IMMUNOLOGY - Roit I. - Mir 2000

Chapter 18. Immunity to Parasitic Infections

■ A significant portion of the global population is infected with parasites. As a rule, they are host-specific and in most cases cause chronic infection. Many parasites are transmitted by invertebrate vectors and feature a complex life cycle, synthesizing different Antigens at various Selection/3.html">Stages of development.

■ Host resistance is mediated by various defense mechanisms. Effector Cells—macrophages, neutrophils, eosinophils, and platelets—possess The ability to destroy both Protozoa and helminths. They secrete cytotoxic compounds, such as highly reactive oxygen metabolites and nitric oxide, and function more efficiently upon activation by cytokines.

■ T cells play the primary role in The Development of Immunity. Antibodies, both alone and in conjunction with Complement, act effectively against extracellular parasites. They enhance the phagocytic and cytotoxic potential of effector cells and can prevent parasites from invading new host cells.

■ Parasites employ various ways to evade the host Immune Response, sometimes exploiting host response mechanisms for their own development and, in most cases, counteracting them.

■ Parasitic worm infections are accompanied by elevated eosinophil counts and increased levels of circulating IgE antibodies. Both Th2 and Th1 cells are important for the Development of the immune response. Th2 cells are essential for the expulsion of intestinal helminths. Mast Cell products interact with eosinophils.

■ T cells required for protective reactions may belong to either CD4⁺ or CD8⁺ populations. Th1 cells provide protection against intracellular protozoa by secreting IFN-γ, which activates macrophages.

■ Parasitic infections are accompanied by The production of large amounts of non-specific antibodies, Splenomegaly, and hepatomegaly. Immunopathological effects are predominantly T-cell-mediated.

As a rule, parasitic infections trigger a range of immunological defense mechanisms, both humoral and cellular, with the efficacy of the response depending on The Nature of the parasite and the stage of infection. This chapter examines the core aspects of immunity to parasitic infections, with a particular focus on diseases caused by some of the most important human parasites (Fig. 18.1).

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Fig. 18.1. Prevalence of parasite infections according to World Health Organization data (1993).

Parasitic protozoa are capable of inhabiting the intestine (e.g., amoebae), the bloodstream (e.g., African trypanosomes), the interior of erythrocytes (e.g., Plasmodium spp.), macrophages (e.g., Leishmania spp. and Toxoplasma gondii), including those localized in The Liver and Spleen (e.g., Leishmania spp.), or Muscles (e.g., Trypanosoma cruzi). Parasitic worms—helminths that infect humans—include trematodes, or flukes (e.g., schistosomes), cestodes, or tapeworms (e.g., broad tapeworm, tapeworms, echinococcus), and nematodes, or Roundworms (e.g., Trichinella spiralis, hookworms, pinworms, ascarids, and filariae). Cestodes and adult hookworms colonize the intestine, adult schistosomes inhabit Blood Vessels, and certain filariae reside in The Lymphatic system (Fig. 18.2). Naturally, such a diverse tissue tropism gives rise to A wide variety of pathological reactions.

Fig. 18.2. Sites of infection in the most common parasitic diseases.

Many helminths have a complex life cycle involving migration through various PARTS OF THE host Organism, passing through specific developmental stages in different Tissues. At The final stage of development, the helminth reaches the site where it matures and spends the remainder of its life cycle (Fig. 18.3). Hookworms and schistosome larvae infect the host by directly penetrating the Skin; tapeworms and roundworms enter The Human Body orally; transmission of filariae depends on an insect intermediate host or vector. Most parasitic protozoa are transmitted by insect vectors, whereas Toxoplasma, Giardia, and amoebae enter the human body orally. Malaria pathogens are transmitted by mosquitoes, trypanosomes by tsetse flies, bugs, etc. (specifically T. cruzi by triatomine bugs of the subfamily Triatominae), and Leishmania by sandflies. The Diversity of transmission routes poses additional challenges for the development of immunization strategies.

Fig. 18.3. Survival timelines, reproduction, and migration routes of helminths in the human body.

KEY FEATURES OF PARASITIC INFECTIONS

A major portion of the global population is infected with parasites

Parasitic diseases constitute a major medical problem, especially in tropical countries (Fig. 18.1). Malaria, for instance, causes 1–2 million deaths annually. Intestinal helminths infect one-third of the global population; the severity of the disease depends on the degree of infection, though in children even moderate infections can cause growth retardation and impaired mental development. Parasitic diseases are also characterized by anemia and wasting.

Parasitic infections share A number of common features. Parasitic protozoa and worms are significantly larger than Bacteria and Viruses (Fig. 18.4) and, accordingly, possess a greater quantity and variety of antigens. Some species are characterized by surface antigen variation—antigenic variation. Parasites with complex life cycles may express certain antigens only at specific developmental stages, eliciting a corresponding specific immune response. For example, in malaria parasites, the protein coat of the sporozoite (the infectious or dissemination stage, by which the plasmodium is transmitted by mosquitoes and infects the host) induces the production of specific antibodies that do not react with the parasite during the erythrocytic stage of its life cycle. The parasitic worm T. spiralis also expresses different antigens at various stages of its life cycle.

Fig. 18.4. Comparative sizes of various parasitic organisms.

Protozoa, which are small enough to parasitize human cells, possess special properties for entering host Cells and Tissues. Malaria plasmodium merozoites (the developmental stage at which the plasmodium is capable of invading erythrocytes) bind to specific receptors On the surface of Blood Cells and use a specialized organelle—the rhoptry—to enter The Cell. Parasitic leishmanias use the complement receptor to facilitate their uptake by host macrophages. These parasites can also enter cells by interacting with the mannose-fucose receptor on the macrophage surface.

Most parasites are host-specific

Over millions of years of evolution, parasitic organisms have adapted remarkably well to their hosts and exhibit a pronounced host Specificity. For instance, the pathogens responsible for avian, rodent, or human malaria are capable of multiplying exclusively within the organism of their specific host. There are certain exceptions to this rule: for example, the parasitic protozoan T. gondii can not only infect and multiply within all nucleated mammalian cells, but can also infect immature mammalian erythrocytes, cultured insect cells, and the nucleated erythrocytes of birds and fish. Similarly, the pork tapeworm is capable of infecting humans.

Host resistance to parasitic infection can be genetically determined

The resistance of individual hosts to infection varies and may be controlled by various immune response genes. Certain mouse strains (and some humans) possessing specific MHC genes lack the ability to actively produce antibodies against one of the surface Peptides of malaria parasite sporozoites because their T cells fail to become sensitized. At the same time, the presence of certain HLA antigens, which are widespread among West African populations but rarely found in Caucasians, appears to correlate with immunity to severe forms of malaria.

Non-MHC genes can also be of significant importance.

✵ Mouse susceptibility to infection with Leishmania donovani and certain other parasites is determined by a single dominant Gene that regulates macrophage activation (see Chapter 1).

✵ Merozoites of the malaria pathogen Plasmodium vivax use a specific surface receptor—the Duffy blood group antigen—to enter erythrocytes. This antigen is absent in some African ethnic groups—possibly As a result of selective pressure—making them highly resistant to infection by this parasite.

Most helminth infections are characterized by a heavy parasite burden concentrated in a relatively small number of individuals; however, it should be noted that this is not necessarily due to genetic differences in resistance. Behavioral studies indicate that even within small communities, individuals vary greatly in their risk of infection due to substantial differences in their opportunities for contact with parasites.

Many parasitic infections are chronic diseases

It is not advantageous for a parasite to cause the death of its host, at least until transmission to a new host has taken place. In chronic infection, the pattern of the immune response changes over time and depends on the presence of circulating antibodies, persistent antigenic stimulation, and The formation of immune complexes (Fig. 18.5). Immunosuppression and immunopathological reactions are typical of chronic infections.

Fig. 18.5. Immune complex deposition in Nephrotic Syndrome characteristic of quartan malaria. Micrograph (low-voltage fluorescence Electron Microscopy) of a renal glomerulus (biopsy material from a Nigerian child). In malaria caused by Plasmodium malariae, Glomerulonephritis may develop as a result of immune complex deposition. The section is stained with FITC conjugated to IgG against human antigens; granular deposition of IMMUNOGLOBULINS is visible within the capillary loops of the renal glomerulus. (Photo courtesy of Dr. V. Houba.)

Host resistance depends on diverse immune effector mechanisms

The development of immunity is a complex process based on the interaction of many cell types over a period of time. Effects are often exerted locally, and various cells secreting distinct mediators may be located at sites of immunological rejection. Furthermore, the immune reactions that prevent parasite multiplication within the body may differ from those responsible for establishing final resistance. In some helminth infections, "concomitant immunity" develops; the primary infection is not eliminated but becomes stabilized, and the host acquires resistance to reinfection by new helminths of the same species.

The humoral response as such is essential for eliminating extracellular parasites, such as those localized in the blood (Fig. 18.6), Body Fluids, or the gut. However, the predominant type of response required for protection depends on the Nature of the parasite. For example, antibodies alone or in combination with complement can damage certain extracellular parasites, yet their action is enhanced when they function in concert with effector cells. As noted above, during the course of a single infection, different effector mechanisms are recruited to combat the parasite at various stages of its life cycle. Thus, in malaria, antibodies directed against extracellular forms of the parasite block their ability to invade new cells, whereas a cell-mediated response prevents the development of schizonts in hepatocytes. Protective immunity to malaria does not correlate directly with antibody levels and can be induced even in their absence. This has been demonstrated in mice immunized with a specially engineered strain of Salmonellatyphimurium; The Genome of this bacterial strain was genetically modified to incorporate a gene encoding a surface antigen of the malaria parasite sporozoite. Upon subsequent challenge with sporozoites, these animals developed immunity to the malaria pathogen despite the absence of specific antibodies.

Fig. 18.6. Pairs of adult schistosomes in the mesenteric blood vessels. Schistosomes are highly resistant to the intensive action of immune effector mechanisms. Adult worms can persist in the host for an average of 3–5 years. (Photo courtesy of Dr. A. Agnew.)