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Leishmaniasis

Leishmaniasis is a group of parasitic diseases that affect 15 million people, mainly children and young adults, in 88 countries worldwide. It is estimated that 350 million people are at risk of leishmaniasis.

There are almost two dozen types of single-celled parasites, Leishmania, which are responsible for these diseases. They are spread by the bite of an infected sandfly. Infection may lead to slow-to-heal ulcers at the site of the sandfly bite (cutaneous leishmaniasis), damage to the linings of the nose and throat (mucosal leishmaniasis), widespread skin disease (diffuse cutaneous leishmaniasis) or may affect internal organs such as the liver, spleen and bone marrow (visceral leishmaniasis or 'kala azar').  

Diagnosis
Drugs for leishmaniasis
Vaccine Research
Sandfly control
Future
References

Every year there are about 1.5 million new cases of cutaneous leishmaniasis (mainly in Afghanistan, Pakistan, Syria, Saudi Arabia, Algeria, Iran, Brazil, and Peru) and 0.5 million cases of visceral leishmaniasis (mainly in India, Bangladesh, Nepal, Sudan, and Brazil), but there are also many more infections without symptoms ANCHOR.

All forms of leishmaniasis cause considerable suffering and hinder economic growth in developing countries. Leishmaniasis is ranked ninth in the global analysis of infectious diseases. With more than 70,000 deaths per year from visceral leishmaniasis, it is second only to malaria for deaths associated with parasitic infection. Leishmaniasis is widely recognised as one of the major neglected diseases associated with povertyANCHOR.

In many parts of the world, leishmaniasis is a zoonotic disease, ie it can pass between animals and people. In southern Europe, visceral leishmaniasis affects a large proportion of the dog populationANCHOR. Here, human visceral leishmaniasis is largely associated with HIV infection. The spread of HIV in developing countries poses additional future challenges for leishmaniasis controlANCHOR.

Diagnosis

Good diagnostic tests are an essential weapon against infectious disease. In leishmaniasis, new molecular tests have been developed for both canine visceral leishmaniasis and various forms of human leishmaniasisANCHOR ANCHOR. The recent completion of full genome sequencing of three of the main species of Leishmania that infect peopleANCHOR will be invaluable for developing new tests to predict the severity of the infection or the sensitivity of the parasites to drugs.

Drugs for leishmaniasis

Visceral leishmaniasis, if untreated, is invariably fatal. Cutaneous leishmaniasis is not fatal, but drug treatment is important to speed up healing and to limit the formation of disfiguring scarsANCHOR. The most affordable drugs for leishmaniasis, antimonials, were developed over 50 years ago and are toxic. In addition, in India, where much of the world’s visceral leishmaniasis is concentrated, drug resistant parasites mean these drugs are now ineffective. Newer drugs have been identified in the last decade, largely by screening likely compounds for their direct action against the parasite in the test tube and subsequently testing them in mice and hamsters for their ability to cure leishmaniasisANCHOR ANCHOR.

Many of the tested drugs were chosen as they have already been used against other diseases, especially cancer and fungal infections. This means that much of the expense of drug development had already been incurred and research using animals could be minimised. The first new oral drug for leishmaniasis that was identified in this way, Miltefosine, is now licensed for use in India, though cost is a major factor restricting its widespread availability.

A number of public-private ventures and some major funding initiatives in drugs for tropical diseases should improve the number of affordable drugs in future. Examination of Leishmania genome sequences also provides new opportunities to identify novel weaknesses in the parasite that could be targeted by drugs.

Other types of drugs are also being developed that target the immune system rather than the parasite itself. These 'immune modulators' enhance natural immunity and lead to more rapid cures. One such drug, which targets a primitive recognition system in phagocytic cells (involved in initial immune system response and wound healing) is Imiquimod, a cream used in the treatment of skin cancer. Proven to have benefit in mouse models, this is now being tested in patients and initial studies show some promise, particularly in combination with other drugsANCHOR.

Vaccine research

A greater understanding of the origin and development of the various forms of leishmaniasis, gained from studies in animals and patients, should uncover further targets for immunotherapy. At present, no commercially available vaccines exist for use in people against any form of leishmaniasis. A vaccine for use in dogs has been produced in BrazilANCHOR, and there is good reason to believe that the development of human vaccines will be possible.

Most importantly it has been known for centuries that once an individual is cured of leishmaniasis, further infections do not usually lead to disease. This knowledge underpinned the old tradition in the Middle East of vaccinating with live parasites in a site where scar formation was less disfiguring. This procedure is now rarely used for ethical reasonsANCHOR. However, experimental vaccines have still not been able to reach the levels of this natural protection.

Recent studies in mice have provided a clearer picture of the major immune responses needed to generate effective immunity to Leishmania, including protection against visceral leishmaniasis. This new information is being channeled into the development of a new generation of vaccines. Whilst a prophylactic vaccine (ie one which prevents infection) is most desirable, there is also considerable interest in generating vaccines that can be used therapeutically. These harness the power of the immune system to work in combination with, or in place of, drugs for the treatment of active disease. This approach has been shown to be effective in miceANCHOR ANCHOR.

Various substances present in the sandfly are also introduced into the human during a bite, and these boost infection. Some of these substances are made by the sandfly itself to aid its feeding, others are of parasite origin. There is evidence that vaccination against some of these products can also protect against leishmaniasisANCHOR.

Our new knowledge of parasite genomesANCHOR also provides immense opportunities for identifying potential targets for vaccination, such as the parasites' antigens (molecules that stimulate an immune response) and virulence factors (molecules that enhance its ability to cause disease). Genetic manipulation of parasites, so that they fail to express certain virulence factors, may also allow the development of weakened live vaccines. These will require extensive safety testing using animals before use in people.

Sandfly Control

Sandfly control by the use of pyrethroids can be effective but spraying programmes are difficult to sustain. Bednets have shown some impact in reducing human infections, but the small size of the sandfly either requires nets with an unacceptably small mesh or insecticide impregnation.

There have been promising studies using insecticide impregnated dog collars; this reduces the number of sandfly bites and leads to a reduction in the incidence of disease in dogs. As well as the clear veterinary impact, this has a beneficial knock-on effect for human infections. These studies showed that reducing disease in dogs indirectly reduces disease in people as sandflies often pick up parasites from feeding on infected dogsANCHOR.

Future

The World Health Organization classifies leishmaniasis as a category 1 disease ("emerging and uncontrolled") and there is an urgent need to develop new ways to prevent, treat and cure the diseaseANCHOR.

Sustainable delivery of such new drugs and vaccines in a difficult economic climate will also pose immense challenges for the future.


References

  1. World Health Organization (accessed 16 July 2007) Leishmeniasis. http://www.who.int/tdr/diseases/leish/default.htm
  2. Alvar J, Yactayo S and Bern C (2006) Leishmaniasis and poverty. Trends Parasitol 22, 552
  3. Alvar J, Canavate C, Molina R, et al (2004) Canine leishmaniasis. Adv Parasitol 57, 1
  4. Cruz I, Nieto J, Moreno J et al (2006) Leishmania/HIV co-infections in the second decade. Indian J Med Res 123, 357
  5. Disch J, Caligiorne RB, Maciel F et al (2006) Single-step duplex kDNA-PCR for detection of Leishmania donovani complex in human peripheral blood samples. Diagn Microbiol Infect Dis 56, 395
  6. Francino O, Altet L, Sanchez-Robert E et al (2006) Advantages of real-time PCR assay for diagnosis and monitoring of canine leishmaniosis. Vet Parasitol 137, 214
  7. Peacock CS, Seeger K, Harris D et al (2007) Comparative genomic analysis of three Leishmania species that cause diverse human disease. Nat Genet 39, 839
  8. Murray HW, Berman JD, Davies CR and Saravia NG (2005) Advances in leishmaniasis. Lancet 366, 1561
  9. Mishra J, Saxena A and Singh S (2007) Chemotherapy of leishmaniasis: past, present and future. Curr Med Chem 14, 1153
  10. Sundar S and Chatterjee M (2006) Visceral leishmaniasis - current therapeutic modalities. Indian J Med Res 123, 345
  11. Modabber F, Buffet PA, Torreele E et al (2007) Consultative meeting to develop a strategy for treatment of cutaneous leishmaniasis. Institute Pasteur, Paris. Kinetoplastid Biol Dis 6, 3
  12. Dantas-Torres F (2006) Leishmune vaccine: the newest tool for prevention and control of canine visceral leishmaniosis and its potential as a transmission-blocking vaccine. Vet Parasitol 141, 1
  13. World Health Organization (accessed 16 July 2007) Leishmeniasis. http://www.who.int/tdr/diseases/leish/default.htm
  14. Basu R, Bhaumik S, Basu JM et al (2005) Kinetoplastid membrane protein-11 DNA vaccination induces complete protection against both pentavalent antimonial-sensitive and -resistant strains of Leishmania donovani that correlates with inducible nitric oxide synthase activity and IL-4 generation: evidence for mixed Th1- and Th2-like responses in visceral leishmaniasis. J Immunol 174, 7160
  15. Mukhopadhyay S, Sen P, Bhattacharyya S et al (1999) Immunoprophylaxis and immunotherapy against experimental visceral leishmaniasis. Vaccine 17, 291
  16. Anderson JM, Oliveira F, Kamhawi S et al (2006) Comparative salivary gland transcriptomics of sandfly vectors of visceral leishmaniasis. BMC Genomics 7, 52 
  17. Peacock CS, Seeger K, Harris D et al (2007) Comparative genomic analysis of three Leishmania species that cause diverse human disease. Nat Genet 39, 839
  18. Gavgani AS, Hodjati MH, Mohite H and Davies CR (2002) Effect of insecticide-impregnated dog collars on incidence of zoonotic visceral leishmaniasis in Iranian children: a matched-cluster randomised trial. Lancet 360, 374
  19. World Health Organization (accessed 16 July 2007) Leishmeniasis. http://www.who.int/tdr/diseases/leish/default.htm

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