Concomitant infections are common in nature and often involve parasites. A number of examples of the interactions between protozoa and viruses, protozoa and bacteria, protozoa and other protozoa, protozoa and helminths, helminths and viruses, helminths and bacteria, and helminths and other helminths are described. In mixed infections the burden of one or both the infectious agents may be increased, one or both may be suppressed or one may be increased and the other suppressed. It is now possible to explain many of these interactions in terms of the effects parasites have on the immune system, particularly parasite-induced immunodepression, and the effects of cytokines controlling polarization to the Th1 or Th2 arms of the immune response. In addition, parasites may be affected, directly or indirectly, by cytokines and other immune effector molecules and parasites may themselves produce factors that affect the cells of the immune system. Parasites are, therefore, affected when they themselves, or other organisms, interact with the immune response and, in particular, the cytokine network. The importance of such interactions is discussed in relation to clinical disease and the development and use of vaccines.

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Concomitant infections, parasites and immune responses.

Publisher Summary The exploitation of genetic resistance to disease is an important consideration in livestock development programs, where conventional disease control measures are not effective or are too costly. Such an approach may be directly applicable to African animal trypanosomiasis. In African trypanosomiasis, the control measures currently in use include diagnosis and treatment, chemoprophylaxis, and control or eradication of tsetse with insecticides. At present, there is no effective field vaccine available against African trypanosomiasis. The major constraints to the development of a vaccine include the existence of the different species of trypanosomes and of different serodemes within the same species, all with the capability of producing different repertoires of variable antigen types (VATS). This chapter discusses the available information on the aspects of trypanotolerance, with regard to cattle, sheep, goats, wildlife, and man. It describes experimental results derived from mouse models and the relevance of these models to trypanosomiasis of livestock. The genetic resistance to trypanosomiasis is not necessarily associated with low productivity. Trypanotolerance is not a stable characteristic, and evidence suggests that it can be supplemented or reduced by a number of factors affecting the host and its environment, which include age and sex; maternally-derived immunity, intensity of challenge, virulence, previous exposure, stress, and susceptibility to other diseases. Investigations of trypanotolerance also represent an exciting approach to the important interactions between host and parasite. Trypanotolerance exists as an innate characteristic and that it is probably inherited as a dominant trait. While the level of trypanotolerance can be reduced under certain circumstances, it can also be enhanced, for example, by previous exposure. Therefore, there is hope that it may be possible in the future to supplement the level of trypanotolerance both by genetic selection and by immunological or therapeutic procedures.

Host Susceptibility to African Trypanosomiasis: Trypanotolerance

Trypanosomosis, or sleeping sickness, is a major disease constraint on livestock productivity in sub-Saharan Africa. To identify quantitative trait loci (QTL) controlling resistance to trypanosomosis in cattle, an experimental cross was made between trypanotolerant African N'Dama (Bos taurus) and trypanosusceptible improved Kenya Boran (Bos indicus) cattle. Sixteen phenotypic traits were defined describing anemia, body weight, and parasitemia. One hundred seventy-seven F2 animals and their parents and grandparents were genotyped at 477 molecular marker loci covering all 29 cattle autosomes. Total genome coverage was 82%. Putative QTL were mapped to 18 autosomes at a genomewise false discovery rate of <0.20. The results are consistent with a single QTL on 17 chromosomes and two QTL on BTA16. Individual QTL effects ranged from ≈6% to 20% of the phenotypic variance of the trait. Excluding chromosomes with ambiguous or nontrypanotolerance effects, the allele for resistance to trypanosomosis originated from the N'Dama parent at nine QTL and from the Kenya Boran at five QTL, and at four QTL there is evidence of an overdominant mode of inheritance. These results suggest that selection for trypanotolerance within an F2 cross between N'Dama and Boran cattle could produce a synthetic breed with higher trypanotolerance levels than currently exist in the parental breeds.

https://www.pnas.org/content/pnas/100/13/7443.full.pdf

Mapping of quantitative trait loci controlling trypanotolerance in a cross of tolerant West African N’Dama and susceptible East African Boran cattle

THERE is currently much interest in the devices evolved by parasites which enable them to evade the immune responses mounted by their hosts1. One such device is the phenomenon of antigenic variation associated with the salivarian trypano-some infections of man and animals in Africa2,3. Typically these infections show successive waves of blood parasitaemia. Each succeeding trypanosome population is characterised by a novel variant-specific glycoprotein antigen present in the parasite surface coat and not reactive with antibodies induced against preceding variants4,5. Antigenic variation has a clear role in the evasion of host immunity and leads to chronic and usually fatal infections. More recently we have become aware of a possible additional component of the evasion mechanism, generalised immunodepression.

Immunodepression, high IgM levels and evasion of the immune response in murine trypanosomiasis.

Nitric oxide (NO) is an important effector molecule of the immune system in eliminating numerous pathogens. Peritoneal macrophages from Trypanosoma brucei brucei-infected mice express type II NO synthase (NOS-II), produce NO, and kill parasites in the presence of L-arginine in vitro. Nevertheless, parasites proliferate in the vicinity of these macrophages in vivo. The present study shows that L-arginine availability modulates NO production. Trypanosomes use L-arginine for polyamine synthesis, required for DNA and trypanothione synthesis. Moreover, arginase activity is up-regulated in macrophages from infected mice from the first days of infection. Arginase competes with NOS-II for their common substrate, L-arginine. In vitro, arginase inhibitors decreased urea production, increased macrophage nitrite production, and restored trypanosome killing. In vivo, a dramatic decrease in L-arginine concentration was observed in plasma from infected mice. In situ restoration of NO production and trypanosome killing were observed when excess L-arginine, but not D-arginine or L-arginine plus N(omega)-nitro-L-arginine (a NOS inhibitor), was injected into the peritoneum of infected mice. These data indicate the role of L-arginine depletion, induced by arginase and parasites, in modulating the L-arginine-NO pathway under pathophysiological conditions.

l-Arginine Availability Modulates Local Nitric Oxide Production and Parasite Killing in Experimental Trypanosomiasis

In an investigation of the immunosuppression associated with trypanosomiasis, the thymus-derived lymphocytes (T cells) and the thymus-independent lymphocytes (B cells) in mice with subacute Trypanosoma brucei infections were studied. It was shown that: (a) there was a massive plasma cell response in lymph nodes and spleen which replaced the thymus-dependent areas; (b) a failure of antibody production at the cellular level occurred as shown by the absence of IgM PFC responses to SRBC and lipopolysaccharide; (c) T cells appeared relatively normal as judged by their ability to proliferate following a primary stimulus with oxazolone unless measured during the terminal stages of the disease; (d) immune competence was rapidly restored after treatment with a trypanocidal drug.

It appeared that immunosuppression was closely associated with the presence of living trypanosomes, possibly mediated through a B-cell defect. The mechanism whereby this might occur is discussed.

The nature of immunosuppression in Trypanosoma brucei infections in mice. II. The role of the T and B lymphocytes.

In rats in which N. brasiliensis infection was superimposed on a previously existing T. brucei infection of 3 weeks' duration, the normal process of immune expulsion of adult worms did not occur, the production of circulating protective antibody (IgG) and of reaginic antibody (IgE) was grossly impaired and there was no increase in the numbers of mast cells in the intestinal villi. In contrast to this failure of humoral and immediate-type responses, cell-mediated immunity, as measured by oxazolone sensitization of mice with a T. brucei infection, still occurred to a significant extent although not so markedly as in uninfected mice. These results, which provide further evidence that infection with T. brucei may induce a significant degree of immunosuppression of the host, are discussed with particular regard to the aetiology of the phenomenon.

Immunosuppression in Trypanosoma brucei infections in rats and mice

The functional integrity of the mononuclear phagocytic system (MPS) in mice infected with Trypanosoma brucei was investigated with regard to its possible significance in the aetiology of the immunosuppression characteristic of this disease.

In infected mice the spleens and lymph nodes were grossly enlarged, and on histological examination it was shown that the MPS of the liver, lymph nodes, spleen and bone marrow was markedly expanded. Macrophages presented an active appearance and often contained cellular debris. Clearance of intravenously injected sheep red blood cells (SRBC) was increased, in that 1 hour after injection, 2–6 times more 51Cr-labelled SRBC had disappeared from the circulation of infected, compared to uninfected mice; this was due largely to an increased uptake by the expanded phagocytic system of the liver.

The intrinsic immunogenic potential of individual macrophages appeared to be unimpaired as judged by the ability of SRBC-containing macrophages from infected mice to elicit a response in syngeneic normal recipient mice.

It was concluded that the only evidence that immunosuppression might be associated with an altered activity of the MPS was an increased hepatic uptake of particulate antigen with a relative failure of splenic uptake. Together these might be responsible for a reduction in the concentration of antigen in the tissues of an enlarged spleen below the level necessary to initiate the formation of antibody.

The nature of immunosuppression in Trypanosoma brucei infections in mice. I. The role of the macrophage.

The pathogenesis and immunology of African trypanosomiasis in domestic animals

Mice infected with T. brucei GVR 23/1 or T. brucei GVR 35/1 for 21 days were treated with the Erlangen diamidine 98/202 (6-amidino-2-[4′ amidino-phenyl] thionaphthene-dilactate) at either 5 mg/kg or 35 mg/ kg. At both these dose levels the parasites were initially cleared from the circulation although the infections eventually relapsed due to reinvasion from the central nervous system. If the 98/202 therapy is followed by treatment with 5-nitroimidazole only a small number of mice are permanently cured. Adverse reactions, especially at the 35 mg/kg dose level, were noted in one experiment. The Erlangen diamidine given to infected mice three days after infection was able to permanently cure both Trypanosoma brucei stabilates.

G.M. Urquhart

Papers

The nature of immunosuppression in Trypanosoma brucei infections in mice. II. The role of the T and B lymphocytes.

Immunosuppression in Trypanosoma brucei infections in rats and mice

The nature of immunosuppression in Trypanosoma brucei infections in mice. I. The role of the macrophage.

The pathogenesis and immunology of African trypanosomiasis in domestic animals

The use of Erlangen diamidine 98/202 in relapsing Trypanosoma brucei infections in mice