Immunity to Parasites



Immunity to Parasites



Infectious diseases, as pointed out earlier, rarely result from the deliberate activities of a malicious microorganism. In most cases, disease occurs because of the host’s reaction to the infection or because the invader inadvertently causes damage to its host. Well-adapted parasites do not make these mistakes. They have evolved in such a way that their presence in the host is scarcely noticed. They exploit the host’s resources without causing irreparable damage or triggering an effective defensive response. Parasitic infections caused by protozoan parasites or helminths may be noticed only by production losses. Indeed, in many cases, the presence of parasites comes to our attention only when they are present in unusually large numbers or when they damage critical organs by accident. Sometimes, of course, a parasite may deliberately cause disease. For instance, the protozoan parasite Toxoplasma gondii causes its rodent hosts to become slow, confused and fearless so that they are more readily eaten by cats, its alternative host.


A consistent feature of all parasite infestations however, is that they block or significantly delay the innate and adaptive defenses of their host so that they may persist for sufficient time to reproduce. Some parasites may simply delay their destruction until they complete a single life cycle. Other well-adapted parasites may contrive to survive for the life of their host protected from immunological attack by sophisticated and specific evasive strategies (Figure 27-1).



In contrast to the acute, short-lived infections caused by bacteria and viruses, infections by parasitic protozoa or helminths are long-lasting. Ideally, a successful parasite will regulate a host’s immune responses, selectively suppressing these to permit parasite survival, while at the same time allowing other responses to proceed and thus preventing the death of the host from other infections. In addition, many parasites make use of the host’s metabolic or control pathways for their own purposes. Epithelial growth factor and IFN-γ can enhance the growth of Trypanosoma brucei, whereas IL-2 and GM-CSF promote the growth of Leishmania amazonensis. The sharing of cytokines by host and parasites in this way reflects the long history of their association and their success in adapting to a parasitic lifestyle. It is evident that these parasites must have evolved very effective mechanisms to prevent immunological destruction.



Immunity to Protozoa


Innate Immunity


The mechanisms of innate resistance to protozoa are similar to those that prevent bacterial and viral invasion, although species influences are of much greater significance. For example, T. brucei, Trypanosoma congolense, and Trypanosoma vivax do not cause disease in the wild ungulates of East Africa but will kill domestic cattle, presumably as a result of lack of mutual adaptation. Similarly, the coccidia are extremely host specific; for example, Toxoplasma gondii tachyzoites can infect any species of mammal, but their coccidian stages affect only felids (e.g., cats).


These species differences are reflected by more subtle genetic influences within breeds. Thus some breeds of African cattle, most notably N’Dama, are resistant to infection by pathogenic trypanosomes. This “trypanotolerance” results from selection of the most resistant animals over many generations and results in a greater ability to control infection as well as resistance to the pathological effects of the parasite. The γ/δ T cells of N’Dama are much more responsive to trypanosome antigens than are the γ/δ T cells of non-native cattle. Trypanotolerant animals produce more IL-4 and less IL-6 than susceptible animals. At the same time trypanotolerant animals show neither the severe anemia nor the production loss seen in susceptible cattle. Trypanotolerant animals produce high levels of IgG against T. congolense cysteine protease. Since this enzyme contributes to the pathology of infection, these antibodies may partially account for their tolerance.



Adaptive Immunity


Like other invaders, protozoa stimulate both antibody- and cell-mediated immune responses. In general, antibodies control parasites in blood and tissue fluids, whereas cell-mediated responses are directed largely against intracellular parasites.


Serum antibodies directed against protozoan surface antigens may opsonize, agglutinate, or immobilize them. Antibodies together with complement and cytotoxic cells may kill them, and some antibodies (called ablastins) may inhibit their division. In genital infections of humans due to Trichomonas vaginalis, a local IgE response is stimulated. This triggers an allergic reaction that increases vascular permeability, permitting IgG antibodies to reach the site of infection and immobilize and eliminate the organisms.


In babesiosis the infective stages of the organisms (sporozoites) invade red blood cells. Infected red cells incorporate Babesia antigens into their membranes. These in turn induce antibodies that opsonize the red cells and cause their removal by phagocytosis. Infected red cells may also be destroyed by antibody-dependent cell-mediated responses. Macrophages and cytotoxic lymphocytes can recognize the Babesia antigen-antibody complexes on the surface of infected erythrocytes. T cell cytotoxicity may be important early in infection when the number of infected erythrocytes is small.


Intracellular parasites use many different and unique strategies to invade cells and inhibit intracellular killing. Most gain entry to a cell by employing host-mediated processes such as phagocytosis or induced uptake. Apicomplexans such as Toxoplasma and Cryptosporidium, however, actively penetrate cells using a system of adhesion-based motility called “gliding.” Once inside, these parasites reside in specially modified vacuoles. Protective immunity against apicomplexan protozoa, such as Cryptosporidium, Eimeria, Neospora, Plasmodia, and Toxoplasma species, is generally mediated by Th1 responses. For example, T. gondii is an obligate intracellular parasite whose tachyzoites grow within cells, especially macrophages (Figure 27-2). The parasites produce perforin-like molecules that permeabilize the cell membrane and permit the tachyzoites to escape and invade other cells. They penetrate these cells by “gliding” through a molecular junction in the cell membrane and do not trigger proper phagosome formation or maturation. Toxoplasma tachyzoites are therefore not destroyed since their “parasitophorous vacuoles” do not mature and fuse with lysosomes. Toxoplasma can grow inside cells in an environment free of antibodies, oxidants, or lysosomal enzymes. Toxoplasma-infected dendritic cells are attacked and killed by perforins from natural killer (NK) cells. However, the released parasites can then invade the NK cells! These infected NK cells, in contrast, are not effectively targeted by other NK cells.



The production of IL-12 and IFN-γ is essential for the early control of Toxoplasma infection. The toxoplasma actin-binding protein profilin is the ligand for TLR11. TLR11 on dendritic cells signals through the MyD88 pathway stimulating IL-12 and IFN-γ production. T. gondii cyclophilin also stimulates IL-12 production from dendritic cells through CCR5. The IL-12 and IFN-γ in turn trigger a strong Th1 response. Some antibodies are produced that, together with complement, destroy extracellular organisms and prevent its spread between cells (Figure 27-3). This response, however, has little or no influence on the intracellular forms of the parasite. The intracellular organisms are only destroyed by the IL-12-dependent Th1 response. Activated Th1 cells secrete IFN-γ in response to Toxoplasma ribonucleoproteins. This IFN-γ activates macrophages, permitting lysosome-vacuole fusion and killing the intracellular organisms. In addition, cytotoxic T cells can destroy Toxoplasma tachyzoites and Toxoplasma-infected cells on contact. T. gondii tachyzoites, however, may convert into a cyst form containing bradyzoites. The cysts are weakly immunogenic and do not stimulate inflammation. It is possible that this cyst stage is not recognized as foreign. As a result, the cysts persist indefinitely within tissues.



Th1-mediated responses resulting in the activation of macrophages are important in many protozoan diseases in which the organisms are resistant to intracellular destruction. One of the most significant destructive pathways in M1 cells is the production of nitric oxide (NO). Nitrogen radicals formed by the interaction of NO with other oxidants are lethal for many intracellular protozoa. However, protozoa are also experts in surviving within macrophages; for example, Leishmania, Toxoplasma, and Trypanosoma cruzi, can migrate into safe intracellular vacuoles by blocking phagosome maturation. Leishmania and T. cruzi can suppress the production of oxidants or cytokine production, whereas T. gondii can promote macrophage apoptosis. T. gondii tachyzoites can inhibit proinflammatory cytokine production by preventing nuclear translocation of NF-κB.


In Theileria parva infection (East Coast fever) of cattle, sporozoites can invade α/β and γ/δ T cells, as well as B cells. The parasite then activates NF-κB by continuously phosphorylating its inhibitor proteins Iκ-Bα and Iκ-Bβ (Chapter 8). The NF-κB thus persists, maintains the cell in an activated state, and prevents its apoptosis. The activated cells produce both IL-2 and IL-2R. As a result, a loop is established, by which infected cells secrete IL-2, which in turn stimulates their growth. As Theileria schizonts develop within lymphocytes, the infected cells enlarge and proliferate. Since the parasite divides synchronously with its host cell, there is a rapid increase in parasitized cells resulting in overwhelming infection and death. Some animals, however, may recover from infection and become solidly immune. In these animals, CD8+ T cells can kill infected lymphocytes by recognizing parasite antigens in association with MHC class I molecules. In susceptible animals, the parasites interfere with MHC class I expression.


Infection of chickens or mammals with Eimeria oocysts generally leads to strong, species-specific immunity that can prevent reinfection. This immune response inhibits the growth of trophozoites, the earliest invasive stage, within intestinal epithelial cells. This growth inhibition is reversible since the arrested stages can be transferred to normal animals and complete their development uneventfully. Studies in mice suggest that resistance to primary infection is mediated by multiple cell-mediated mechanisms that involve CD4+ T cells and their cytokines IL-12 and IFN-γ, macrophages, and NK cells. In contrast, resistance to secondary challenge is mediated by CD8+ T cells. In chickens, IFN-γ, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β), as well as intraepithelial CD8+ α/β T cells, appear to be essential for anticoccidial immunity. It is interesting to note that Eimeria-susceptible chickens express much more IL-10 in their intestines than do resistant chickens, both constitutively and after infection. Given that IL-10 promotes a Th2 bias, it is likely that this is the cause of reduced resistance in susceptible birds.


For many years it was thought that a common feature of many protozoan infections was premunition, a term used to describe resistance that is established after the primary infection has become chronic and is only effective if the parasite persists in the host. It was believed, for example, that only cattle actually infected with Babesia were resistant to clinical disease. If all organisms were removed from an animal, resistance was believed to wane immediately. Studies have shown that this is not entirely true. Cattle cured of Babesia infection by chemotherapy are resistant to challenge with the homologous strain of that organism for several years. Nevertheless, the presence of infection does appear to be mandatory for protection against heterologous strains. Babesiosis is also of interest since splenectomy of infected animals will result in clinical disease. The spleen not only serves as a source of antibodies in this disease but also removes infected erythrocytes. Splenic macrophages and dendritic cells trigger a Th1 response involving both NK cells and γ/δ T cells. They also generate NO. The absence of NO in splenectomized animals permits the disease to reappear.



Leishmaniasis


The importance of immunity in determining the course and nature of a protozoan disease is best seen in canine leishmaniasis. Canine leishmaniasis is caused by Leishmania infantum or its New World synonym Leishmania chagasi and transmitted by biting sandflies. When the promastigote forms of this parasite are injected by a sandfly into the skin of dogs, they are rapidly phagocytosed by neutrophils. When the neutrophils undergo apoptosis, the parasites are released and then engulfed by macrophages and dendritic cells in which the organisms differentiate into amastigotes. Leishmania amastigotes are obligate intracellular parasites. They divide within the macrophages until the cells rupture, and the released organisms are then phagocytosed by neighboring cells. Depending on the degree of host immunity, the parasites may be restricted to the skin (cutaneous disease); alternatively, infected dendritic cells may migrate to lymph nodes or enter the circulation and lodge in the internal organs, leading to disseminated visceral disease. Although infection is widespread in endemic areas, most dogs are resistant to Leishmania, and only 10% to 15% develop visceral disease.


Macrophages are the main host cells for Leishmania and the effector cells for parasite killing. Parasites divide within the phagolysosomes of infected macrophages. Their resistance to intracellular destruction is a result of multiple mechanisms. (One study of 245 macrophage genes showed that 37% were suppressed by Leishmania infection). Leishmania lipophosphoglycan delays phagosome maturation, preventing the production of NO and inhibiting macrophage responses to cytokines. The parasite also reduces the antigen-presenting ability of macrophages by suppressing major histocompatibility complex (MHC) class II expression. As a result of their persistence, the parasites trigger chronic inflammation. Initially characterized by granulocyte invasion, this is followed by macrophages, lymphocytes, and NK cells that collectively form granulomas.


The clinical signs of leishmaniasis are directly linked to the immune response of the infected dog. In susceptible animals, the organisms may spread from the skin to the local lymph node, spleen, and bone marrow within a few hours. In resistant dogs, the parasites remain restricted to the skin and draining lymph node and either remain healthy or develop a mild, self-limited disease. These resistant dogs mount a weak antibody response but a strong and effective Th1 response. They may have low antibody titers, but they produce IFN-γ in response to parasite antigens, generate type I granulomas, mount strong delayed hypersensitivity responses, and eventually destroy the parasites. Resistance to Leishmania has a strong genetic component; for example, Ibizian hounds appear to be resistant to this parasite. There is also an association between resistance and certain MHC class II alleles as well as some Slc11a1 (Nramp) alleles in dogs (see Box 6-1).


Susceptible dogs, in contrast, mount a Th2 response characterized by high antibody levels but poor cell-mediated immunity. These differences have been attributed to the activities of IL-10–producing regulatory T cells. In addition, the parasite may actively suppress transcription of the IL-12 gene, ensuring that a Th2 response predominates. Chronic, progressive disease develops in susceptible dogs. Parasite-laden macrophages accumulate, but the organism continues to multiply. These macrophages spread throughout the body, resulting in disseminated infection. Dogs develop severe generalized nodular dermatitis, granulomatous lymphadenitis, splenomegaly, and hepatomegaly. They show polyclonal (occasionally monoclonal) B cell activation involving all four IgG classes, as well as hypergammaglobulinemia, and they develop lesions associated with type II and type III hypersensitivity. Thus excessive immunoglobulin production can lead to development of an immune-mediated hemolytic anemia, thrombocytopenia, and the production of antinuclear antibodies. Glomerulonephritis, uveitis, and synovitis may result from chronic immune complex deposition, leading to renal failure and death. Significantly elevated antihistone antibodies are a feature of dogs with Leishmania-associated glomerulonephritis. There is a positive correlation between the levels of these antihistone antibodies and the urine protein-to-creatinine ratio since these antibodies increase the probability of developing glomerulonephritis.



Evasion of the Immune Response


Despite their antigenicity, parasitic protozoa survive within their host by using multiple evasion mechanisms acquired over many millions of years of evolution. For example, T. gondii can avoid neutrophil attachment and phagocytosis. T. parva invades and destroys T cells. Other protozoa such as the trypanosomes may promote the development of suppressive regulatory cells or stimulate the B cell system to exhaustion. Plasmodium falciparum can suppress the ability of dendritic cells to process antigen.


Parasite-induced immunosuppression may promote parasite survival. For example, Babesia bovis is immunosuppressive for cattle. As a result, its host vector, the tick Boophilus microplus, is better able to survive on infected animals. Infected cattle have more ticks than noninfected animals, and the efficiency of transmission of B. bovis is enhanced. It must be pointed out, however, that parasite-induced immunosuppression may kill the host as a result of secondary infection, so it is not always beneficial to the parasite. Death in bovine trypanosomiasis is commonly due to bacterial pneumonia or sepsis following immunosuppression.


In addition to immunosuppression, protozoa have evolved two other effective evasive techniques. One involves becoming less antigenic, and the other involves the ability to alter surface antigens rapidly and repeatedly. An example of a nonantigenic organism is the bradyzoite stage of T. gondii, which, as mentioned previously, does not appear to stimulate a host response. Some protozoa may mask themselves with host antigens. Examples of these include Trypanosoma theileri in cattle and Trypanosoma lewisi in rats, both nonpathogenic trypanosomes that survive in the bloodstream because they are covered by host serum proteins and are not regarded as foreign. T. brucei, a pathogenic trypanosome of cattle, may also adsorb host serum proteins or soluble red cell antigens, reducing its antigenicity.


Although reduced antigenicity may be considered the ultimate evasive technique, many protozoa, especially the trypanosomes, successfully employ repeated antigenic variation. If cattle are infected with the pathogenic trypanosomes T. vivax, T. congolense, or T. brucei and their parasitemia measured at regular intervals, the numbers of circulating organisms are found to fluctuate greatly. Periods of high parasitemia alternate regularly with periods of low or undetectable parasitemia (Figure 27-4). Serum from infected animals contains antibodies against trypanosomes isolated before bleeding but not against those that develop subsequently. Each period of high parasitemia corresponds to the expansion of a population of trypanosomes with a new surface glycoprotein antigen. The elimination of this population by antibodies leads to a rapid fall in parasitemia. Among the survivors, however, some parasites express new surface glycoproteins and grow without hindrance. As a result, a fresh population arises to produce yet another period of high parasitemia (Figure 27-5). This cyclical fluctuation in parasite levels, with each peak reflecting the appearance of a new population with new surface glycoproteins, can continue for many months.




The major surface antigens of these trypanosomes are known as variant surface glycoproteins (VSGs). These are the antigens targeted by host antibodies. The VSGs produced early in trypanosome infections tend to develop in a predictable sequence. However, as the infection progresses, the production of VSGs becomes more random. The VSGs form a thick coat on the surface of the trypanosome. When antigenic change occurs, the VSGs in the old coat are shed and replaced by an antigenically different VSG. Analysis indicates that these trypanosomes possess about 200 VSG genes, with an additional 1600 silent genes, of which two thirds are pseudogenes. Antigenic variation occurs as a result of repeated DNA breaking and repair, replacing an active VSG gene with one from the silent gene pool. Since only a small part of the tightly packed VSG is exposed to host antibodies, it is not even necessary for the complete molecule to change. Replacement of exposed epitopes by gene conversion is sufficient for effective variation (Chapter 17). Early in infections, complete VSG gene replacement occurs. Later on, partial replacement and point mutations can create new antigenic specificities. In some cases, the expressed VSG gene can be constructed as a mosaic from several archival pseudogenes. The potential for recombination-based variation is therefore absolutely enormous.


Trypanosomiasis is not the only protozoan infection in which variation of surface antigens occurs. It has also been recorded in infections by B. bovis, the plasmodia, and the intestinal parasite Giardia lamblia.


Since parasitic protozoa must evade the immune responses, it is not surprising that they preferentially invade immunosuppressed individuals. Organisms that are normally controlled by the immune response, such as T. gondii or Cryptosporidium bovis, can grow and produce severe disease in immunosuppressed animals. For this reason, acute toxoplasmosis and cryptosporidiosis commonly occur in humans immunosuppressed for transplantation purposes or for cancer therapy and in those infected with human immunodeficiency virus (HIV).



Adverse Consequences


The immune responses against protozoa may cause hypersensitivity reactions that contribute to disease. Type I hypersensitivity is a feature of trichomoniasis and results in local irritation and inflammation in the genital tract. Type II cytotoxic reactions are of significance in babesiosis and trypanosomiasis, in which they contribute to the anemia. In babesiosis, red cells express parasite antigens on their surfaces and are thus recognized as foreign and eliminated by hemolysis and phagocytosis. In trypanosomiasis, either fragments of disrupted organisms or possibly preformed immune complexes bind to red cells and provoke their elimination, causing anemia. Immune complex formation on circulating red cells is not the only problem of this type in trypanosomiasis. In some cases, excessive immune complex formation can lead to vasculitis and glomerulonephritis (type III hypersensitivity; see Chapter 30). Immune complex lesions are a marked feature of visceral leishmaniasis, as described previously.


Trypanosome infections may trigger an enormous increase in IgM-secreting cells so that very high levels of IgM are found in the blood of infected animals. Some of these antibodies are directed against autoantigens. These include rheumatoid factor–like molecules, and antibodies against thymocytes, single-stranded DNA, red cells, and platelets. In T. congolense–infected cattle, these polyclonally stimulated B cells are BoCD5+. As pointed out earlier, CD5+ B1 cells are of a different lineage to conventional B2 cells (Chapter 15). The mechanism of this polyclonal B cell activation is unknown.


It is probable that a type IV hypersensitivity reaction contributes to the inflammation that occurs when Toxoplasma cysts break down and release fresh tachyzoites. Extracts of T. gondii (toxoplasmin), if administered intradermally to infected animals, will cause a delayed hypersensitivity response (Figure 27-6).


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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Immunity to Parasites

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