Introductory Chapter: Leishmania Parasites – Epidemiology and Immunopathogenesis

1. Introduction

Leishmaniases are a group of diseases caused by protozoan parasites from over 20 species belonging to subfamily Leishmaniinae [1, 2]. The parasites are transmitted by over 90 species phlebotomine sandflies from one host to the other by the bite of an infected female [3].

Clinical manifestations of leishmaniasis range from self-healing cutaneous lesions to potentially fatal visceral form. All clinical manifestations depend on the parasite species and the host’s genetic and immunological response [4].

These pathologies affect predominantly the poorest people, mainly in tropical countries, exerting a high impact on mortality and morbidity rates. The risk factors for the development of the disease are associated with malnutrition, socioeconomic conditions, population mobility, environmental changes, and climate changes [3].

Due to the high global incidence and prevalence rates, mainly in developing countries, leishmaniases are among the 10 most neglected diseases (ND) in the world [5]. Worldwide, 99 countries are endemic to Leishmaniasis, where more than 12 million people are infected, and 20,000 to 30,000 deaths occur annually [3, 5]. Cutaneous leishmaniasis (CL) is endemic in 89 countries, visceral leishmaniasis (VL) in 80 countries, and both clinical forms are endemic in 71 countries. In the Americas, Brazil is the main country endemic for both CL and VL. Leishmania-HIV coinfection has intensified the burden of leishmaniasis, which have been reported by 42 countries around the world [3, 5].

These neglected diseases present many challenges, such as a lack of vector control strategies, different parasite strains, parasite resistance, and canine leishmaniasis treatment with low effectiveness, which makes it increasingly difficult to control these diseases.

2. Experimental leishmaniasis

Leishmaniasis affects a wide variety of hosts, whether they are natural reservoirs or “accidental” hosts in the Leishmania life cycle [3, 6].

Proposing an experimental model that can demonstrate what happens in both the wild host and the accidental host is a major challenge. The use of rodents as mice (Mus spp.) and hamster (Cricetinae spp.), as an experimental model, has been proposed as a good alternative to study the Leishmania-host relationship. Other models as dogs and primates are also used for leishmaniasis study, principally to test the efficacy of leishmanial vaccines [7, 8, 9]. In fact, there are a plethora of animal models for leishmaniasis study each of them with their peculiarities, advantages, and disadvantages. Mice with different genetic backgrounds are used for experimental studies involving parasites of the Leishmania genus, mainly susceptibility and resistance studies [4]. Different response profiles to the parasite infection are observed, and it is possible to classify these mice as sensitive, resistant, and intermediate. The hamster model is commonly used to study cutaneous leishmaniasis caused by L. brasiliensis, but it can also be used to isolate species that are difficult to cultivate [8]. The choice of model is related to which individual will provide the best answer to the question the researcher proposed. In leishmaniasis studies, mice and hamster are most commonly used [10]. There is, however, no consensus on the best animal model to be used, but regardless of the model chosen for the study, it is necessary to keep in mind animal welfare, the concept of the 3Rs, and approval of the experimental protocol by the Ethics Committee of Animal Use.

3. Visceral leishmaniasis

Visceral leishmaniasis (VL) is a life-threatening and tropical neglected disease, one of the world’s six priority endemic diseases. In the New World, the protozoan Leishmania infantum infects several mammal species, including humans and dogs, which causes the visceral form. In urban areas, canines play a role in the transmission and maintenance of the parasite, which is evidence of a temporal correlation between the occurrence of human and canine visceral leishmaniasis [11]. In several countries, it is an uncontrolled disease and a severe public health issue. To establish public measures for the prophylaxis of this disease, screening the canine population and infected dogs is one of the primary forms of control of VL.

In human visceral leishmaniasis, the liver function and morphology are modified due to inflammatory reactions in the portal and intralobular region that may be locally concentrated or diffusely localized. Besides the involvement of this organ, the parasite could lead to augmenting the spleen; thus, hepatosplenomegaly is a frequent clinical sign. Other clinical signs described are irregular bouts of fever, weight loss, enlargement of the spleen and liver, and anemia [3].

Unlike humans, which develop only visceral form, in canines, the first clinical signs observed are skin lesions such as periorbital alopecia, exudative dermatitis, hyperkeratosis of the footpad, and onychogryphosis. Other frequent signs are hepatosplenomegaly, enlargement of lymph nodes, weight loss, cachexia, epistaxis, pancytopenia, hypergammaglobulinemia, ocular lesions, and chronic renal failure [12, 13, 14, 15].

4. Treatment, an urgent need for new drugs

Historically, several treatments against leishmaniasis have been used in the past, such as quinine, arsenicals, and turpentine injection. With variable results, none of them had proven effectiveness. In 1912, the doctor Gaspar Viana used the tartar emetic, trivalent antimonial (SbIII), for the first time successfully in the therapy of ATL [16]. Between 1920 and 1930, pentavalent antimonials (SbV) were introduced in the treatment of visceral leishmaniasis, reducing treatment from 3 to 4 months to weeks. In the 1940s, new formulations of pentavalent antimonials appeared, which are less toxic and still used today: meglumine antimoniate, Glucantime®, and sodium stibogluconate, Pentostam® [17].

Despite the few advances in research on antimonials in recent decades, they are still the first-choice therapy against leishmaniasis. The treatment is long, with intramuscular administration, which sometimes requires hospitalization, causing discomfort to the patient, and high costs [18]. The other drugs available for leishmaniasis treatment are mainly amphotericin B and miltefosine.

Amphotericin B is an antifungal produced by culturing the actinomycetes Streptomyces nodosus used to combat systemic infections and is presented as amphotericin deoxycholate and in liposomal form. Liposomal amphotericin B was first used in the treatment of ATL by Sampaio & Mardsen [19]. It is the drug of choice in cases of parasite resistance to antimonials [20].

Miltefosine is an alkylphosphocholine originally developed as an antineoplastic chemotherapy drug. In the 1980s, during its evaluation for this therapeutic purpose, its potent action against leishmaniasis was discovered. In 2002, it was registered in India as the first oral treatment for visceral leishmaniasis [21]. Studies using miltefosine in the treatment of the cutaneous form of the disease resulted in good efficacy against L. (V.) panamensis, but for L. (V.) braziliensis there was no adequate efficacy [22].

Several active compounds have been tested against leishmaniasis, such as ketoconazole [23], itraconazole [24], fluconazole [25], terbinafine [26], and azithromycin [27], all with variable results. Thermal treatments, such as thermotherapy [28] and cryotherapy [29] have also been tested in the treatment of skin lesions; however, the lack of specificity and the need for professionals trained in the technique makes it difficult to advance the treatment. The search for new drugs should not be discontinued, as the disease progresses, and patients continue to wait for effective and low-toxicity medications.

Acknowledgments

This research was funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES (Finance Code 001), by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (26/211.680/2021) and Fundação de Amparo à Pesquisa e Desenvolvimento Científico e Tecnológico do Maranhão (APP-12233/22). HSR (CNPq 150336/2023-3) and FA-S (FAPERJ E-26/203.513/2023) are postdoctoral research fellows. KC (315225/2021-1) and ALA-S (313348/2021-9) are research productivity fellows by Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq.