Parasites include single-celled protozoa, complex multicellular worms (helminths), and ectoparasites (e.g., ticks and mites). Parasitic infections are major health problems, particularly in lower resource countries. It is estimated that approximately 30% of the world’s population suffers from parasitic infestations. In 2022 there were over 200 million cases of malaria and over 600,000 deaths. The magnitude of the public health problem is the principal reason for the great interest in immunity to parasites and for the development of immunoparasitology as a distinct branch of immunology.
Most parasites go through complex life cycles, part of which occurs in humans (or other vertebrates) and part of which occurs in intermediate hosts, such as flies, ticks, and snails. Humans are usually infected by bites from infected intermediate hosts or by sharing a particular habitat with an intermediate host. For instance, malaria and trypanosomiasis are transmitted by insect bites, and schistosomiasis is transmitted by exposure to water in which infected snails reside. Many parasitic infections are chronic because of weak innate immunity and the ability of parasites to evade or resist elimination by adaptive immune responses. Furthermore, many antiparasitic drugs are not effective at killing the organisms. Individuals living in endemic areas require repeated chemotherapy because of continued exposure; such treatment is often not possible because of expense and logistic problems.
Innate Immunity to Parasites
Although different protozoan and helminthic parasites have been shown to activate different mechanisms of innate immunity, these organisms are often able to survive and replicate in their hosts because they are well adapted to resisting host defenses. The principal innate immune response to protozoa is phagocytosis, but many of these parasites are resistant to phagocytic killing and may even replicate within macrophages. Some protozoa express surface molecules that are recognized by TLRs and activate phagocytes. Plasmodium species (the protozoa that are responsible for malaria), Toxoplasma gondii (the agent that causes toxoplasmosis), and Cryptosporidium species (a major cause of diarrheal disease in HIV-infected patients) all express glycolipids that can activate TLR2 and TLR4. Eosinophils con tribute to the innate response to helminths by releasing gran ule contents that are capable of destroying worm integuments. Phagocytes may also attack helminthic parasites and secrete microbicidal substances to kill organisms. However, many helminths have thick integuments that make them resistant to the cytocidal mechanisms of neutrophils and macrophages, and they are too large to be ingested by these phagocytes. Some protozoa and helminths activate the alternative pathway of complement, but they have also developed effective strategies for evading the complement system.
Adaptive Immunity to Parasites
Different protozoa and helminths vary greatly in their structural and biochemical properties, life cycles, and pathogenic mechanisms. It is therefore not surprising that different parasites elicit distinct adaptive immune responses (Table 1). Some pathogenic protozoa have evolved to survive within host cells, so protective immunity against these organisms is mediated by mechanisms similar to those that eliminate intracellular bacteria and viruses. In contrast, metazoa such as helminths survive in extracellular tissues, and their elimination often depends on special types of antibody responses.
Table1. Immune Responses to Disease-Causing Parasites a
The principal defense mechanism against protozoa that survive within macrophages is cell-mediated immunity, particularly macrophage activation by Th1 cell–derived cytokines. Infection of mice with L. major, a protozoan that survives within the endosomes of macrophages, illustrates how the dominance of Th1 or Th2 responses determines disease resistance or susceptibility (Fig. 1). Resistance to the infection is associated with activation of Leishmania-specific Th1 cells, which produce IFN-γ and thereby activate macrophages to destroy intracellular parasites. Conversely, activation of Th2 cells by the protozoa results in increased parasite survival and exacerbation of lesions because Th2 cytokines inhibit classical macrophage activation. Most inbred strains of mice are resistant to infection with L. major, but inbred BALB/c and some related strains of mice are highly susceptible and die if they are infected with high doses of parasites. The resistant strains produce large amounts of IFN-γ in response to leishmanial antigens, whereas the strains that are susceptible to fatal leishmaniasis produce more IL-4 in response to the parasite. Promoting the Th1 response or inhibiting the Th2 response in susceptible strains increases their resistance to the infection. The mechanisms of this striking difference between strains of mice are not defined, and the relevance to human susceptibility to protozoal infections is not established.
Fig1. Role of T cells and cytokines in determining the outcome of infections. Naive CD4+ T lymphocytes may differentiate into Th1 cells (A), which activate phagocytes to kill ingested microbes, and Th2 cells (B), which inhibit this classical pathway of macrophage activation. The balance between these two T-cell subsets may influence the outcome of infections, as illustrated by Leishmania infection in mice—most mouse strains develop Th1 responses against the parasite and effectively clear the organisms, but BALB/c mice develop strong Th2 responses and succumb to the infection. IFN, Interferon; IL, interleukin; TNF, tumor necro sis factor.
Protozoa that replicate inside various host cells and lyse these cells stimulate specific antibody and CTL responses, simi lar to cytopathic viruses. An example of such an organism is the malaria parasite, which resides mainly in red blood cells and in hepatocytes during its life cycle. It was thought for many years that antibodies were the major protective mechanism against malaria, and early attempts at vaccinating against this infection focused on generating protective antibodies. It is now apparent that the CD8+ T-cell response against parasites residing in hepatocytes is an important defense against the spread of this intra cellular protozoan. The cytokine IFN-γ has been shown to be protective in many protozoal infections, including malaria, toxoplasmosis, and cryptosporidiosis.
Defense against many helminthic infections is mediated by type 2 immunity, consisting of group 2 innate lymphoid cells and Th2 cells. Helminths stimulate differentiation of naive CD4+ T cells to the Th2 subset and activate ILC2s. These cells produce the cytokines IL-4 and IL-13, which increase goblet cell mucus production, which promotes expulsion of worms. Tuft cells, a specialized intestinal cell type, increase in number in response to IL-4 during helminth infection and secrete IL-25, which further amplifies type 2 responses. IL-5 produced by Th2 cells activates eosinophils, which destroy the integument of helminths. IgE, also induced by IL-4 and IL-13, may trigger mast cell activation and inflammation at the site of infection.
Adaptive immune responses to parasites can also contribute to tissue injury. Some parasites and their products induce granulomatous responses with concomitant fibrosis. Schistosoma mansoni eggs deposited in the liver stimulate CD4+ T cells, which in turn activate macrophages and induce DTH reactions. DTH reactions result in the formation of granulomas around the eggs; an unusual feature of these granulomas, especially in mice, is their association with Th2 responses. (Granulomas are generally induced by Th1 responses against persistent antigens) Such Th2-induced granulomas serve to contain the schistosome eggs, but severe fibrosis associated with this chronic cell-mediated immune response leads to cirrhosis, disruption of venous blood flow in the liver, and portal hypertension. In lymphatic filariasis, lodging of the parasites in lymphatic vessels leads to chronic cell-mediated immune reactions and ultimately to fibrosis. This results in lymphatic obstruction and severe lymphedema. Chronic and persistent parasitic infestations are often associated with the formation of complexes of parasite anti gens and specific antibodies. The complexes can be deposited in blood vessels and kidney glomeruli and produce vasculitis and nephritis, respectively. Immune complex dis ease is a complication of schistosomiasis and malaria.
Immune Evasion by Parasites
Parasites evade protective immunity by reducing their immunogenicity and by inhibiting host immune responses. Different parasites have developed effective ways of resisting immunity (Table 2).
• Parasites change their surface antigens during their life cycle in vertebrate hosts. Two forms of antigenic variation are well defined. The first is a stage-specific change in antigen expression, such that the mature tissue stages of parasites produce antigens different from those of the infective stages. For example, the infective sporozoite stage of malaria para sites is antigenically distinct from the merozoites that reside in the host and are responsible for chronic infection. By the time the immune system has responded to infection by sporozoites, the parasite has differentiated, expresses new anti gens, and is no longer a target for immune elimination. A more remarkable example of antigenic variation in parasites is the continuous variation of major surface antigens seen in African trypanosomes, such as Trypanosoma brucei and Trypanosoma rhodesiense. Continuous antigenic variation in trypanosomes is mainly due to changes in expression of the genes encoding the major surface antigen. Infected patients show waves of blood parasitemia, and each wave consists of parasites expressing a surface antigen that is different from the preceding wave. Thus, by the time the host produces anti bodies against the parasite, an antigenically different organ ism has grown out. More than 100 such waves of parasitemia can occur in a single infection. One consequence of antigenic variation in parasites is that it is difficult to effectively vaccinate individuals against these infections.
• Parasites become resistant to immune effector mechanisms during their residence in vertebrate hosts. Perhaps the best examples are schistosome larvae, which travel to the lungs of infected animals and during this migration develop a tegument that is resistant to damage by complement and by CTLs.
• Protozoan parasites may conceal themselves from the immune system either by living inside host cells or by developing cysts that are resistant to immune effectors. Some helminthic parasites reside in intestinal lumens and are sheltered from cell-mediated immune effector mechanisms. Parasites may also shed their antigenic coats, either spontaneously or after binding specific antibodies. The shedding of antigens renders the parasites resistant to subsequent anti body-mediated attacks. Entamoeba histolytica is a protozoan parasite that sheds antigens and can also convert to a cyst form in the lumen of the large intestine.
• Parasites inhibit host immune responses by multiple mechanisms. T-cell anergy to parasite antigens has been observed in severe schistosomiasis involving the liver and spleen and in filarial infections. The mechanisms of immunologic unresponsiveness in these infections are not well understood. In lymphatic filariasis, the infection of lymph nodes with sub sequent architectural disruption may contribute to deficient immunity. Some parasites, such as Leishmania, stimulate the development of regulatory T cells, which suppress the immune response enough to allow persistence of the para sites. More nonspecific and generalized immunosuppression is observed in malaria and African trypanosomiasis. This immune deficiency has been attributed to the production of immunosuppressive cytokines by activated macrophages and T cells and defects in T-cell activation.
Table2. Mechanisms of Immune Evasion by Parasites
The consequences of parasitic infestations for health and economic development are devastating. Attempts to develop effective vaccines against these infections have been actively pursued for many years but the progress has been slow.
