The large size, complex structure, varied metabolic activity, and synthetic prowess of most parasites provide their human host with an intense antigenic challenge. Generally, the resulting immunologic response is vigorous, but its role in modulating the parasitic invasion differs significantly from that in viral and bacterial infections. It is apparent from the chronic course and frequent recurrences typical of many parasitic diseases that complete acquired resistance resulting in sterile immunity is often absent. Immunity does, however, frequently serve to moderate the intensity of the infection and its associated clinical manifestations. In fact, clinical recovery and resistance to reinfection in some instances require the persistence of viable organisms at low concentration within the body of the host (premunition = infection immunity). An excellent example of this is seen in patients infected with Toxoplasma gondii.
Immune response to parasites vigorous but often relatively ineffective
All those immune responses generally exercised against the more primitive viral and bacterial microorganisms, including innate responses, driven by the complement system, dendritic cells and natural killer cells, and adaptive (acquired) responses, driven by antibodies, cytokines (lymphokines), cytotoxic T lymphocytes, activated macrophages, memory cells, and ADCC mechanisms, have been shown to play a part in modulating parasitic infection.
Innate immune responses are usually immediate, less specific and evolutionarily considered older than adaptive responses. Innate responses often depend on pattern recognition molecules leading to the destruction of bound organisms by complement activation and phagocytosis. Receptor engagement and activation is often critical to further involvement by adaptive responses. One example of innate responses manifest against parasite infections including those seen against malaria. The innate immune response to malaria involves multiple mechanisms, but rarely results in clearance of the parasite. Like other protozoan parasites, Plasmodium falciparum induces the production of IFN-γ by NK cells and subsequent phagocytosis of free parasites by macrophages. NK cells themselves can also lyse parasite-infected erythrocytes. Complicating the picture, improper activation of innate immune mechanisms during malaria may contribute to the disease. For instance, activation of the complement system is a very common finding in human malaria, but excessive complement activation appears to be associated with increased risk of cerebral malaria and severe malarial anemia in children. Likewise, iron sequestration mediated by hepcidin, another innate immune response against malaria, may also worsen anemia by decreasing erythropoiesis.
Overall, parasites are well adapted to resisting host innate defenses. Adaptive responses, therefore, are critical in attempts by the host to control such infections and include both humoral and cell-mediated responses. As already noted, they are usually not perfect.
Antibodies are one line of defense against parasites. They play roles in opsonization, neutralization, complement activation, and ADCC adaptive responses. Antibodies are largely responsible for eliminating populations of trypanosomes from infected individuals. Interestingly, these antibodies are not formed as a result of classical immune stimulation, but because the antigenic signal coming from the trypanosomes consists of T-independent type antigens that can directly stimulate B cells to form antibody. In this case, the antibody is not the classical IgG, but IgM. Although this is useful in eliminating the dominant population of trypanosomes present, another wave of parasites arises because of antigenic variation. Antibodies, if present in high enough concentration, can neutralize sporozoites and merozoites of malaria, thereby preventing them from invading their target host cells, hepatocytes, and red blood cells. Antibody generation against malarial sporozoites using attenuated and recombinant vaccines is currently undergoing multiple pilot clinical trials in developing countries where malaria is endemic. Complement activation does not usually result in direct parasite killing. In fact, many protozoan parasites have evolved mechanisms to avoid complement-mediated killing. Instead, complement appears to play a role in cell-mediated and especially ADCC responses against parasites.
✺ All elements of immune response mobilized
On invasion of tissue, many helminths, and the schistosomes in particular, stimulate the production of IgE, the Fc portion of which binds to mast cells and basophils. Interaction of the antibody with parasitic antigen triggers the release of histamine and other mediators from the attached cells. These may injure the worm directly or, by increasing vascular permeability and stimulating the release of chemotactic factors, may lead to the accumulation of other cells and IgE antibodies capable of initiating antibody-dependent, cell-mediated destruction of the parasite. This is augmented by complement. The specific killer cell involved is often the eosinophil. These cells attach by their Fc receptor site to IgE antibody-coated parasites and degranulate, releasing a major basic protein that is directly toxic to the worm.
✺ IgE response to worm infections attracts eosinophils
✺ Eosinophils bind to IgE-coated parasite and release toxic protein
Cellular immunity is likewise important as an adaptive response. It is a hallmark of cutaneous Leishmania tropica infections. Skin lesion biopsies show the presence of lymphocytes and macrophages working in synergy to contain parasites. Activated macrophages are quite capable of destroying engulfed leishmanial parasites. However, defects in this type of cooperation can be seen in leishmanial infections that result in mucocutaneal leishmaniasis. Lesions containing these parasites contain plenty of macrophages, but few or no lymphocytes.
Cytotoxic T cells, or CD8+ T cells, play a very important part in response to many protozoan infections. These cells not only produce INF-γ, but can also produce TNF-α, and recently have been show to produce IL-17. Collectively, all the cytokines have been shown to have varying roles for protective responses in toxoplasmosis, malaria, Chagas disease, and leishmaniasis.
Many cellular responses also work in consort with antibody responses to assist in modulating parasitic infections. An excellent example of this is seen in the case of many nematode infections such as Trichinella, Ancylostoma, Necator, and Strongyloides, where intimate association with intestinal tissue is an integral part of the life cycle. Such interactions lead to inflammatory responses that are the result of antigen signaling through the Peyer patches, movement of cells to mesenteric lymph nodes, and clonal expansion of both T and B cells that migrate back to the intestinal epithelium to promote inflammatory responses that depend on both antibody and cell-mediated constituents. The whole idea of inflammation in this instance is to produce an environment inhospitable for the worms, or to induce worm expulsion as in the case of Trichinella.
Many parasites are capable of evading host immune responses. The strategies used vary considerably and allow the parasite to successfully propagate and spread to other hosts. If immune responses were completely successful in eliminating parasites, parasites would no longer be a problem. However, if all parasites killed their hosts, transmission would be interrupted. What good is a dead host to a parasite? The techniques by which parasites have been shown to evade the consequences of the host’s specific adaptive responses are numerous. Included among them are seclusion within immunologically protected areas of the body, continual alteration of surface antigens (antigenic variation), molecular mimicry, and active evasion or suppression of the host’s effector mechanisms. Several Protozoa are shielded from the host defenses by virtue of their intracellular location. Some have even found ways to avoid or survive the normally lethal environment of the macrophage, a first-line defense cell normally intent on destroying pathogens it encounters. Trypanosoma cruzi, for example, escapes from phagosomes into the cytoplasm early during host infection. Toxoplasma gondii inhibits the fusion of phagosomes with lysosomes, thus preventing phagolysosome formation. Leishmania species, capable of neither of these feats, are resistant to the action of lysosomal enzymes and survive in macrophage phagolysosomes. Once macrophages have been activated to sufficient levels; however, the tables are somewhat turned on these parasites.
✺ Some intracellular Protozoa escape phagosome, prevent phagosome/lysosome fusion, or avoid phagolysosome destruction
In the examples given above, T cruzi and T gondii have alternate mechanisms for escaping host responses. They do so by becoming intracellular in cell types not normally involved in immune responsiveness. The gut lumen is perhaps the largest immunologic sanctuary within the body, because, unless the integrity of the intestinal mucosa is breached by injury or inflammation, this barrier protects lumen-dwelling parasites, many of which are surrounded by a protective tegument, or cuticle, from most of the effective humoral and cellular immune mechanisms of the host, allowing survival and the opportunity to reproduce.
✺ Encysted and intestinal parasites relatively inaccessible to host defenses
Most immune effector mechanisms are directed against the surface antigens of the parasite, and alteration of these antigens may blunt the immunologic attack. Many parasites undergo developmental changes within their hosts that are generally accompanied by alterations in surface antigens. Immune responses directed at an early developmental stage may be totally ineffective against a later stage of the same parasite. Such stage-specific immunity is very evident in malaria because different life cycle stages express different antigens and even give rise to different types of responses. The issue of stage-specific immunity in malaria is further compounded by species-specific immunity. No wonder we still do not have a totally effective vaccine against this disease. Even more intriguing is the ability of some parasites to vary the antigenic characteristics of a single developmental stage. The trypanosomes that cause African sleeping sickness circulate in the bloodstream coated with a thick glycoprotein surface coat. The development of humoral antibody to this coating results in the elimination of parasites from the blood expressing the dominant surface coat. However, within this dominant population of parasites are a few that have undergone antigenic variation and produced a new variant surface glycoprotein coat. This less dominant population gives rise to the next dominant population and this process repeats itself over and over. Over 1000 variant types can arise via this process. The process is genetically and not immunologically driven. The expression of individual genes from this large genetic repertoire is controlled by the sequential transfer of a duplicate copy of each gene to an area of the parasite genome responsible for gene expression. Continued antigenic variation, unfortunately, causes host immunosuppression with attendant consequences.
✺ Antigenic shifts occur with developmental changes in parasite
✺ Trypanosomal antigenic variation outpaces immunologic response
✺ Antigenic glycoprotein variants of trypanosomes selected from preexisting genetic repertoire
Several protozoan and helminthic pathogens are thought to be capable of neutralizing antibody-mediated attack by shedding and, later, regenerating specific surface antigens. Adult schistosomes, in addition, may immunologically hide from the host by masking themselves with host blood group antigens and immunoglobulins and through a process known as molecular mimicry by which they produce substances that are transported to their tegument that mimic substances naturally found within the host.
✺ Antigenic shedding and masking with host antigens
Several parasites can destroy or inactivate immunologic mediators. Tapeworm larvae produce anticomplementary chemicals, and T cruzi splits the Fc component of attached antibodies, rendering it incapable of activating complement. Several Protozoa, most notably T brucei species that are responsible for African sleeping sickness, induce polyclonal B-cell activation leading to the production of nonspecific immunoglobulins and eventual exhaustion of the antibody-producing capacity of the host. This and other Protozoa can produce nonspecific suppression of both cellular and humoral effector mechanisms, also enhancing the host’s susceptibility to a variety of unrelated secondary infections. Patients with disseminated leishmaniasis display a specific inability to mount a cellular immune response to parasitic antigens in the absence of evidence of generalized immunosuppression.
✺ Parasites may destroy immunologic mediators
✺ Some parasites cause immune suppression
Finally, the thick, tough cuticle of many adult helminths renders them impervious to immune effector mechanisms designed to deal with the less robust microbes.
✺ Cuticle helps resist immune effectors