Parasitic Infection

PARASITIC INFECTION

Protozoa are a diverse group of parasites, but malaria, leishmaniasis, and trypanoso-miasis globally account for most of the prob-lems encountered in parasitic diseases. The balance between host and parasite is two-fold. The parasite may be too virulent for the host or may evade the immune surveil-lance and thus kills the host. Conversely, the immune response may be vigorous and kill the parasite, thereby jeopardizing its survival. Thus, the survival of any parasite depends on a balance between induction of immunity and escape from surveillance.

Malaria

The worldwide incidence of malaria is esti-mated at 300 million–500 million people, and at least 1 million die each year of the disease, mostly of cerebral malaria and usually young children. Cerebral malaria is usually associated with infection with

Plasmodium falciparum and not Plasmodium vivax. Patients react to protozoal infec-tion with activation of macrophages and monocytes with the release of cytokines TNF, IL-1, and IL-6. Clinically, they pro-duce fever, leukocytosis, and acute phase reactants.

Although most protozoa stimulate the production of IgG and IgM antibodies, these antibodies are probably not protec-tive, and thus vaccines have not yet been successful in the control or prevention of malaria. Also in the case of malaria, pro-tozoa invade erythrocytes and hepatocytes and thus are hidden from the immune response. Clinically, many of the signs and symptoms of these patients are related to the destruction of red blood cells and hepa-tocytes; therefore, anemia, jaundice, sple-nomegaly, hypostasis, hypotension, tender hepatomegaly, and biphasic fever are hall-marks of the disease.

Interestingly, there have been several mutations in the host that help provide resistance to malarial infection. Most strik-ing has been the appearance of the het-erozygous sickle cell trait (Hbas), which confers a survival advantage in endemic disease. Second, the absence of the red cell Duffy antigen (receptor for plasmodium vivax) is quite protective. Finally, the pres-ence of HLA-B53 in individuals is associ-ated with resistance to the disease.

Evasion mechanisms of protozoa fall into three major categories. The first is entrance of the organism into the host cell, where it avoids immune surveillance. One example is malaria, as noted previously. Others include toxoplasma, leishmania, and Trypanosoma cruzi, which enter and can grow inside macrophages. For example, leishmania binds C3 avidly and thus serves as a ligand for the CR3 receptor on macro-phages. If one uses monoclonal antibodies to the CR3 receptor, this inhibits the uptake of the parasite into macrophage. Another approach is used by toxoplasma in which they prevent fusion of phagocytic vacuoles containing the parasite with lysosomes and thus are not destroyed. Finally, try-panosomes need activatedmacrophages for killing; thus they are resistant to intracellu-lar killing in nonactivated macrophages.

A second mechanism for evasion is anti-genic variation. Trypanosoma brucei is an excellent example of this. In this scenario, the trypanosomes are initially destroyed by host antibody. However, the organism resurfaces in the body with a different set of antigens or glycoproteins. The process continues, and the parasite possesses a number of genes that code for these anti-gens and can vary the genes used. Even-tually, the parasite succeeds and avoids host elimination. This type of variation is known as phenotypic variation and dif-fers from the genotypic variation seen in influenza epidemics.

As in bacteria, protozoa can also sup-press the immune response. Malaria and leishmania organisms release soluble anti-gens that nonspecifically suppress the im-mune response by acting on lymphocytes or the reticuloendothelial system. Several parasites undergo development stages that are resistant to complement-mediated lysis. Finally, leishmania can down-regu-late expression of MHC class II expression of parasitized macrophages, which reduces the effectiveness of CD8+ T cells.

In summary, protozoa have developed a wide variety of techniques to evade the immune system. This makes it extremely difficult both to eliminate these protozoa and to produce vaccines that are effective against them. Thus, the field is wide open to new and innovative approaches to elimi-nate this class of organisms.