Parasites And The Immune System Past Paper PDF

Parasites and the immune system Mike Barrett 15th Nov 2024 Nieuwenhuizen et al. doi:10.1371/image.pntd.v07.i08.g001 The microbial origins of life Mike Barrett 26th November 2024 6:...

Parasites and the immune system Mike Barrett 15th Nov 2024 Nieuwenhuizen et al. doi:10.1371/image.pntd.v07.i08.g001 The microbial origins of life Mike Barrett 26th November 2024 6:30 p.m. Venue to be arranged. Intended Learning outcomes You should understand 1. The broad different ways whereby parasites evade destruction by the mammalian immune system 2. The specific process of antigenic variation employed by African trypanosomes to stay ahead of the host antibody response 3. The IgE mediated response to parasitic helminths and modulation of the immune system by these macroparasites, and possible routes to exploit this to modulate the immune system more generally For any microbe to establish within an host and become infectious it must have a mechanisms of bypassing the immune system Different organisms have evolved different mechanisms as listed on the slide Antigenic variation, whereby microbes sequentially express different surface antigens to the immune system is a relatively common way of staying one step ahead of the immune system The African trypanosome offers the best studied example of an organism that employs antigenic variation to outwit the host immune response  AVOIDANCE OF DESTRUCTION BY THE IMMUNE SYSTEM 1. LOCATION Intracellular Plasmodium liver, erythrocyte Leishmania macrophage T. cruzi macrophage, neuron, muscle Toxoplasma macrophage 2. Cysts Toxoplasma Echinococcus AVOIDANCE OF DESTRUCTION BY THE IMMUNE SYSTEM 2. ANTIGENIC MIMICRY Schistosoma 3. IMMUNOSUPPRESSION T. cruzi T. brucei Filarial worms Schistosoma AVOIDANCE OF DESTRUCTION BY THE IMMUNE SYSTEM 4. ANTIGENIC VARIATION T. brucei Borrelia Neisseria Giardia Pneumocystis Plasmodium Antigenic variation in African trypanosomes Human African trypanosomiasis Credit: Jorge Atouguia Trypanosomes in blood Credit: Dr Laurence Tetley T. brucei Procyclic trypomastigotes (midgut) Metacyclic trypomastigotes Tsetse fly (salivary glands) Mammal Short stumpy bloodstream forms Long slender (free in blood) bloodstream forms (free in blood and CSF) Tf receptor VSG Nutrient transporters Number of Parasites Weeks after infection Successive waves of parasitaemia African trypanosomes have over 1,000 different genes encoding for different versions of the coat protein  Gene duplication in antigenic variation 1. Make RNA 2. Make cDNA 3. Label cDNA Trypanosome expressing red Trypanosome expressing blue coat coat ELC BC BC RNA pol I: rRNA (a-amanitin insensitive) RNA poll II: mRNA (a-amanitin sensitive) RNA poll III: tRNA & snRNA etc. (a-amanitin insensitive) VSG transcription is a-amanitin insensitive. However, no evidence could be found that active expression sites were found in the nucleolus. Nucleus Nucleolus  Bloodstream form T. brucei possess a second RNA polymerase I containing body Antibodies to RNA pol I revealed that bloodstream form trypanosomes had a nuclear body, in addition to the nucleolus, that contains RNA pol 1. The body is transcriptionally active, but lacks rRNA encoding genes Nucleolus RNA polymerase I containing body  Mono-allelic expression of VSG genes in T. brucei The identification of an Expression Site body suggests that the expression of one VSG gene at a time involves plugging one expression site at a time into the body. Switching then comes about either by placing a new expression site into the ES-body, or transferring a new VSG gene to the site already in the body. Parasitic Worms and the Hygiene Hypothesis Virus Bacterium Protozoan Infectious agents come in a variety of sizes Protozoan parasite Metazoan (multi- celled) parasite  Immunological responses that are effective against “micro-organisms” are less effective against “macro-organisms” e.g. parasitic worms Complement proteins, for example, that can lyse bacteria or protozoa do not penetrate worm surface barriers Antibodies that can bind to and opsonise microbes are also less effective against the relatively large helminths  Therefore, specific immunological responses have evolved to attack helminths For example, the immunoglobulin class IgE is specifically produced against helminths IgE can bind helminths and act to recruit Eosinophils to the worms Eosinophils release proteins eg the major basic protein that can compromise worms Different classes of antibody Credit: Fvasconcellos Credit:Saeed El-Ashram  However, as worms are difficult to attack, and since the attack mechanisms can cause significant “bystander damage” to host tissue, mechanisms have evolved to diminish immune responses to helminths This involves the regulatory T cell network  However, as worms are difficult to attack, and since the attack mechanisms can cause significant “bystander damage” to host tissue, mechanisms have evolved to diminish immune responses to helminths This involves the regulatory T cell network Moreover, helminths produce secreted molecules that also trigger immunosuppression in hosts  According to the “hygiene hypothesis”, in the developed world where helminth infections are comparatively rare today, the lack of triggering the regulatory T cell network has left us vulnerable to making inappropriate immune response to various “allergens” e.g. pollen and house dust mite debris Apart from allergies, other immunological conditions e.g. autoimmune diseases where the immune system attacks our own tissues might be more common where our immune systems are “trained” to suppress activity  Worm therapy? Nieuwenhuizen et al. doi:10.1371/image.pntd.v07.i08.g001  A more “palatable” approach to exploiting the mechanisms worms use to modulate host immunity is possible! e.g. Protein ES-62 is secreted by a parasitic worm (Acanthocheilonema viteae) of rodents and the protein triggers anti-inflammatory immune responses  Protein ES-62 when purified and injected can decrease inflammation and ameliorate autoimmune and inflammatory disease e.g. rheumatoid arthritis BUT – the protein itself triggers an immune response so cannot be use therapeutically SO – small chemical molecules that mimic the protein’s activity have been developed and are being trialed as anti-inflammatory drugs Al-Riyami, L. et al. (2013) J. Med. Chem. 56, 9982-10002 Summary 1. Parasites can establish long term infections in mammalian hosts by evading immune effector mechanisms by a range of methods, including taking up residence in difficult to reach sites, varying their antigenic profile, modulating host immunity in various ways 2. African trypanosomes that cause sleeping sickness have over a thousand different genes encoding separate coat proteins, and can express these sequentially to constantly change the profile detected by the immune system 3. Parasitic helminths are relatively large and immunity requires different effectors than those used against smaller microorganisms. This includes production of IgE and eosinophil attack. Responses are modulated to minimise bystander damage. Reduced infection rates with parasitic worms might be partially to blame for a rise in allergic diseases where the immune system responds inappropriately to various allergens. Learning about the ways in which immunity is modulated in worm infections may enable development of novel immunomodulatory drugs. Interested in Parasites? To join the Microbiology degree for L3 and L4 if you are attending this course and are down for 2D (Microbiology and Immunology) You will be eligible to join. Contact myself: [email protected] The microbial origins of life Mike Barrett 26th November 2024 6:30 p.m. Venue to be arranged.