 (e.g. IL-4/5/13) ⇒
no T-cell reaction, no IFN-gamma-production ⇒ macros stay infected
Describe the principles of tissue invasion by Entamoeba histolytica.
1) sticks to mucus in intestine
2) degrades MUC2 mucins with cystein protease ⇒ inserts amoebapore to destroy the adhered (intestinal epithelial) cell (no receptor required)
3) subversion of the immune reaction: CP cleaves pIL-1 to IL-1 ⇒ activates NFkB in neighboring cells ⇒ produce cytokines and inflammatory mediators
4) Neutrophils barge in between the epithelial cells and and are swallowed by Entamoeba
5) dying neutrophils contain mediators ⇒ further damage the cells and macrophages release TNFalpha ⇒ induces apoptose and inflammation
⇒ invasive amoebiasis of gut epithelium
can also travel to liver (but evolutionary dead end)
Describe the journey of the Plasmodium sporozoite from the mosquito bite to the liver.
1) mosquito injects sporozoite to skin
2) travel to blood vessels
3) travel with blood stream to the liver
4) pass through Kupffer cells to enter one of the hepatocytes with assistance of the apical complex
5) binds to HSPGs with CS-protein and TRAP, wanders through some and spontaneously settles down in one to convert into shizont stage and proliferate into millions of merozoites (same invasion strategy as Toxoplasma)
How do liver stages induce protective immune responses and how are they killed?
Before sporozoite enters hepatocyte: excreted antigens recognized by toll like receptors⇒ can induce NFKB and NO production, killing the exoerythrocytic form (EEF) of plasmodium
sporozoite inside hepatic cell: cell can present antigen to CD8 T-cells via MHC1
at exit of mature EEF from hepatocyte:
-excreted antigens recognized by dendritic cells ⇒ recruit cytotoxic and helper T-cells to kill parasites
What are problems with anti-merozoite vaccine approaches? Explain.
merozoites invade very fast = only shortly extracellular
merozoite antigens trigger strong antibody responses but do not protect yet
multiple merozoite invasion pathways (e.g. disposable dafi binding proteins)
⇒ have multiple immune evasion strategies: varying sequence while maintaining function, redundancy in multi gene families, reduced antigenicity
What are the immunological mechanisms that typically lead to protective immunity
against parasitic worms?
TH2-response:
first contact:
- antigen is recognized by T-cells, which recruit eosinophils with IL-5 and B-cells with IL-4 and IL-13 (also recognizing antigens as foreign)
- develop specialized IgG and IgE antibodies, IgE binds to nurse cell⇒ degranulates it and attracts eosinophiles⇒ stimulate intestinal cells to widen and produce mucus and cytotoxic granula, all bind to parasite, which is flushed down
What are the immunological hallmarks of helminth infections and auto-immune diseases?
TH2 immune response: IgE development and eosinophily (IL-4, -5 and -13)
other immune responses have problems due to overlaps
What factors determine the disease spectrum in patients with Onchocerca volvulus infections?
- number of filariae in host
- immune response against microfilariae
- if tending towards inflammation or not
- susceptibility of patient to immune modulation of parasite:
~30% hyperreactive: strong pathology with inflammation around mostly dead filariae
~30% hyporeactive: cellular suppressed with swollen lymph nodes, produce microfilariae
~30% silent resistant: no filariae
How does mebendazole, the major anti-helminthic drug, act?
selectively inhibits synthesis of microtubules ⇒ destroys extant cytoplasmic microtubules in parasite intestinal cells⇒ blocks uptake of glucose and other nutrients⇒ gradual immobilization and eventual death of the helminths
How do Schistosoma eggs reach the intestine or the bladder?
- eggs are laid in blood vessels close to bladder or liver
- can not move actively⇒ adhere to endothelia, excrete proteins to induce TH2 response
- immune cells (macrophages and eosinophils) and antibodies gather around egg and excrete cell lysing enzymes
- blood epithel tissue is lyzed and eggs escorted to intestine or bladder
Describe the temporal development of immune responses to a Schistosoma spp. infection.
- cercaria trigger TH1, but calmed down by parasite proteases (cleave antibodies and inhibit macrophages)
- adults don’t induce immune response ⇒ can dress up in host cell proteins (camouflage)
- adults can induce cancer in liver/bladder
- eggs proteins induce strong TH2 response to reach bladder/intestine, also to prevent other schistosomas from infecting the already infected host
The pathogenesis of an infection by Schistosoma spp. is closely linked to the eggs. Explain!
1) egg proteins induce TH2 response, activating macrophages and eosinophiles to help them lyse blood vessel walls/tissues to get escorted to bladder and intestine ⇒ constantly irritating the organs/tissues
2) egg antigens lead to shift from TH1 to TH2 immune response, where IL-4 and IL-13 activate arginase in macrophages to deposit collagen and form granulomas ⇒ liver becomes enlarged
