Immunity To Protozoa.
Relatively few (less than 20) species of protozoa infect humans, but among these are four of the most formidable parasites of all, in terms of numbers affected and severity of disease: malaria, the African and American trypanosomes, and Leishmania (top left). These owe their success to combinations of the strategies found among bacteria and viruses: long-distance spread by insect vectors (compare plague, typhus, yellow fever), intracellular habitat (compare tuberculosis, viruses), antigenic variation (compare influenza) and immunosuppression (compare HIV). However, these strategies are so highly developed that complete acquired resistance to protozoal infections is quite exceptional, and what immunity there is often serves merely to keep parasite numbers down (‘premunition’) and the host alive, to the advantage of the parasite. The rationale for vaccination is correspondingly weak, especially because some of the symptoms of these diseases appear to be brought about by the immune response rather than the parasite itself.
In contrast, the intestinal protozoa (bottom left) generally cause fairly mild disease, except when immunity is deficient or suppressed. Nevertheless, together with the intestinal worm infections described on the next page, they add up to a tremendous health burden on the inhabitants of tropical countries.
African trypanosomes Trypanosoma gambiense and T. rhodesiense, carried by tsetse flies, cause sleeping sickness in West and East Africa, respectively. The blood form, although susceptible to antibody and complement, survives by repeatedly replacing its surface coat of glycoprotein ‘variant antigen’ by a gene-switching mechanism; the number of variants is unknown but large (perhaps as many as 1000). High levels of non-specific IgM, including autoantibodies, coexist with suppressed antibody responses to other antigens such as vaccines; this may be due to polyclonal activation of B cells by a parasite product (compare bacterial lipopolysaccharides). Humans are resistant to the trypanosomes of rodents because of a normal serum factor (high- density lipoprotein [HDL]) that agglutinates them – a striking example of innate immunity.
Malaria Malaria kills more than one million people each year, most of them children, and most of them in the world’s poorest countries. Plasmodium falciparum (the most serious species), P. malariae, P. vivax and P. ovale are transmitted by female Anopheles mosquitoes. There is a brief liver stage, against which some immunity can be induced, probably via cytotoxic T cells, followed by a cyclical invasion of red cells, against which antibody is partially effective; anti- genic variation, polymorphism and polyclonal IgG production may account for the slow development of immunity. Despite over 40 years of research, there is still no 100% effective vaccine (but see below). Vaccination protects against the red cell stage in certain animal models, and also against the sexual gamete state. Recently, a recombinant vaccine consisting of a sporozoite antigen fused to hepatits B surface antigen has shown real promise in African children. Human red cells lacking the Duffy blood group, or containing fetal haemoglobin (sickle cell disease), are ‘naturally’ resistant to P. vivax and P. falciparum, respectively. P. malariae is specially prone to induce immune complex deposition in the kidney. High levels of the cytokine TNF (see Fig.24) are found in severe cases of malaria, and this may represent over-stimulation of macrophages by a parasite product – a form of pathology also seen in Gram-negative bacterial septicaemia (see Fig. 34). Malaria was one of the first diseases to be experimentally treated by the use of anti-TNF antibody, although without success so far; in fact TNF may also have a role in protective immunity.
Babesia spp., or piroplasms, are tick-borne cattle parasites resembling malaria which occasionally infect humans, particularly following removal of the spleen or immunosuppressive therapy. In cattle and dogs an attenuated vaccine has been strikingly successful.
Theileria (East Coast fever), a cattle infection resembling malaria, except that the ‘liver’ stage occurs in lymphocytes, is unusual in being killed by cytotoxic T cells, i.e. it behaves essentially like a virus.
Leishmania A confusing variety of parasites, carried by sandflies, which cause an even more bewildering array of diseases in different parts of the tropics, although only in about 5% of exposed individuals. The organisms inhabit macrophages, and the pathology (mainly in the skin and viscera) seems to depend on the strength of cell-mediated immunity and/or its balance with antibody (compare leprosy). Cutaneous leishmaniasis in Africa is unusual in stimulating self-cure and subsequent resistance. This example of protection has apparently been known and applied in the Middle East for many centuries (‘leishmanization’). There is evidence from mouse experiments that resistance is mediated by TH1 cells and can be compromised by TH2 cells, and also that nitric oxide (see Fig. 9) may be a major killing element.
Trypanosoma cruzi, the cause of Chagas’ disease in Central and South America, is transmitted from animal reservoirs by reduviid bugs. It infects many cells, notably cardiac muscle and autonomic nervous ganglia. There is some suggestion that cell-mediated autoimmunity against normal cardiac muscle may be responsible for the chronic heart failure, and similarly with the nervous system, where uptake of parasite antigens by neurones and actual similarity between host and parasite have both been shown to occur. The organism has been killed in vitro by antibody and eosinophils, but the only prospect for vaccination seems to be against the blood stage. A better prospect would be to get rid of the poor housing in which the vector flourishes.
Toxoplasma spp. T. gondii is particularly virulent in the fetus and immunosuppressed patients, chiefly affecting the brain and eye. It can survive inside macrophages by preventing phagolysosome formation (compare tuberculosis), but cell-mediated immunity can overcome this. Toxoplasma stimulates macrophages and suppresses T cells, leading to varied effects on resistance to other infections.
Entamoeba histolytica normally causes disease in the colon (amoebic dysentery), but can move via the blood to the liver, etc., and cause dangerous abscesses by direct lysis of host cells. Some animals, and perhaps humans, may develop a degree of immunity to these tissue stages but not to the intestinal disease.
Giardia, Balantidium, Cryptosporidium, Isospora spp., etc. normally restrict their effects to the gut, causing dysentery and occa- sionally malabsorption, but can be a severe complication of AIDS (see Fig. 28).