APPENDIX 3

Immunization against T. cruzi

Immunization against trypanosomes needs to be targeted at the surface membrane of the parasite, which presents a number of considerations. American trypanosomes, such as T. cruzi, differ from African trypanosomes and do not employ the dramatic surface modulation seen with African trypanosomes, such as T. bruceigambiense and T. b. rhodesiense, that cause sleeping sickness. T. cruzi’s evasive strategies are to share antigens with host cells and to alter host antigens so that when host antibodies attack the parasites they simultaneously attack host cells (Avila 1994, Brener 1994). This is an evasive function of the surface membrane.

A most vital part of any parasite is its surface, which is the site of nutrient acquisition, the site of dealing with host immunity, and the site where it protects itself from biotic and abiotic components of the environment. The surface membrane of T. cruzi as well as similar protozoa exhibits a wide variety of housekeeping functions. For example, it is responsible for ion balance, nutrient transport, and resisting the physical and chemical perils offered by the vinchuca’s gut. The parasite’s surface is also a key participator in the adherence to and penetration of host cells. Moreover, it is this organelle that deals effectively with the host’s immune response.

The more that is known about T. cruzi’s surface, the more we can learn about how it penetrates cells, what it eats, and how it eats. Consequently, extensive research is being done concerning the biochemistry of T. cruzi’s surface, especially on how it interacts with the host’s immune system.

T. cruzi has a very complex life cycle, which is composed of various stages that pass through a multitude of microenvironments within its mammalian and insect hosts. These microenvironments present many hostile elements which must be overcome since they are essential to the parasite as home or transportation and provide the protozoan with the space and nutrients to survive and reproduce. The capabilities of the organism cannot be assumed to be the same in each environment, since the environments differ so dramatically. If T. cruzi alters its surface to deal with environments, it also consequently alters the basis for attack by the host immune system. T. cruzi’s basic survival strategy is alteration of its surface as it passes through various stages within the vector insectfrom trypomastigotes in the foregut, to epimastigotes in the midgut, and to metacyclic trypomastigotes in the hindgut, which are passed in the feces and deposited on the skin of the animal/human host, and, within the host, from metacyclics in the blood, to amastigote forms in tissues, to trypomastigotes circulating in the blood (see Figure 7).

In comparison, African trypanosomes pass through only two stages, trypomastigote and epimastigote. Within a vertebrate host, African trypanosomes multiply as trypomastigotes in the blood and lymph, whereas T. cruzi multiplies intracellularly as amastigotes. African trypanosomes survive by continually varying their coats and presenting new antigens, thereby exhausting the immune system and setting the stage for secondary infections.

African trypanosomes change their surface coat to defeat the immune system, but American trypanosomes have taken up an intracellular existence and interacted with several broad modulations of vertebrate immune function to evade immunity in more subtle but equally effective ways in terms of its survival. T. cruzi doesn’t undergo a dramatic alteration of the glycoprotein coat as do African trypanosomes, but it does have many different strains (See Appendix 2: Strains of T. cruzi). In Bolivia well over a hundred strains of T. cruzi have been identified which have different surface architecture. T. cruzi uses its surface architecture as an immunoprophylactic. For example, once T. cruzi trypomastigotes have penetrated host cells, surface components protect it from lysosomal enzymes and products ofoxidative burst.

The adaptive successes of African and American trypanosomes lie with their surface coat, which is quite able to outsmart immune systems of the host. Generally speaking, the outer surface of any parasite is one of the most important organs in its symbiotic relationship because it provides an interface between the parasite and its vertebrate and invertebrate hosts. A large measure of the success of trypanosomes lies in their ability to modulate their outer surface in response to attack from host antibodies and immune cells and to hostile components from the environment they encounter in the insect gut and in the cells, fluids, and tissues of a vertebrate host. If prophylactic vaccinations are developed against T. cruzi and the African trypanosomes, they will probably have to somehow alter or incapacitate the outer surface of the parasite.

African trypanosomes have coats of glycoprotein, which are capable of producing thousands of antigenic variations. After African metacyclic trypomastigotes have infected a person, the humoral immune system responds by producing antibodies primarily of two classes, IgM and IgG. The IgM class is the first of these defense proteins produced in response to infection. They destroy by agglutination and lysis all antigenically identical organisms within a given population of parasites. Some trypomastigotes escape because they have different surface antigens, however, and they quickly reproduce until there is another attack by a new variety of IgM antibodies. Another group survives with antigenic variations on their surface coats, and another IgM antibody contingent rushes out to kill them. Eventually, the parasites win this battle because their possibility of variation and survival is greater than the strength of the host’s immune system, continually weakened by the stress of the attacks. Moreover, continual lysing of antigens releases toxic substances into the victim’s body. Every wave of antibodies quickly becomes useless because the trypanosomes have selected new coats with new antigens which evade the previous antibodies (Katz, Despommier, and Gwadz 1988). In short, African trypanosomes display a “moving target,” a continual variation of antigenic coatings, so that just as the host mounts an antibody response to one, another type proliferates (Schmidt and Roberts 1989).