Immunity to Protozoa and Worms

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Chapter 15 Immunity to Protozoa and Worms

• Parasites stimulate a variety of immune defense mechanisms.

• Parasitic infections are often chronic and affect many people. They are generally host specific and most cause chronic infections. Many are spread by invertebrate vectors and have complicated life cycles. Their antigens are often stage specific.

• Innate immune responses are the first line of immune defense.

• T and B cells are pivotal in the development of immunity. Both CD4 and CD8 T cells are needed for protection from some parasites, and cytokines, chemokines, and their receptors have important roles.

• Effector cells such as macrophages, neutrophils, eosinophils, and platelets can kill both protozoa and worms. They secrete cytotoxic molecules such as reactive oxygen radicals and nitric oxide (NO^•). All are more effective when activated by cytokines. Worm infections are usually associated with an increase in eosinophil number and circulating IgE, which are characteristic of TH2 responses. TH2 cells are necessary for the elimination of intestinal worms.

• Parasites have many different escape mechanisms to avoid being eliminated by the immune system. Some exploit the host response for their own development.

• Inflammatory responses can be a consequence of eliminating parasitic infections.

• Parasitic infections have immunopathological consequences. Parasitic infections are associated with pathology, which can include autoimmunity, splenomegaly, and hepatomegaly. Much immunopathology may be mediated by the adaptive immune response.

• Vaccines against human parasites are not yet routinely available.

Parasite infections

Parasitic infections typically stimulate a number of immune defense mechanisms, both antibody and cell mediated, and the responses that are most effective depend upon the particular parasite and the stage of infection. Some of the more important parasitic infections of humans (Fig. 15.1) affect the host in diverse ways. Parasitic protozoa may live:

• in the gut (e.g. amoebae);

• in the blood (e.g. African trypanosomes);

• within erythrocytes (e.g. Plasmodium spp.);

• in macrophages (e.g. Leishmania spp., Toxoplasma gondii);

• in liver and spleen (e.g. Leishmania spp.); or

• in muscle (e.g. Trypanosoma cruzi).

Fig. 15.1 Important parasitic infections of humans

Important parasitic infections, including data from the World Health Organization (1993). Their sizes range from 1 m for the tapeworm to around 10^− 5 m for Plasmodium spp. (cf. Fig. 15.w1).

Parasitic worms that infect humans include trematodes or flukes (e.g. schistosomes), cestodes (e.g. tapeworms), and nematodes or roundworms (e.g. Trichinella spiralis, hookworms, pinworms, Ascaris spp., and the filarial worms).

Tapeworms and adult hookworms inhabit the gut, adult schistosomes live in blood vessels, and some filarial worms live in the lymphatics (Fig. 15.2). It is clear that there is widespread potential for damaging pathological reactions.

Fig. 15.2 Sites of infection of medically important parasites

Sites of infection of medically important parasites.

Many parasitic worms pass through complicated life cycles, including migration through various parts of the host’s body:

• hookworms and schistosome larvae invade their hosts directly by penetrating the skin;

• tapeworms, pinworms, and roundworms are ingested; and

• filarial worms depend upon an intermediate insect host or vector to transmit them from person to person.

Most protozoa rely upon an insect vector, apart from Toxoplasma and Giardia spp. and amoebae, which are transmitted by ingestion. Thus:

• malarial parasites are spread by mosquitoes;

• trypanosomes by tsetse flies;

• T. cruzi by triatomine bugs; and

• Leishmania by sandflies.

Parasitic infections are often chronic and affect many people

Parasitic infections present a major medical problem, especially in tropical countries (see Fig. 15.1), for example:

• malaria kills 1–2 million people every year;

• intestinal worms infect one-third of the world’s population – the severity of disease depends upon the worm burden, but in children even moderate intensities of infection may be associated with stunted growth and slow mental development.

Anemia and malnutrition are also associated with parasitic disease.

Over millions of years of evolution, parasites have become well adapted to their hosts and show marked host specificity. For example, the malarial parasites of birds, rodents, or humans can each multiply only in their own particular kind of host.

There are some exceptions to this general rule, for example:

• the protozoan parasite T. gondii is not only able to invade and multiply in all nucleated mammalian cells, but can also infect immature mammalian erythrocytes, insect cell cultures, and the nucleated erythrocytes of birds and fish;

• similarly, the tapeworm of the pig can also infect humans.

Protozoan parasites and worms are considerably larger than bacteria and viruses (Fig. 15.w1), and have very different strategies for avoiding the host immune response.

Fig. 15.w1 Comparative size of various parasites

Comparative size of various parasites.

Q. Apart from size, what is the basic biological difference between bacterial pathogens and parasites, and how would this affect the way they are recognized by the immune system?

A. Bacteria are prokaryotes, whereas parasites are eukaryotes. The plasma membrane and cell wall structures in bacteria are different, so they have distinct pathogen-associated molecular patterns (PAMPs, see Chapter 6). In addition, protein synthesis (initiated with formyl methionine) is different in prokaryotes.

Parasites that have complicated life histories may express certain antigens only at a particular stage of development, giving rise to a stage-specific immune response. Thus, the protein coat of the sporozoite (the infective stage of the malarial parasite transmitted by the mosquito) induces the production of antibodies that do not react with the erythrocytic stages. The different stages of the worm T. spiralis also display different surface antigens.

Protozoa that are small enough to live inside human cells have evolved a special mode of entry:

• the merozoite, the invasive form of the blood stage of the malarial parasite, binds to certain receptors on the surface of the erythrocyte and uses a specialized organelle, the rhoptry, to enter the cell.

• Leishmania spp. parasites, which inhabit macrophages, use complement and Fc receptors to encourage the cells to engulf them.

Leishmania can also gain entry to the cell by using the mannose receptor (see Fig. 7.11) on the macrophage surface.

Immune defenses against parasites

Host resistance to parasite infection may be genetic

The resistance of individual hosts to infection varies, and may be controlled by a number of genes. These may be MHC, non-MHC, or other genes (Fig. 15.3).

Fig. 15.3 Human gene polymorphisms that affect the outcome of parasite infection

Human gene polymorphisms that affect the outcome of parasite infection.

One should not assume that host genetic background is the only reason determining the outcome of infection. There may be many factors involved. In most helminth infections, for example, a heavy worm burden occurs in comparatively few individuals, but may cluster in families, implying a genetic basis. On the other hand, studies have shown that human behavior can account for large variation in exposure between families.

Many parasitic infections are long-lived

It is not in the interest of a parasite to kill its host, at least not until transmission to another host has been ensured. During the course of a chronic infection the type of immune response may change and immunosuppression and immunopathological effects are common.

Host defense depends upon a number of immunological mechanisms

The development of immunity is a complex process arising from the activation of both adaptive and innate immune responses and the switching on of many different kinds of cell over a period of time. Effects are often local and many cell types secreting different mediators may be present at sites of immune rejection. Moreover, the processes involved in controlling the multiplication of a parasite within an infected individual may differ from those responsible for the ultimate development of resistance to further infection.

In some helminth infections a process of ‘concomitant immunity’ occurs, whereby an initial infection is not eliminated, but becomes established, and the host then acquires resistance to invasion by new parasites, mostly worms, of the same species.

In very general terms, humoral responses are important to eliminate extracellular parasites such as those that live in blood (Fig. 15.4), body fluids, or the gut.

Fig. 15.4 Adult schistosome worm pairs in mesenteric blood vessels

Although very exposed to immune effectors, adult schistosomes are highly resistant and can persist for an average of 3–5 years.

(Courtesy of Dr Alison Agnew.)

However, the type of response conferring most protection varies with the parasite. For example, antibody, alone or with complement, can damage some extracellular parasites, but is better when acting with an effector cell.

As emphasized above, within a single infection different effector mechanisms act against different developmental stages of parasites. Thus in malaria:

• antibody against extracellular forms blocks their capacity to invade new cells;

• cell-mediated responses prevent the development of the liver stage within hepatocytes.

Innate immune responses

The innate and adaptive immune responses are co-evolving to allow mammals to identify and eliminate parasites.

The innate immune system provides the first line of immune defense by detecting the immediate presence and nature of infection.

Many different cells are involved in generating innate responses including phagocytic cells and NK cells. It is also becoming clear that early recognition of parasites by antigen-presenting cells (APCs), for example dendritic cells, determines the phenotype of the adaptive response (Fig. 15.5).

Fig. 15.5 Cytokines secreted by the different subsets of T cells

The cytokines secreted by the different subsets of T cells are shown. Note the importance of antigen presenting cells, e.g. DCs and B cells in driving maturation of different TH cell subsets.

Innate immune recognition relies on pattern recognition receptors (PRRs) that have evolved to recognize pathogen-associated molecular patterns (PAMPs).

Q. Which groups of receptors and soluble molecules recognize PAMPs?

A. Toll-like receptors (see Fig. 6.20), the mannose receptor (see Fig. 7.11) and scavenger receptors (see Fig. 7.10) allow phagocytes to directly recognize pathogens. Ficolins, collectins, and pentraxins act as soluble opsonins by binding to pathogen surfaces (see Fig. 6.w3).

A unifying feature of these targets is their highly conserved structures, which are invariant between parasites of a given class.

Although many parasites are known to activate the immune system in a non-specific manner shortly after infection, it is only recently that attention has been given to the mechanisms involved.

While major advances are being achieved in the area of microbial recognition by PRRs, a small but growing number of studies show that parasites also possess specific molecular patterns capable of engaging PRRs. Examples of some parasite PAMPs along with their receptors are given in Figure 15.6.

Fig. 15.6 Innate immune receptors involved in parasite recognition

Innate immune receptors involved in parasite recognition.

Toll-like receptors recognize parasite molecules

The discovery of the TLR family, an evolutionarily conserved group of mammalian PRRs involved in antimicrobial immunity, has enriched our understanding of how innate and adaptive immunity are mutually dependent.

A few studies have examined the role of TLRs in immunity to parasites. For example:

• T. gondii binds TLR11 via profilin and associates with TLR3, TLR7, and TLR9 via the endoplasmic reticulum protein UNC93B1;

• TLR9 mediates innate immune activation by the malaria pigment hemozoin;

• lyso-phosphatidylserine (lyso-PS) from S. mansoni, glycophosphatidylinositol (GPI) anchors, and Tc52 from T. cruzi are capable of signaling through TLR2.

Interestingly, TLR2 triggering by these diverse parasite patterns leads to different immune outcomes: for S. mansoni, triggering leads to the development of fully mature dendritic cells capable of inducing a Treg response (see Chapter 11), characterized by elevated IL-10 levels; for T. cruzi, mature dendritic cells induce a TH1 response (see Chapter 7) with raised levels of IL-12. This dichotomous response could, in part, be explained by the cooperation between TLR2 and other TLRs. However, there has been difficulty in assigning definitive contributions of TLRs to activation by specific parasite proteins since samples are easily contaminated, e.g. with bacterial PAMPs.

Classical human PRRs also contribute to recognition of parasites

Classical PRRs also play important roles in the innate response to parasite infection (see Fig. 15.6) and include collectins (e.g. MBL), pentraxins (e.g. CRP), C-type lectins (e.g. macrophage mannose receptor, and scavenger receptors (e.g. CD36) – see Chapters 6 and 7. For example, MBL binds mannose-rich LPG from Leishmania, Plasmodium, trypanosomes, and schistosomes; and polymorphisms in the MBL gene are associated with increased susceptibility to severe malaria.

Complement receptors are archetypal PRRs

Complement receptors, in particular CR3, are archetypal PRRs involved in innate immune responses (see Fig. 15.6). They are truly multifunctional, being involved in phagocyte adhesion, recognition, migration, activation, and microbe elimination.

Why then is CR3, a linchpin of phagocyte responses, the favored portal of entry for diverse intracellular parasites, including Leishmania via LPG?

• CR3 offers a multiplicity of binding sites, enabling opsonic or non-opsonic binding;

• phagocytosis by CR3 alone does not generate an oxidative burst in phagocytic cells;

• binding of CR3 suppresses the secretion of IL-12.

Q. What effect would suppression of IL-12 secretion have on the immune response?

A. Because IL-12 promotes the development of the TH1 response, reduced expression will tend to reduce macrophage-mediated immunity.

In isolation, CR3 is not an activating receptor. It requires cooperation from other receptors, most notably Fc receptors, for pathogen killing. Helminths have also exploited this chink in the immune armory. Hookworm NIF has been shown to bind a domain in the α subunit of CR3, presumably to downregulate cell-mediated immunity.

Adaptive immune responses to parasites

T and B cells are pivotal in the development of immunity

In most parasitic infections, protection can be conferred experimentally on normal animals by the transfer of spleen cells, especially T cells, from immune animals.

The T cell requirement is also demonstrable because nude (athymic) or T-deprived mice fail to clear otherwise non-lethal infections of protozoa such as T. cruzi or Plasmodium yoelii, and T cell-deprived rats fail to expel the intestinal worm Nippostrongylus brasiliensis (Fig. 15.7).

Fig. 15.7 Parasitic infections in T cell-deprived mice

The first two graphs plot the increase in number of blood-borne protozoa (parasitemia) following infection. (1) T. cruzi multiplies faster (and gives fatal parasitemia) in mice that have been thymectomized and irradiated to destroy T cells (Thym x). In normal mice, parasites are cleared from the blood by day 16. Reconstitution of T cell-deprived mice with T cells from immune mice restores their ability to control the parasitemia. In these experiments both thymectomized groups were given fetal liver cells to restore vital hematopoietic function. (2) P. yoelii causes a self-limiting infection in normal mice and the parasites are cleared from the blood by day 20. In nude mice the parasites continue to multiply, killing the mice after about 30 days. (3) This graph illustrates the time course of the elimination of the intestinal nematode N. brasiliensis from the gut of rats. In normal rats the worms are all expelled by day 13, as determined by the number of worm eggs present in the rats’ feces. T cells are necessary for this expulsion to occur, as shown by the establishment of a chronic infection in the gut of nude rats.

Counterintuitively, many parasites require signals from immune cells to thrive – for example, schistosomes fail to develop in the absence of hepatic CD4⁺ lymphocytes.

B cells also play key roles in regulating and controlling immunity to parasites. For example:

• B cells and antibodies are required for resistance to the parasitic gastrointestinal nematode Trichuris muris; and

• passive transfer of IgG can protect people from malaria.

Both CD4 and CD8 T cells are needed for protection from some parasites

The type of T cell responsible for controlling an infection varies with the parasite and the stage of infection, and depends upon the kinds of cytokine they produce. For example, CD4⁺ and CD8⁺ T cells protect against different phases of Plasmodium infection:

• CD4⁺ T cells mediate immunity against blood-stage P. yoelii;

• CD8⁺ T cells protect against the liver stage of Plasmodium berghei.

The action of CD8⁺ T cells is twofold:

• they secrete IFNγ, which inhibits the multiplication of parasites within hepatocytes;

• they are able to kill infected hepatocytes, but not infected erythrocytes.

Q. By what mechanism are the hepatocytes killed, and why do the CD8⁺ cells not recognize infected erythrocytes?

A. The CD8⁺ T cells recognize parasite antigens presented by MHC class I molecules and induce apoptosis in the target, via Fas ligand, tumor necrosis factor (TNFα), lymphotoxin, and granzymes. Erythrocytes do not express MHC molecules.

The immune response against T. cruzi depends not only upon CD4⁺ and CD8⁺ T cells, but also on NK cells and antibody production; the same is true for the immune response against T. gondii.

CD8⁺ T cells confer protection in mice depleted of CD4⁺ T cells, both through their production of IFNγ and because they are cytotoxic for infected macrophages.

NK cells, stimulated by IL-12 secreted by the macrophages, are another source of IFNγ – chronic infections are associated with reduced production of IFNγ.

These observations probably underlie the high incidence of toxoplasmosis in patients with AIDS, who are deficient in CD4⁺ T cells.

CD4⁺ T cells are critical for the expulsion of intestinal nematodes and as immunity to T. muris can be transferred to a SCID (severe combined immune deficiency) mouse by the transfer of CD4⁺ T cells alone there is no evidence for a role of CD8⁺ T cells.

The cytokines produced by CD4⁺ T cells can be important in determining the outcome of infection. As TH1 and TH2 cells have contrasting and cross-regulating cytokine profiles, the roles of TH1 or TH2 cells in determining the outcome of parasitic infections have been extensively investigated.

As a result of early studies, predominantly in mouse infections, certain dogmas have arisen suggesting that:

• TH1 responses mediate killing of intracellular pathogens; and

• TH2 responses eliminate extracellular ones.

However, this is very much an oversimplification of the true picture, and based on work in animal models that may not fully recapitulate the human immune system.

Although the TH1/TH2 paradigm may be a useful tool in some situations, it is probably more realistic in humans to consider that TH1 and TH2 phenotypes represent the extremes of a continuum of cytokine profiles, and that perhaps it may be more accurate to look at the role of the cytokines themselves in the resolution of infectious disease, particularly as new TH subsets are being discovered, e.g. TH17, TH22, and TH9, and their roles in immunity to parasites investigated.

Regulatory T cells are able to modulate the extremes of both TH2 and TH1 responses.

Cytokines, chemokines, and their receptors have important roles

Q. What experimental methods can be used to elucidate whether a particular cytokine is needed to clear a parasite infection?

A. Experiments with cytokine-knockout animals or cytokine blocking with specific antibody can determine whether a particular cytokine is required. This can be confirmed by observing whether exogenously administered cytokine speeds recovery.

Cytokines not only act on effector cells to enhance their cytotoxic or cytostatic capabilities, but also act as growth factors to increase cell numbers, while chemokines attract cells to the sites of infection. Thus in malaria, the characteristic enlargement of the spleen is caused by an enormous increase in cell numbers.

Other examples include:

• the accumulation of macrophages in the granulomas that develop in the liver in schistosomiasis;

• the eosinophilia characteristic of helminth infections; and

• the recruitment of eosinophils and mast cells into the gut mucosa that occurs in worm infections of the gastrointestinal tract.

Mucosal mast cells and eosinophils are both important in determining the outcome of some helminth infections and proliferate in response to the products of T cells – IL-3, granulocyte–macrophage colony stimulating factor (GM-CSF), and IL-5 respectively.

However, an increase in cell number can itself harm the host. Thus administration of IL-3 to mice infected with Leishmania major can exacerbate the local infection and increase the dissemination of the parasites, probably through the proliferation of bone marrow precursors of the cells the parasites inhabit.

IL-10 and transforming growth factor-β (TGFβ), the regulatory cytokines (see Chapter 11), downregulate the proinflammatory response and thus minimize pathological damage.

Chemokines are key molecules in recruiting immune cells by chemotaxis, but also act in leukocyte activation, hematopoiesis, inflammation, and antiparasite immunity.

Protozoan parasites have been most studied in the context of chemokines and their diverse roles in the parasite–host relationship. For example, T. gondii possesses cyclophilin-18, which binds to the chemokine receptor CCR5 and induces IL-12 production by dendritic cells.

T cell responses to protozoa depend on the species

T cell-mediated immunity operating to control protozoan parasites depends on the species of animal infected and the location and complexity of the parasite life cycle within the host.

For example, in mouse models, the induction of TH

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