Parasite Immune Evasion strategies.

1. The host­parasite relationship is based on the subtle interplay between parasite survival strategies and host defence mechanisms • Successful parasites have evolved strategies for survival & development in both invertebrate and vertebrate hosts. • The goal of a parasite is to propagate within the host and be transmitted to the next host. • The goal of the parasitised host is to cure or limit the infection. • These 2 goals are in conflict…. Who will win?

2. Parasite Immune Evasion strategies. Parasites need time in host to complete complex development, to reproduce (sexually or asexually) & to ensure transmission. Chronic infections (from a few months to many years) are normal, therefore parasite needs to avoid immune elimination. Parasites have evolved immune evasion strategies.

3. Protozoan immune evasion strategies. 1. Anatomical seclusion in the vertebrate host. Parasites may live intracellularly. By replicating inside host cell parasites avoid immune response. Plasmodium lives inside Red Blood Cells (RBC’S) which have no nucleus, when infected not recognised by immune cells. Other stages of Plasmodium live inside liver cells. Leishmania parasites and Trypanosoma cruzi live inside macrophages.

4. 2. Anatomical seclusion in the invertebrate host. Plasmodium ookinetes develop in serosal membrane & are beyond reach of phagocytic cells (hemocytes). 3. Antigenic variation. In Plasmodium, different stages of the life cycle express different antigens.. Antigenic variation also occurs in the extracellular protozoan, Giardia lamblia, and in the trypanosome T. brucei. Trypanosomes have “gene cassettes” of variant surface glycoproteins (VSG’s) which allow them to switch to different VSG. VSG is switched regularly. The effect of this is that host mounts immune response to current VSG but parasite is already switching VSG to another type which is not recognised by the host

5. 4. Shedding or replacement of surface e.g. Entamoeba histolytica. 5. Immunosupression – manipulation of the immune response e.g. Plasmodium. 6. Anti-immune mechanisms - Leishmania produce anti-oxidases to counter products of macrophage oxidative burst.

6. Helminth immune evasion mechanisms in the vertebrate host. • Large size.Difficult for immune system to eliminate large parasites. Primary response is inflammation to initiate expulsion, often worms are not eliminated. • 2) Coating with host proteins. Tegument of cestode & trematode worms, is able to adsorb host components, e.g. RBC Ags, thus giving the worm the immunological appearance of host tissue. Schistosomes take up host blood proteins, e.g. blood group antigens & MHC class I & II molecules, therefore, the worms are seen as “self”. • 3) Molecular mimicry. The parasite is able to mimic a host structure or function. The discovery in schistosomes of antigens common to both vertebrate and invertebrate hosts, followed by the extension of these observations to numerous parasites has led to the concept of molecular mimicry.

7. 4) Anatomical seclusion – Oddly, even Trichinella spiralis can live inside mammalian muscle cells for many years. 5) Shedding or replacement of surface e.g. trematodes, hookworms. 6) Immunosupression – manipulation of the immune response. High burdens of nematode infection often carried with no outward sign of infection. Growing evidence that parasite secreted products include anti-inflammatory agents which act to suppress the recruitment and activation of effector leukocytes, or which block chemokine-receptor interactions.

8. Evolutionary/ecological consequences of being a parasite The good news: In some ways, you are in a beautiful, warm, predictable environment. Imagine yourself sitting on the beach with food washing up on the tide, all you have to do is pick it up ... the host takes care of homeostasis (after all, it needs to regulate a constant environment for the sake of its own internal function) and goes to the effort of foraging and processing food for you. The bad news: At the same time, it's in the host's interest to get rid of you. Unless you can minimize your impact or find some way to contribute to the "internal ecology" of the host, the host is going to spend all of its time evolving tricks to kill you or convince you to leave. The energy that hosts spend on defense against parasites can be huge, because the alternative is allowing a continuing drain on resources. There are many parallels with free living organisms, e.g. the trade-off between allocating resources to competition within a patch or to dispersal between patches. However, the big difference between parasites and non-parasites is that in parasite biology the "patches" are living, coevolving, and actively hostile.

9. Therefore there are trade offs: evolutionary and physiological Life, including aspects of this course, is full of trade off scenarios. Does natural selection favour: Maximum fecundity Maximum survival These two objectives cannot be maximized because resources invested in reproduction are not available for survival and vice versa. The solution to this trade off will depend on other factors, both biotic and abiotic.

19. Parasitol Res (2009) 104:217–221 • DOI 10.1007/s00436-008-1297-5 • REVIEW • An update on the use of helminths to treat Crohn’s and other autoimmunune diseases • Aditya Reddy & Bernard Fried

20. Abstract This review updates our previous one (Reddy and Fried, Parasitol Research 100: 921–927, 2007) on Crohn’s disease and helminths. The review considers the most recent literature on Trichuris suis therapy and Crohn’s and the significant literature on the use of Necator americanus larvae to treat Crohn’s and other autoimmune disorders. The pros and cons of helminth therapy as related to autoimmune disorders are discussed in the review. We also discuss the relationship of the bacterium Campylobacter jejuni and T. suis in Crohn’s disease. The significant literature on helminths other than N. americanus and T. suis as related to autoimmune diseases is also reviewed.

21. Helminth therapy with N. americanus Hookworm infection with both N. americanus and A. duodenale occurs predominantly among the worlds most impoverished people and is a common chronic infection, with an estimated 740 million cases, mainly in areas of rural poverty in the tropics and subtropics (de Silva et al. 2003). The major hookworm-related injury in humans occurs when the adult parasites cause an iron-deficiency anemia resulting from intestinal blood loss (Hotez and Pritchard 1995; Stoltzfus et al. 1997; Albonjco et al. 1998).

22. The chronic anemia associated with moderate to severe hookworm infection is a handicap to the affected human and limits the individual’s prospects of a better future (Joven et al. 2005). Despite its associated morbidity, hookworm infections have apparent beneficial effects on hosts suffering from diseases including CD which are linked to overactive immune systems. Some researchers have infected themselves with hookworms and reported good results in regard to alleviating preexisting symptoms associated with a disease state (Svoboda 2006). Lawrence claims his severe asthma and seasonal allergies went into remission using the same helminthic therapy offered herein (Svoboda 2006).

23. Helminth therapy with T. suis: Summers et al. (2005a, b, c, 2006) have successfully utilized the pig whipworm, T. suis, in patients with IBD and further clinical trials are anticipated. T. suis is a porcine whipworm and though genetically similar to T. trichiura, does not propagate in the human intestinal tract (Bee 1976). Hymenolepis diminuta treatment against colitis in a rat model Further reasons to proceed carefully with helminth therapy for colitis related disorders was presented by Hunter et al. (2007) who examined the ability of the tapeworm H. diminuta to affect the course of oxazolone-induced colitis (a TH2 model) in the rat. Hunter et al. (2007) found that infection with H. diminuta caused a significant exacerbation of oxazoloneinduced colitis. Interestingly, Hunter et al. (2007) have shown that H. diminuta infection is beneficial in other models of colitis. The information from their study is presented as a caveat to the position that parasitic helminths in general can be considered as a therapy for different inflammatory disorders without necessitating careful analysis of the immunologic basis of the condition.

24. Other autoimmune diseases Based on the hypothesis that chronic inflammatory bowel disease might be inhibited by stimulating a Th2 immune environment, Summers et al. (2005a, b) modified disease pathology in 29 CD and 54 ulcerative colitis (UC) patients by inoculating them with TSO. Previous studies involving animals have shown that parasite infection can alter the course of autoimmune diseases (Reddy and Fried 2008). Understanding mechanisms by which helminths manipulate immune responses and modulate autoimmune diseases such as IBD, rheumatoid arthritis and Type 1 diabetes may help to develop novel therapies for these diseases. CAN WE USE PARASITES TO ALLEVIATE DISEASE?