How protozoan parasites are transmitted, evade and modulate to establish themselves in susceptible hosts

Protozoan pathogens such as Plasmodium, Leishmania, Trypanosoma and Entamoeba are responsible for several of the most widespread and lethal human diseases. Their successful survival depends mainly on evading the host immune system by, for example, penetrating and multiplying within cells, varying their surface antigens, eliminating their protein coat, and modulating the host immune response. Immunosuppression is sometimes caused directly by parasite products and sometimes involves antigenic mimicry, which often appears in association with parasitic diseases. Common strategies used by these parasites to evade and modulate the immune system include; Seclusion from Immune System Intracellular parasites are generally protected from both immune surveillance and effector function. Leishmaniasis is transmitted through the bite of Phlebotomus or Lutzomyia species sandfly. Its infective stage called the promastigotes contains surface glycoproteins gp63 and gp36 which bind complement and trigger phagocytosis of the parasite by macrophages/monocytes to assume intracellular status. Moreover, the larval stage of the muscle nematode trichinella transforms the muscle cell into a specialized nurse cell that protects it and provides nutrients. This parasitic worm survives there for the lifetime of the host. Plasmodium ookinetes develop in serosal membrane of invertebrates & are beyond reach of phagocytic cells (haemocytes). Antigenic Variation Trypanasomiasis is transmitted through the bite of Glossina species fly. Trypanosoma brucei species coats itself with a dense protein that mainly comprises of (over 95%) the variable surface glycoprotein (VSG) that is responsible for the antigenic character of the parasite. Trypanosomes have gene cassettes of variant surface glycoproteins (VSGs) which allow them to switch to different VSG. VSG is switched regularly (intervals of 5-7 days) with the effect that the host mounts immune response to a current VSG when the parasite is already switching VSG to another type which is not recognised by the host. That is, monoclonal antibodies raised against one clone do not recognise or lyse other clones. A parasite expressing the new VSG will escape antibody detection and replicate to continue the

infection. This allows the parasite to survive for months or years in the host. Up to 2000 genes are involved in this process. Anti-immune mechanisms Example of Leishmania species Once phagocytised and the phagosome fused with the lysosme, Leishmania parasites are

exposed to products of oxidative and arginine metabolism i.e. hydroxyl ions, hydrogen peroxide, superoxide ions and nitric oxide. However, the parasites have their own oxygenscavenging enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. All helminth and protozoan parasites examined to date have at least one of these enzymes. Interfering with Complement: Leishmania is completely covered with lipophosphoglycan (LPG). This elongated LPG binds complement, assisting direct entry of the parasite into macrophages. The parasite avoids damage by complement by the extreme length of the LPG. The lytic C5b-9 complex forms too far away from the parasite membrane. Immunosupression Manipulation of the immune response e.g. Plasmodium Malaria parasites enter human blood from infected mosquitoes. The organisms invade and promptly remodel red blood cells. They coat the surface of infected red cell with a protein called PfEMP1, made by the var gene family. Using this versatile surface protein, the parasite evades the host's immune system using two basic strategies; (i) The protein sticks infected red blood cells to the blood vessel lining, removing the infected cells from circulation, where they would probably be destroyed. (ii) During a malaria infection, a small percentage of each generation of parasites switches to a different version of PfEMP1 that the body has never seen before. In its new disguise, P. falciparum can invade more red blood cells and cause another wave of fever, headaches, nausea, and chills.

Shedding or replacement of surface proteins E.g. Entamoeba histolytica. Entamoeba histolytica is a human pathogen that may invade the intestinal mucosa, causing amoebic colitis or hepatic abscesses when the trophozoites travel through the portal circulation to the liver. It is usually transmitted by ingestion of cysts which survive outside the host in water, soils and on foods. Lipopeptidophosphoglycan (LPPG) is a molecular pattern of E. histolytica recognized by the human immune system. The structural changes in lipophosphoglycan-like (LPGs) and lipophosphopeptidoglycan molecules (LPPGs) form new pathogen-associated molecular patterns (PAMPs) which are not recognized by the pattern recognition receptors of the innate immunity. In other words, the mechanism that converts a non-pathogenic into a pathogenic strain is related to changes in the surface composition, and thus the ability of the parasite to evade host defence mechanisms

Helminths Evasion Mechanisms 1. 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. We will describe schistosome evasion strategies in more detail in the next lecture. 3. Anti-immune mechanisms

e.g. liver fluke larvae secretes enzyme that cleaves Ab. 4. Migration e.g. Hookworms, move about gut avoiding local inflammatory reactions. 5. Production of parasite enzymes Many nematodes which colonise alimentary tract of host secrete acetylcholinesterases (AChEs), enzymes generally associated with termination of neuronal impulses via hydrolysis of acetylcholine at synapses and neuromuscular junctions. This unusual phenomenon has been known for some time, yet the physiological function of the enzymes remains undetermined.