The Immunology of Babesiosis
World Small Animal Veterinary Association World Congress Proceedings, 2014
Andrew Leisewitz, BVSc(Hons), MMedVet(Medicine), PhD, DECVIM-CA
Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, South Africa

There are more than 100 known Babesia species. This is one of the most common infectious diseases of animals worldwide and it has gained increasing interest as its zoonotic potential has become increasingly recognised.1

The immune responses to Babesia infection have not been extensively studied. Most of the work that has been done has focussed on bovine infections. There are a few studies on the human disease and on murine models using human parasites. Almost no work has been done evaluating the immune response in the domestic dog to its Babesia parasites. The similarities between babesiosis and malaria have been recognized for decades and the similarities and differences have been reviewed more recently.2 A huge amount of work has been done evaluating host response to malaria infections.3 Immune responses to intraerythrocytic vector-borne apicomplexan parasites must be assumed to be broadly similar and as such this review will consider what has been shown for this larger group of parasites, and where Babesia-specific data are available it has been discussed in particular.

Innate immune responses are crucial to all subsequent host responses.4 The questions, 'Which cell is first to detect which parasite-associated antigen and in which organ?' are crucial questions in understanding the immunology to any infectious agent. Cells of the innate immune system are these crucial sentinels. The numerous mechanisms that parasitic protozoa of medical importance have developed to evade innate immune responses are testimony to the key role this leg of the immune system plays in defending the host.

It has long been appreciated that the degree of illness in humans is correlated with parasite density and that survival is linked to the ability to control the replication of blood stage parasites early in the disease course. It has similarly been shown in rodent models of varying genetic susceptibility to infection that the ability to control the parasitaemia is correlated with outcome. It is also interesting to note that severe combined immunodeficient mice (mice lacking B- and T-cells, thus having no adaptive immune system) and nude mice (mice lacking T-cells) exhibit ascending and peak parasitaemia levels that are comparable to mice with intact immune systems. This can be taken to mean that initial innate immune responses are crucial to early parasite control. In a mouse model depleted of natural killer cells (NK) or genetically deficient in NK cells (also cells of the innate immune system), a higher initial peak parasitaemia is seen and this is followed by a serious recrudescing infection in the chronic phase. Interestingly, it was also shown that it is not the traditional cytolytic function of NK cells that is essential to protection but rather their early IFNγ production. Probably the most crucial cell of the innate immune response is the most professional of all antigen-presenting cells, the dendritic cell (DC) and the role of these cells in antigen presentation has been studied in murine and human malaria infection. As cells of the innate immune system, they are rich in pathogen recognition receptors (PRR) that detect pathogen-associated molecular patterns (PAMP) and it is most likely the spleen where the initial parasite detection during the blood stage infection occurs. The precise nature of the PAMP in malaria or Babesia is a subject of much debate, but the glycosylphosphatidylinositol anchor on the parasite cell membrane has been a leading candidate.5 Babesia parasites also carry these molecules and as such this may well be a crucial molecule in innate recognition of this genus as well. It is also known that CpG motifs in the babesial DNA act as a PAMP that activates innate immune responses.

Antibody-dependant mechanisms of immunity are unlikely to play any role in the first few bouts of infection. Neither B-cell depletion nor immune serum transfer to immunodeficient mice alter parasite dynamics. Despite this, it is clear (in experimental malaria models anyway) that eventual clearance of an infection is antibody dependant.

The specific role of T-cells has been demonstrated in athymic (nude) mice which show an elevated and persistent B. microti parasitaemia not seen in thymus-intact mice. Mice infected with B. rodhaini and treated with antithymocyte serum experience high parasitaemia and mortality. Lastly, the adoptive transfer of immune thymocytes to immunodeficient mice enables immunodeficient mice to clear their B. microti infection. This immune pathology is particularly dependant on the Th1 type T-cell response. Cytotoxic T-cells play no role at all in parasite clearance. The significance of the fact that parasites were killed within intact erythrocytes was noted 40 years ago. This means that direct cell lysis is not required for the killing of parasites.6 The intraerythrocytic killing of the parasite is T-cell dependant, involving specifically the IFN-γ-producing CD4+ T-cell subset.7 Some have proposed the IFN-γ is directly responsible for parasite killing, but it seems more likely the NO production induced by IFN-γ is the kill molecule. Regulatory populations of T-cells have been studied in malaria infections in humans and murine models and been found to play a significant role in the balance between parasite growth and host tissue damage. They have been shown to inhibit effector T-cell responses during infection, which results in inadequate control of the pathogen and in some cases persistence of a low level infection. Their ability to modulate effector T-cell responses plays an important role in limiting damage to host tissues as a result of the proinflammatory host response to an infection.8

In the real world multiple coinfections and infestations are the rule rather than the exception and the effect of these comorbidities can be complex with their often contrasting effects on the immune system. It was noted decades ago that mice could be protected from malaria and Babesia infections if they were first infected with various bacteria (most notably BCG). The effect of concurrent verminosis on malaria infection have been studied in both mice and the human host with humans appearing to be protected against severe malaria disease phenotypes with certain helminth infestations.9

It is clear that the genetic background of the host plays a very important role in resistance or susceptibility to disease. The fighting dog breeds have been shown to be at greater risk for B. gibsoni compared to B. canis infection. In another survey, it appeared that intact male, neutered male, and neutered female dogs were at increased risk of canine babesiosis compared to intact female dogs. Several dog breeds, notably toy breeds, had a lower risk of babesiosis in a hospital population of dogs in South Africa. Another South African study indicated that fighting dog breeds were more likely to develop a complicated Babesia disease phenotype.

The importance of the spleen in malaria has recently been reviewed.10 An immunohistochemical study in the bovine spleen has shown that what happens during babesial infections is remarkably (although not surprisingly) similar to what has been described for malaria infections. The functions of the spleen during malaria infection include blood filtering and phagocytosis, immune response, and as a source of extramedullary haemopoiesis. The role of the spleen for protection against malaria was initially described based on the effects of splenectomy in experimental animal models and the greatest majority of humans that contract babesiosis are splenectomised.1 Splenectomy or congenital asplenia yields a resistant animal model fully susceptible to malaria. It has further been shown that protection is dependent on normal splenic architecture. Reconstitution of splenectomised mice with whole spleen cell suspensions does not provide protection.

References

1.  Homer MJ, Aguilar-Delfin I, Telford SR 3rd, Krause PJ, Persing DH. Babesiosis. Clinical Microbiology Reviews. 2000;13(3):451–469.

2.  Krause PJ, Daily J, Telford SR, Vannier E, Lantos P, Spielman A. Shared features in the pathobiology of babesiosis and malaria. Trends in Parasitology. 2007;23(12):605–610.

3.  Langhorne J, Quin SJ, Sanni LA. Mouse models of blood-stage malaria infections: immune responses and cytokines involved in protection and pathology. Chemical Immunology. 2002;80:204–228.

4.  Stevenson MM, Riley EM. Innate immunity to malaria. Nature Reviews Immunology. 2004;4(3):169–180.

5.  Schofield L, Grau GE. Immunological processes in malaria pathogenesis. Nature Reviews Immunology. 2005;5(9):722–735.

6.  Clark IA, Richmond JE, Wills EJ, Allison AC. Immunity to intra-erythrocytic protozoa. Lancet. 1975;2(7945):1128–1129.

7.  Igarashi I, Suzuki R, Waki S, Tagawa Y, Seng S, Tum S, et al. Roles of CD4(+) T cells and gamma interferon in protective immunity against Babesia microti infection in mice. Infection and Immunity. 1999;67(8):4143–4148.

8.  Belkaid Y, Tarbell K. Regulatory T cells in the control of host-microorganism interactions (*). Annual Review of Immunology. 2009;27:551–589.

9.  Adegnika AA, Kremsner PG. Epidemiology of malaria and helminth interaction: a review from 2001 to 2011. Current Opinion in HIV and AIDS. 2012;7(3):221–224.

10. Del Portillo HA, Ferrer M, Brugat T, Martin-Jaular L, Langhorne J, Lacerda MV. The role of the spleen in malaria. Cellular Microbiology. 2012;14(3):343–355.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Andrew Leisewitz, BVSc (Hons), MMedVet (Med), PhD, ECVIM-CA
Department of Companion Animal Clinical Studies
Faculty of Veterinary Science
University of Pretoria
Pretoria, South Africa


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