Immunity to Parasites

In infectious disease terminology, parasitic infection refers to infection with animal

parasites such as protozoa, helminths, and ectoparasites (e.g., ticks and mites). Such
parasites currently account for greater morbidity and mortality than any other class of
infectious organisms, particularly in developing countries. It is estimated that about
30% of the worlds population suffers from parasitic infestations. Malaria alone affects
more than 100 million people worldwide and is responsible for about 500,000 deaths
annually. The magnitude of this 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. Most 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 anti-parasitic drugs are
not effective at killing the organisms. Individuals living in endemic areas require
repeated chemotherapy because of continued exposure, and 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),
andCryptosporidium species (the major parasite that causes diarrhea in HIV-infected patients) all
express glycosyl phosphatidylinositol lipids that can activate TLR2 and TLR4. Phagocytes may
also attack helminthic parasites and secrete microbicidal substances to kill organisms that are too
large to be phagocytosed. However, many helminths have thick teguments that make them
resistant to the cytocidal mechanisms of neutrophils and macrophages, and they are too large to
be ingested by phagocytes. Some helminths may activate the alternative pathway of complement,
although, as we will discuss later, parasites recovered from infected hosts appear to have
developed resistance to complement-mediated lysis.

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 16-4 ). 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 is often dependent on
special types of antibody responses.

TABLE 16-4
Immune Responses to Disease-Causing Parasites
Parasite Diseases Principal Mechanisms of Protective
Protozoa
Plasmodium species Malaria Antibodies and CD8 + CTLs
Leishmania donovani Leishmaniasis (mucocutaneous CD4 + T H 1 cells activate macrophag
disseminated) phagocytosed parasites
Trypanosoma brucei African trypanosomiasis Antibodies
Entamoeba histolytica Amebiasis Antibodies, phagocytosis
Metazoa
Schistosoma species Schistosomiasis Killing by eosinophils, macrophages
Filaria (e.g., Wuchereria Filariasis Cell-mediated immunity; role of antib
bancrofti )
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Selected examples of parasites and immune responses to them are listed.
The principal defense mechanism against protozoa that survive within macrophages is cell-
mediated immunity, particularly macrophage activation by T H 1 cellderived cytokines .
Infection of mice with Leishmania major , a protozoan that survives within the endosomes of
macrophages, is the best documented example of how dominance of T H 1 or T H 2 responses
determines disease resistance or susceptibility (see Fig. 16-6 ). Resistance to the infection is
associated with activation of Leishmania-specific CD4+ T H 1 cells, which produce IFN- and
thereby activate macrophages to destroy intracellular parasites. Conversely, activation of T H 2
cells by the protozoa results in increased parasite survival and exacerbation of lesions because of
the macrophage-suppressive actions of T H 2 cytokines. A good example of this difference is seen
in Leishmania infections in different inbred mouse strains. 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 large numbers of parasites. After infection,
the resistant strains produce large amounts of IFN- 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 T H 1 response or inhibiting the T H 2 response in susceptible strains
increases their resistance to the infection. The mechanisms of this striking difference between
strains of mice are not defined.

Protozoa that replicate inside various host cells and lyse these cells stimulate specific antibody
and CTL responses, similar 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 antibodies. It is now
apparent that the CTL response against parasites residing in hepatocytes is an important defense
against the spread of this intracellular protozoan. The cytokine IFN- has been shown to be
protective in many protozoal infections, including malaria, toxoplasmosis, and cryptosporidiosis.

Defense against many helminthic infections is mediated by the activation of T H 2 cells, which
results in production of IgE antibodies and activation of eosinophils . Helminths stimulate
differentiation of naive CD4 + T cells to the T H 2 subset of effector cells, which secrete IL-4 and
IL-5. IL-4 stimulates the production of IgE, which binds to the Fc receptor of eosinophils and
mast cells, and IL-5 stimulates the development of eosinophils and activates eosinophils. IgE
coats the parasites, and eosinophils bind to the IgE and are activated to release their granule
contents, which destroy the helminths (see Chapter 20 ). The combined actions of mast cells and
eosinophils also contribute to expulsion of the parasites from the intestine (see Fig. 10-9 ). The
expulsion of some intestinal nematodes may be due to IL-4dependent mechanisms that do not
require IgE, such as increased peristalsis.

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 T H 2
responses. (Granulomas are generally induced by T H 1 responses against persistent antigens;
see Chapter 19 .) Such T H 2-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 antigens and specific antibodies. The complexes can be deposited in blood vessels and
kidney glomeruli and produce vasculitis and nephritis, respectively (see Chapter 19 ). Immune
complex disease 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 remarkably effective ways of resisting
immunity ( Table 16-5 ).

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 parasites 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 antigens, and is no longer a target for immune elimination. The
 second and more remarkable example of antigenic variation in parasites is the continuous
variation of major surface antigens seen in African trypanosomes such as Trypanosoma
brucei andTrypanosoma 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 previous wave. Thus, by the time the host produces antibodies
against the parasite, an antigenically different organism 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. The biochemical basis of this change is not known.

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. Shedding of antigens renders the parasites resistant to subsequent antibody-mediated
attack. 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, infection of lymph nodes with subsequent 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 parasites. More non-specific 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.

TABLE 16-5
Mechanisms of Immune Evasion by Parasites
Mechanism of Immune Evasion Examples
Antigenic variation Trypanosomes, Plasmodium
Acquired resistance to complement, CTLs Schistosomes
Mechanism of Immune Evasion Examples
Inhibition of host immune responses Filaria (secondary to lymphatic obstruction), trypanoso
Antigen shedding Entamoeba
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CTL, cytotoxic T lymphocyte.
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. Although the progress has been slower than one would have hoped, elucidation of
the fundamental mechanisms of immune responses to and immune evasion by parasites holds
promise for the future.

Immunity to Fungi
Fungal infections, also called mycoses, are important causes of morbidity and mortality
in humans. Some fungal infections are endemic, and these infections are usually caused
by fungi that are present in the environment and whose spores enter humans. Other
fungal infections are said to be opportunistic because the causative agents cause mild or
no disease in healthy individuals but may infect and cause severe disease in
immunodeficient persons. Compromised immunity is the most important predisposing
factor for clinically significant fungal infections. Neutrophil deficiency as a result of
bone marrow suppression or damage is frequently associated with such infections.
Opportunistic fungal infections are also associated with immunodeficiency caused by
HIV and by therapy for disseminated cancer and transplant rejection. A serious
opportunistic fungal infection associated with AIDS is Pneumocystis
jiroveci pneumonia, but many others contribute to the morbidity and mortality caused
by immune deficiencies.

Different fungi infect humans and may live in extracellular tissues and within
phagocytes. Therefore, the immune responses to these microbes are often combinations
of the responses to extracellular and intracellular bacteria. However, less is known about
antifungal immunity than about immunity against bacteria and viruses. This lack of
knowledge is partly due to the paucity of animal models for mycoses and partly due to
the fact that these infections typically occur in individuals who are incapable of
mounting effective immune responses.

Innate and Adaptive Immunity to Fungi

The principal mediators of innate immunity against fungi are neutrophils and macrophages.
Patients with neutropenia are extremely susceptible to opportunistic fungal infections.
Phagocytes and dendritic cells sense fungal organisms by TLRs and lectin-like receptors
called dectins (see Chapter 4 ). Neutrophils presumably liberate fungicidal substances, such as
reactive oxygen species and lysosomal enzymes, and phagocytose fungi for intracellular killing.
Virulent strains of Cryptococcus neoformans inhibit the production of cytokines such as TNF and
IL-12 by macrophages and stimulate production of IL-10, thus inhibiting macrophage activation.

Cell-mediated immunity is the major mechanism of adaptive immunity against fungal

infections. Histoplasma capsulatum, a facultative intracellular parasite that lives in macrophages,
is eliminated by the same cellular mechanisms that are effective against intracellular bacteria.
CD4 + and CD8 + T cells cooperate to eliminate the yeast forms of C. neoformans, which tend to
colonize the lungs and brain in immunodeficient hosts.Pneumocystis jiroveci is another fungus
that causes serious infections in individuals with defective cell-mediated immunity.

Many extracellular fungi elicit strong T H 17 responses, which are driven in part by the activation
of dendritic cells by fungal glucans binding to dectin-1, a receptor for this fungal polysaccharide.
Dendritic cells activated via this lectin receptor produce T H 17-inducing cytokines, such as IL-6
and IL-23 (see Chapter 10 ). The T H 17 cells stimulate inflammation, and the recruited
neutrophils and monocytes destroy the fungi. Individuals with defective T H 17 responses are
susceptible to chronic mucocutaneous Candida infections. T H 1 responses are protective in
intracellular fungal infections, such as histoplasmosis, but these responses may elicit
granulomatous inflammation, which is an important cause of host tissue injury in these
infections. Fungi also elicit specific antibody responses that may be of protective value.