Protozoa: Pathogenesis and Defenses

In: Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 78.


Resistance to parasitic protozoa appears to be similar to resistance against other infectious agents, although the mechanisms of resistance in protozoan infections are not yet as well understood. Resistance can be divided into two main groups of mechanisms: (1) nonspecific mechanism(s) or factor(s) such as the presence of a nonspecific serum component that is lethal to the parasite; and (2) specific mechanism(s) involving the immune system (Fig. 78-1). Probably the best studied nonspecific mechanisms involved in parasite resistance are the ones that control the susceptibility of red blood cells to invasion or growth of plasmodia, the agents of malaria. Individuals who are heterozygous or homozygous for the sickle cell hemoglobin trait are considerably more resistant to Plasmodium falciparum than are individuals with normal hemoglobin. Similarly, individuals who lack the Duffy factor on their red blood cells are not susceptible to P vivax. Possibly both the sickle cell trait and absence of the Duffy factor have become established in malaria-endemic populations as a result of selective pressure exerted by malaria. Epidemiologic evidence suggests that other inherited red blood cell abnormalities, such as thalassanemia and glucose-6-phosphate dehydrogenase deficiency, may contribute to survival of individuals in various malaria-endemic geographical regions. A second well-documented example of a nonspecific factor involved in resistance is the presence in the serum of humans of a trypanolytic factor that confers resistance against Trypanosoma brucei brucei, an agent of trypanosomiasis (sleeping sickness) in animals. There is evidence that other nonspecific factors, such as fever and the sex of the host, may also contribute to the host's resistance to various protozoan parasites. Although nonspecific factors can play a key role in resistance, usually they work in conjunction with the host's immune system (Fig. 78-1).

Different parasites elicit different humoral and/or cellular immune responses. In malaria and trypanosome infections, antibody appears to play a major role in immunity. In both T cruzi and T brucei gambiense infections, antibody-dependent cytotoxic reactions against the parasite have been reported. Although antibody has been shown to be responsible for clearing the African trypanosomes from the blood of infected animals, recent evidence suggests that the survival time of infected mice does not necessarily correlate with the ability of the animal to produce trypanosome-specific antibody. In other words, resistance as measured by survival time may not solely involve the specific humoral immune system. Recent data suggest that cellular immunity is required for resistance to malaria. for example, vaccine trials with a sporozoite antigen indicated that both an active cellular response and sporozoite-specific antibody may be needed for successful immunization.

Cellular immunity is believed to be the single most important defense mechanism in leishmaniasis and toxoplasmosis. In animals infected with Toxoplasma, the activated macrophage has been shown to play an important role in resistance. Accordingly, resistance to the protozoan parasites most likely involves nonspecific factors as well as specific humoral and/or cellular mechanisms. Cytokines are involved in the control of both the immune response and pathology. It has become apparent that there are subsets of both helper (h) and cytotoxic (c) T-cells that produce different profiles of cytokines. For example, the Th-1 subset produces gamma interferon (IFN-α), and interleukin-2 (IL-2) and is involved in cell-mediated immunity. In contrast the Th-2 subset produces IL-4 and IL-6, and is responsible for antibody-mediated immunity. The induction of a particular T-cell subset is key to recovery and resistance. The Th-1 subset and increased IFN-g are important in resistance to Leishmania, T cruzi and Toxoplasma infections, whereas the Th-2 response is more important in parasitic infections in which antibody is a key factor. It is important to recognize that the cytokines produced by one T-cell subset can up or downregulate the response of other T-cell subsets. IL-4 will downregulate Th-1 cells and exacerbate infection and/or susceptibility of mice to Leishmania. The cytokines produced by T and other cell types do not act directly on the parasites but influence other host cell types. The response of cells to cytokines includes a variety of physiological changes, such as changes in glucose, fatty acid and protein metabolism. For example, IL-1 and tumor necrosis factor will increase gluconeogenesis, and glucose oxidation. It should be noted that cytokines influence the metabolism not only of T-cells, but also a variety of other cell types and organ systems. Cytokines can also stimulate cell division and, therefore, clonal expansion of T and B-cell subsets. This can lead to increased antibody production and/or cytotoxic T-cell numbers. The list of cytokines and their functions is growing rapidly, and it would appear that these chemical messages influence all phases of the immune response. they are also clearly involved in the multitude of physiological responses (fever, decreased food intake, etc.) observed in an animal's response to a pathogen, and in the pathology that results.

Unlike most viral and bacterial infections, protozoan diseases are often chronic, lasting months or years. When associated with a strong host immune response, this type of chronic infection is apt to result in a high incidence of immunopathology. The question also arises of how these parasites survive in an immunocompetent animal. The remainder of this chapter treats the mechanisms responsible for pathology, particularly immunopathology, in protozoan disease, and the mechanisms by which parasites evade the immune responses of the host. Finally, because of the very rapid advances in our knowledge of the host-parasite relationship (due primarily to the development of techniques in molecular biology), it is necessary to briefly mention the potential for developing vaccines to the pathogenic protozoa.

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