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General Concepts

Protozoa are one-celled animals found worldwide in most habitats. Most species are free living, but all higher animals are infected with one or more species of protozoa. Infections range from asymptomatic to life threatening, depending on the species and strain of the parasite and the resistance of the host.


Protozoa are microscopic unicellular eukaryotes that have a relatively complex internal structure and carry out complex metabolic activities. Some protozoa have structures for propulsion or other types of movement.


On the basis of light and electron microscopic morphology, the protozoa are currently classified into six phyla. Most species causing human disease are members of the phyla Sacromastigophora and Apicomplexa.

Life Cycle Stages

The stages of parasitic protozoa that actively feed and multiply are frequently called trophozoites; in some protozoa, other terms are used for these stages. Cysts are stages with a protective membrane or thickened wall. Protozoan cysts that must survive outside the host usually have more resistant walls than cysts that form in tissues.


Binary fission, the most common form of reproduction, is asexual; multiple asexual division occurs in some forms. Both sexual and asexual reproduction occur in the Apicomplexa.


All parasitic protozoa require preformed organic substances—that is, nutrition is holozoic as in higher animals.


Resistance is the ability of a host to defend itself against a pathogen. Resistance to protozoan parasites involves three interrelated mechanisms: nonspecific factors, cellular immunity, and humoral immunity.


Protozoal infection results in tissue damage leading to disease. In chronic infections the tissue damage is often due to an immune response to the parasite and/or to host antigens as well as to changes in cytokine profiles. Alternatively, it may be due to toxic protozoal products and/or to mechanical damage.

Escape Mechanisms

Escape mechanisms are strategies by which parasites avoid the killing effect of the immune system in an immunocompetent host. Escape mechanisms used by protozoal parasites include the following.

Antigenic Masking: Antigenic masking is the ability of a parasite to escape immune detection by covering itself with host antigens.

Blocking of Serum Factors: Some parasites acquire a coating of antigen-antibody complexes or noncytotoxic antibodies that sterically blocks the binding of specific antibody or lymphocytes to the parasite surface antigens.

Intracellular Location: The intracellular habitat of some protozoan parasites protects them from the direct effects of the host's immune response. By concealing the parasite antigens, this strategy also delays detection by the immune system.

Antigenic Variation: Some protozoan parasites change their surface antigens during the course of an infection. Parasites carrying the new antigens escape the immune response to the original antigens.

Immunosuppression: Parasitic protozoan infections generally produce some degree of host immunosuppression. This reduced immune response may delay detection of antigenic variants. It may also reduce the ability of the immune system to inhibit the growth of and/or to kill the parasites.


The Protozoa are considered to be a subkingdom of the kingdom Protista, although in the classical system they were placed in the kingdom Animalia. More than 50,000 species have been described, most of which are free-living organisms; protozoa are found in almost every possible habitat. The fossil record in the form of shells in sedimentary rocks shows that protozoa were present in the Pre-cambrian era. Anton van Leeuwenhoek was the first person to see protozoa, using microscopes he constructed with simple lenses. Between 1674 and 1716, he described, in addition to free-living protozoa, several parasitic species from animals, and Giardia lamblia from his own stools. Virtually all humans have protozoa living in or on their body at some time, and many persons are infected with one or more species throughout their life. Some species are considered commensals, i.e., normally not harmful, whereas others are pathogens and usually produce disease. Protozoan diseases range from very mild to life-threatening. Individuals whose defenses are able to control but not eliminate a parasitic infection become carriers and constitute a source of infection for others. In geographic areas of high prevalence, well-tolerated infections are often not treated to eradicate the parasite because eradication would lower the individual's immunity to the parasite and result in a high likelihood of reinfection.

Many protozoan infections that are inapparent or mild in normal individuals can be life-threatening in immunosuppressed patients, particularly patients with acquired immune deficiency syndrome (AIDS). Evidence suggests that many healthy persons harbor low numbers of Pneumocystis carinii in their lungs. However, this parasite produces a frequently fatal pneumonia in immunosuppressed patients such as those with AIDS. Toxoplasma gondii, a very common protozoan parasite, usually causes a rather mild initial illness followed by a long-lasting latent infection. AIDS patients, however, can develop fatal toxoplasmic encephalitis. Cryptosporidium was described in the 19th century, but widespread human infection has only recently been recognized. Cryptosporidium is another protozoan that can produce serious complications in patients with AIDS. Microsporidiosis in humans was reported in only a few instances prior to the appearance of AIDS. It has now become a more common infection in AIDS patients. As more thorough studies of patients with AIDS are made, it is likely that other rare or unusual protozoan infections will be diagnosed.

Acanthamoeba species are free-living amebas that inhabit soil and water. Cyst stages can be airborne. Serious eye-threatening corneal ulcers due to Acanthamoeba species are being reported in individuals who use contact lenses. The parasites presumably are transmitted in contaminated lens-cleaning solution. Amebas of the genus Naegleria, which inhabit bodies of fresh water, are responsible for almost all cases of the usually fatal disease primary amebic meningoencephalitis. The amebas are thought to enter the body from water that is splashed onto the upper nasal tract during swimming or diving. Human infections of this type were predicted before they were recognized and reported, based on laboratory studies of Acanthamoeba infections in cell cultures and in animals.

The lack of effective vaccines, the paucity of reliable drugs, and other problems, including difficulties of vector control, prompted the World Health Organization to target six diseases for increased research and training. Three of these were protozoan infections—malaria, trypanosomiasis, and leishmaniasis. Although new information on these diseases has been gained, most of the problems with control persist.


Most parasitic protozoa in humans are less than 50 μm in size. The smallest (mainly intracellular forms) are 1 to 10 μm long, but Balantidium coli may measure 150 μm. Protozoa are unicellular eukaryotes. As in all eukaryotes, the nucleus is enclosed in a membrane. In protozoa other than ciliates, the nucleus is vesicular, with scattered chromatin giving a diffuse appearance to the nucleus, all nuclei in the individual organism appear alike. One type of vesicular nucleus contains a more or less central body, called an endosome or karyosome. The endosome lacks DNA in the parasitic amebas and trypanosomes. In the phylum Apicomplexa, on the other hand, the vesicular nucleus has one or more nucleoli that contain DNA. The ciliates have both a micronucleus and macronucleus, which appear quite homogeneous in composition.

The organelles of protozoa have functions similar to the organs of higher animals. The plasma membrane enclosing the cytoplasm also covers the projecting locomotory structures such as pseudopodia, cilia, and flagella. The outer surface layer of some protozoa, termed a pellicle, is sufficiently rigid to maintain a distinctive shape, as in the trypanosomes and Giardia. However, these organisms can readily twist and bend when moving through their environment. In most protozoa the cytoplasm is differentiated into ectoplasm (the outer, transparent layer) and endoplasm (the inner layer containing organelles); the structure of the cytoplasm is most easily seen in species with projecting pseudopodia, such as the amebas. Some protozoa have a cytosome or cell “mouth” for ingesting fluids or solid particles. Contractile vacuoles for osmoregulation occur in some, such as Naegleria and Balantidium. Many protozoa have subpellicular microtubules; in the Apicomplexa, which have no external organelles for locomotion, these provide a means for slow movement. The trichomonads and trypanosomes have a distinctive undulating membrane between the body wall and a flagellum. Many other structures occur in parasitic protozoa, including the Golgi apparatus, mitochondria, lysosomes, food vacuoles, conoids in the Apicomplexa, and other specialized structures. Electron microscopy is essential to visualize the details of protozoal structure. From the point of view of functional and physiologic complexity, a protozoan is more like an animal than like a single cell. shows the structure of the bloodstream form of a trypanosome, as determined by electron microscopy.


In 1985 the Society of Protozoologists published a taxonomic scheme that distributed the Protozoa into six phyla. Two of these phyla—the Sarcomastigophora and the Apicomplexa--contain the most important species causing human disease. This scheme is based on morphology as revealed by light, electron, and scanning microscopy. Dientamoeba fragilis, for example, had been thought to be an ameba and placed in the family Entamoebidae. However, internal structures seen by electron microscopy showed that it is properly placed in the order Trichomonadida of flagellate protozoa. In some instances, organisms that appear identical under the microscope have been assigned different species names on the basis of such criteria as geographic distribution and clinical manifestations; a good example is the genus Leishmania, for which subspecies names are often used. Biochemical methods have been employed on strains and species to determine isoenzyme patterns or to identify relevant nucleotide sequences in RNA, DNA, or both. Extensive studies have been made on the kinetoplast, a unique mitochondrion found in the hemoflagellates and other members of the order Kinetoplastida. The DNA associated with this organelle is of great interest. Cloning is widely used in taxonomic studies, for example to study differences in virulence or disease manifestations in isolates of a single species obtained from different hosts or geographic regions. Antibodies (particularly monoclonal antibodies) to known species or to specific antigens from a species are being employed to identify unknown isolates. Eventually, molecular taxonomy may prove to be a more reliable basis than morphology for protozoan taxonomy, but the microscope is still the most practical tool for identifying a protozoan parasite.

Life Cycle Stages

During its life cycle, a protozoan generally passes through several stages that differ in structure and activity. Trophozoite (Greek for “animal that feeds”) is a general term for the active, feeding, multiplying stage of most protozoa. In parasitic species this is the stage usually associated with pathogenesis. In the hemoflagellates the terms amastigote, promastigote, epimastigote, and trypomastigote designate trophozoite stages that differ in the absence or presence of a flagellum and in the position of the kinetoplast associated with the flagellum. A variety of terms are employed for stages in the Apicomplexa, such as tachyzoite and bradyzoite for Toxoplasma gondii. Other stages in the complex asexual and sexual life cycles seen in this phylum are the merozoite (the form resulting from fission of a multinucleate schizont) and sexual stages such as gametocytes and gametes. Some protozoa form cysts that contain one or more infective forms. Multiplication occurs in the cysts of some species so that excystation releases more than one organism. For example, when the trophozoite of Entamoeba histolytica first forms a cyst, it has a single nucleus. As the cyst matures nuclear division produces four nuclei and during excystation four uninucleate metacystic amebas appear. Similarly, a freshly encysted Giardia lamblia has the same number of internal structures (organelles) as the trophozoite. However, as the cyst matures the organelles double and two trophozoites are formed. Cysts passed in stools have a protective wall, enabling the parasite to survive in the outside environment for a period ranging from days to a year, depending on the species and environmental conditions. Cysts formed in tissues do not usually have a heavy protective wall and rely upon carnivorism for transmission. Oocysts are stages resulting from sexual reproduction in the Apicomplexa. Some apicomplexan oocysts are passed in the feces of the host, but the oocysts of Plasmodium, the agent of malaria, develop in the body cavity of the mosquito vector.


Reproduction in the Protozoa may be asexual, as in the amebas and flagellates that infect humans, or both asexual and sexual, as in the Apicomplexa of medical importance. The most common type of asexual multiplication is binary fission, in which the organelles are duplicated and the protozoan then divides into two complete organisms. Division is longitudinal in the flagellates and transverse in the ciliates; amebas have no apparent anterior-posterior axis. Endodyogeny is a form of asexual division seen in Toxoplasma and some related organisms. Two daughter cells form within the parent cell, which then ruptures, releasing the smaller progeny which grow to full size before repeating the process. In schizogony, a common form of asexual division in the Apicomplexa, the nucleus divides a number of times, and then the cytoplasm divides into smaller uninucleate merozoites. In Plasmodium, Toxoplasma, and other apicomplexans, the sexual cycle involves the production of gametes (gamogony), fertilization to form the zygote, encystation of the zygote to form an oocyst, and the formation of infective sporozoites (sporogony) within the oocyst.

Some protozoa have complex life cycles requiring two different host species; others require only a single host to complete the life cycle. A single infective protozoan entering a susceptible host has the potential to produce an immense population. However, reproduction is limited by events such as death of the host or by the host's defense mechanisms, which may either eliminate the parasite or balance parasite reproduction to yield a chronic infection. For example, malaria can result when only a few sporozoites of Plasmodium falciparum—perhaps ten or fewer in rare instances—are introduced by a feeding Anopheles mosquito into a person with no immunity. Repeated cycles of schizogony in the bloodstream can result in the infection of 10 percent or more of the erythrocytes—about 400 million parasites per milliliter of blood.


The nutrition of all protozoa is holozoic; that is, they require organic materials, which may be particulate or in solution. Amebas engulf particulate food or droplets through a sort of temporary mouth, perform digestion and absorption in a food vacuole, and eject the waste substances. Many protozoa have a permanent mouth, the cytosome or micropore, through which ingested food passes to become enclosed in food vacuoles. Pinocytosis is a method of ingesting nutrient materials whereby fluid is drawn through small, temporary openings in the body wall. The ingested material becomes enclosed within a membrane to form a food vacuole.

Protozoa have metabolic pathways similar to those of higher animals and require the same types of organic and inorganic compounds. In recent years, significant advances have been made in devising chemically defined media for the in vitro cultivation of parasitic protozoa. The resulting organisms are free of various substances that are present in organisms grown in complex media or isolated from a host and which can interfere with immunologic or biochemical studies. Research on the metabolism of parasites is of immediate interest because pathways that are essential for the parasite but not the host are potential targets for antiprotozoal compounds that would block that pathway but be safe for humans. Many antiprotozoal drugs were used empirically long before their mechanism of action was known. The sulfa drugs, which block folate synthesis in malaria parasites, are one example.

The rapid multiplication rate of many parasites increases the chances for mutation; hence, changes in virulence, drug susceptibility, and other characteristics may take place. Chloroquine resistance in Plasmodium falciparum and arsenic resistance in Trypanosoma rhodesiense are two examples.

Competition for nutrients is not usually an important factor in pathogenesis because the amounts utilized by parasitic protozoa are relatively small. Some parasites that inhabit the small intestine can significantly interfere with digestion and absorption and affect the nutritional status of the host; Giardia and Cryptosporidium are examples. The destruction of the host's cells and tissues as a result of the parasites' metabolic activities increases the host's nutritional needs. This may be a major factor in the outcome of an infection in a malnourished individual. Finally, extracellular or intracellular parasites that destroy cells while feeding can lead to organ dysfunction and serious or life-threatening consequences.

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. 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. Some interrelationships between host factors involved in resistance to protozoan infections.

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.


The protozoa can elicit humoral responses in which antigen-antibody complexes in the region of antibody excess activate Hageman blood coagulation factor (Factor XII), which in turn activates the coagulation, fibrinolytic, kinin and complement systems. It has been suggested that this type of immediate hypersensitivity is responsible for various clinical syndromes in African trypanosomiasis, including blood hyperviscosity, edema, and hypotension. Similar disease mechanisms would be expected in other infections by protozoa involving a strong humoral immune response.

Immune complexes have been found circulating in serum and deposited in the kidneys and other tissues of humans and animals infected with protozoans. These parasite antigen-antibody complexes, plus complement, have been eluted from kidney tissue in cases of malaria and African trypanosomiasis. Antigen and antibody have been directly visualized in the glomeruli of infected animals by light and electron microscopy. Inflammatory cell infiltrates accompany these deposits, and signs of glomerulonephritis are usually seen. African trypanosomes and presumably their antigens are also found in a variety of extravascular locations. Immune complexes, cellular infiltrates, and tissue damage have been detected in these tissues.

Another important form of antibody-mediated pathology is autoimmunity. Autoantibodies to a number of different host antigens (for example, red blood cells, laminin, collagen, and DNA) have been demonstrated. These autoantibodies may play a role in the pathology of parasitic diseases in two ways. First the antibodies may exert a direct cytotoxic effect on the host cells; for example, autoantibodies that coat red blood cells produce hemolytic anemia. Alternatively, autoantibodies may be pathogenic through a buildup of antigen-antibody complexes in the kidneys or other tissues, leading to glomerulonephritis or other forms of immediate hypersensitivity. A particularly good example of a protozoan infection in which autoimmunity appears to be an important contributor to pathogenesis is T cruzi infection. In this case, there is substantial evidence that host and parasite share cross-reacting antigens. Antibodies and cytotoxic lymphocytes to these antigens appear to be harmful to host tissue. This type of experimental data, combined with the fact that the parasite itself seems not to cause the tissue pathology, lead one to conclude that autoimmunity may play a key role in pathogenesis.

Cellular hypersensitivity is also observed in protozoan diseases. For example, in leishmaniasis (caused by Leishmania tropica), the lesions appear to be caused by a cell-mediated immune response and have many, if not all, of the characteristics of granulomas observed in tuberculosis or schistosomiasis. In these lesions, a continuing immune response to pathogens that are able to escape the host's defense mechanisms causes further influx of inflammatory cells, which leads to sustained reactions and continued pathology at the sites of antigen deposition. During a parasitic infection, various host cell products (cytokines, lymphokines, etc.) are released from activated cells of the immune system. These mediators influence the action of other cells and may be directly involved in pathogenesis. An example is tumor necrosis factor (TNF), which is released by lymphocytes. TNF may be involved in the muscle wasting observed in the chronic stages of African trypanosomiasis. TNF has also been implicated in the cachexia and wasting in Leishmania donovani infection, cerebral malaria in P falciparum in children and decreased survival in T cruzi-infected mice. It is apparent that mediators involved in resistance to protozoan parasites may also lead to pathology during a chronic infection (Fig. 78-1). There appears to be a delicate balance between the factors involved in resistance to infectious agents and those which ultimately produce pathology and clinical disease.

Numerous authors have suggested that toxic products produced by parasitic protozoa are responsible for at least some aspects of pathology. For example, the glycoproteins on the surface of trypanosomes have been found to fix complement. This activation of complement presumably results in the production of biologically active and toxic complement fragments. In addition, trypanosomes are known to release proteases and phospholipases when they lyse. These enzymes can produce host cell destruction, inflammatory responses, and gross tissue pathology. Furthermore, it has been hypothesized that the trypanosomes contain a B-cell mitogen that may alter the immune response of the host by eliciting a polyclonal B-cell response that leads to immunosuppression. Finally it has recently been shown that the African trypanosomes also contain an endotoxin which is presumably released during antibody- mediated lysis. Parasitic protozoa have also been reported to synthesize (or contain) low-molecular-weight toxins. For example, the trypanosomes produce several indole catabolites; at pharmacologic doses, some of these catabolites can produce pathologic effects, such as fever, lethargy, and even immunosuppression. Similarly, enzymes, B-cell mitogen, etc., are presumably released by many if not all of the other parasitic protozoa. There has been limited work on the role of these protozoal products in pathogenesis. However, parasitic protozoa are generally not known to produce toxins with potencies comparable to those of the classic bacterial toxins (such as the toxins responsible for anthrax and botulism). One possible exception is the African trypanosomes which are suggested to contain an endotoxin.

Immune Escape

Parasite escape mechanisms may include a number of different phenomena In antigenic masking, the parasite becomes coated with host components and so fails to be recognized as foreign. In blocking, noncytotoxic antibody combines with parasite antigens and inhibits the binding of cytotoxic antibodies or cells. The parasite may pass part of its life cycle in an intracellular location, for example, in erythrocytes or macrophages, in which it is sheltered from intracellular digestion and from the cytotoxic action of antibody and/ or lymphocytes. Some parasites practice antigenic variation, altering their surface antigens during the course of an infection and thus evading the host's immune responses. Finally, the parasite may cause immunosuppression, reducing the host's immune response either to the parasite specifically or to foreign antigens in general. These strategies are discussed in more detail below.

Masking and Mimicry

Various species of trypanosomes have host immunoglobulins associated with their cell surfaces. There are several reports that these antibodies are not bound to the trypanosomes through their variable regions, but presumably through the Fc portion of their molecule. These antibodies may mask the parasite-that is, prevent immune recognition by the host. However, no evidence other than the presence of immunoglobulins on the surface of the trypanosomes supports this hypothesis. Mimicry, in which the parasite has the genetic information to synthesize antigens identical to those of its host, has not been demonstrated in parasitic protozoa.


It has been hypothesized that in some cases antigen-antibody complexes in serum of infected animals bind to the parasite's surface, mechanically blocking the actions of cytotoxic antibodies or lymphocytes and directly inhibiting the actions of lymphocytes. This type of immune escape mechanism has been proposed for tumor cells and for the parasitic helminths. Because the trypanosomes carry immunoglobulins on their cell surfaces, they may use a similar mechanism; however, no direct evidence has yet been reported.

Intracellular location

Many protozoan parasites grow and divide within host cells. For example, Plasmodium parasites grow first in hepatocytes and then in red blood cells. Leishmania and Toxoplasma organisms are capable of growing in macrophages; one genus of parasitic protozoa, Theilera, not only multiplies in lymphocytes but appears even to stimulate the multiplication of the infected lymphocytes. Although some parasites, such as Plasmodium, are restricted to a limited number of host cell types, others, such as T cruzi and Toxoplasma, appear to be able to grow and divide in a variety of different host cells.

An intracellular refuge may protect a parasite from the harmful or lethal effects of antibody or cellular defense mechanisms. For example, Plasmodium may be susceptible to the actions of antibody only during the brief extracellular phases of its life cycle (the sporozoite and merozoite stages). It should be remembered that Plasmodium actually resides in a membrane-bound vacuole in the host cell. Thus, plasmodia are shielded from the external environment by at least two host membranes (the outer cell membrane and an inner vacuole membrane). Although intracellular plasmodia are very well protected from the host's immune response early in their growth, this strategy does create physiologic problems for the parasite. For example, the parasite must obtain its nutrients for growth through three membranes (two host and one parasite), and must eliminate its waste products through the same three membranes. Plasmodia solve this problem by appropriately modifying the host cell membranes. Parasitic proteins are incorporated into the red blood cell outer membrane. The host eventually responds to these antigens, and this response ultimately leads to the increased removal of infected host cells.

The existence of extracellular phases in the malaria life cycle is important, since immunization against these stages is the rationale for the development of our current vaccine candidates. The protective antigens on these extracellular stages have been purified as potential antigens for a vaccine. However, this approach has problems. For example, the sporozoite stage is exposed to protective antibody for only a brief period, and even a single sporozoite that escapes immune elimination will lead to an infection. Second, the antigenic variability of different isolates and the ability of different strains to undergo antigenic variation are not fully known. Therefore, the effectiveness of the vaccine candidates must still be demonstrated. However a large synthetic peptide containing antigenic sequences from 3 different proteins of P falciparum has been shown to reduce the clinical incidence of malaria by 31% in field trials. There is therefore optimism that a vaccine against P falciparum may be available in the near future.

A number of parasitic protozoa reside in macrophages. Although these organisms are protected from external immune threats, they must still evade digestion by the macrophage. Three strategies have been suggested. First, the parasite may prevent the fusion of lysosomes with the phagocytic vacuole. The actual mechanism responsible for this inhibition is not yet understood, but it has been shown to occur in cells infected with Toxoplasma. A second mechanism is represented by the ability of T cruzi to escape from the phagocytic vacuole into the cytoplasm of the macrophage. Finally, it is possible that some parasites can survive in the presence of lysosomal enzymes, as can the leprosy bacillus. One of the best-studied examples of a protozoan parasite able to survive in the phagolysosome is Leishmania. It has been suggested that the resistance of this parasite to the host's hydrolytic enzymes is due to surface components that inhibit the host's enzymes and/or to the presence of parasitic enzymes that hydrolyze the host's enzymes. As previously noted, at least one protozoan parasite, Theilera, is capable of growing directly in lymphocytes. Therefore, this parasite may escape the host's immune response by growing inside the very cells required for the response.

Antigenic Variation

Three major groups of parasitic protozoa are known to be able to change the antigenic properties of their surface coat. The African trypanosomes can completely replace the antigens in their glycocalyx each time the host exhibits a new humoral response. These alterations in serotype are one important way in which the African trypanosomes escape their host's defense mechanism. Although less well-characterized, similar changes are reported to occur in Plasmodium, Babesia, and Giardia.

It has been estimated that African trypanosomes have approximately 1,000 different genes coding for surface antigens. These genes are located on various chromosomes; however, to be expressed, the gene must be located at the end of a chromosome (telomeric site). The rate at which variation occurs in a tsetse-fly-transmitted population appears quite high. It has been shown that 1 in 10 cells appears to be capable of switching its surface antigen. The order in which the surface coat genes are expressed is not predictable. Much information is available on the nucleotide sequence of the genes coding the coat proteins; however, neither the factor(s) that induces a cell to switch its surface antigens nor the specific genetic mechanism(s) involved in the switch are fully understood. The antibody response does not induce the genetic switch, but merely selects variants with new surface antigens out of the original population. Considerably less information is available on the phenomenon of antigenic variation in malaria or babesiosis. However, antigen variation could be a major problem in reference to the development of a blood stage (merozoite) vaccine for malaria. Finally, antigenic variation has been observed in Giardia lamblia. A number of different gene families coding for surface proteins in Giardia have been identified. Antigenic variation has been suggested to assist Giardia in escaping the host's immune response.


Immunosuppression of the host has been observed with almost every parasitic organism carefully examined to date. In some cases the suppression is specific, involving only the host's response to the parasite. In other cases the suppression is much more general, involving the response to various heterologous and nonparasite antigens. It has not yet been proven that this immunosuppression allows the parasites to survive in a normally immunocompetent host. However, one can postulate that immunosuppression could permit a small number of parasites to escape immune surveillance, thus favoring establishment of a chronic infection. This mechanism might be particularly effective in parasites thai undergo antigenic variation, since it could allow the small number of parasites with new surface antigens to go undetected initially. Immunosuppression experimentally induced by various extraneous agents has certainly been shown to produce higher parasitemias, higher infection rates, or both. Therefore, the hypothesis that parasite-induced immmosuppression increases the chance for a parasite to complete its life cycle makes sense.

It should be noted that immunosuppression can be pathogenic itself. A reduced response to heterologous antigens could favor secondary infections. Humans suffering from malaria or trypanosomiasis have been shown to be immunosuppressed to a variety of heterologous antigens. Secondary infections may often be involved in death from African trypanosomiasis.

A variety of mechanisms have been suggested to explain the immunosuppression observed in protozoan infections. The most common mechanisms proposed are (1) the presence in the infected host of parasite or host substances that nonspecifically stimulate the growth of antibody-producing B cells, rather than stimulating the proliferation of specific antiparasite B-cells; (2) proliferation of suppressor T-cells and/or macrophages that inhibit the immune system by excretion of regulatory cytokines; and (3) production by the parasite of specific immune suppressor substances.

For more information view the source:Medical Microbiology


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