REVIEW published: 31 May 2016 doi: 10.3389/fimmu.2016.00212 Escaping Deleterious Immune Response in Their Hosts: Lessons from Trypanosomatids Anne Geiger1*, Géraldine Bossard1, Denis Sereno1, Joana Pissarra1, Jean-Loup Lemesre1, Philippe Vincendeau2 and Philippe Holzmuller3 1UMR INTERTRYP, IRD-CIRAD, CIRAD TA A-17/G, Montpellier, France, 2UMR 177, IRD-CIRAD Université de Bordeaux Laboratoire de Parasitologie, Bordeaux, France, 3UMRCMAEE CIRAD-INRA TA-A15/G ‘‘Contrôle des maladies animales exotiques et émergentes’’, Montpellier, France The Trypanosomatidae family includes the genera Trypanosoma and Leishmania, proto- zoan parasites displaying complex digenetic life cycles requiring a vertebrate host and an insect vector. Trypanosoma brucei gambiense, Trypanosoma cruzi, and Leishmania spp. are important human pathogens causing human African trypanosomiasis (HAT or sleep- ing sickness), Chagas’ disease, and various clinical forms of Leishmaniasis, respectively. They are transmitted to humans by tsetse flies, triatomine bugs, or sandflies, and affect millions of people worldwide. In humans, extracellular African trypanosomes (T. brucei) Edited by: Alexandre Morrot, evade the hosts’ immune defenses, allowing their transmission to the next host, via the Federal University of Rio de Janeiro, tsetse vector. By contrast, T. cruzi and Leishmania sp. have developed a complex intra- Brazil cellular lifestyle, also preventing several mechanisms to circumvent the host’s immune Reviewed by: Marisa Mariel Fernandez, response. This review seeks to set out the immune evasion strategies developed by the University of Buenos Aires, Argentina different trypanosomatids resulting from parasite–host interactions and will focus on: Julio Aliberti, Cincinnati Children’s Hospital clinical and epidemiological importance of diseases; life cycles: parasites–hosts–vec- Medical Center, USA tors; innate immunity: key steps for trypanosomatids in invading hosts; deregulation *Correspondence: of antigen-presenting cells; disruption of efficient specific immunity; and the immune Anne Geiger responses used for parasite proliferation. [email protected] Keywords: Trypanosomatidae family, parasite–host interactions, immunosuppression, Leishmania sp., Specialty section: Trypanosoma brucei sp., Trypanosoma cruzi This article was submitted to Microbial Immunology, a section of the journal CLINICAL AND EPIDEMIOLOGICAL IMPORTANCE Frontiers in Immunology OF NEGLECTED DISEASES Received: 15 March 2016 Accepted: 17 May 2016 Trypanosomatid parasites interact with a wide range of insects and mammals to complete their life Published: 31 May 2016 cycles. Some species, particularly Trypanosoma brucei gambiense, Trypanosoma brucei rhodesiense, Citation: Trypanosoma cruzi, and Leishmania spp. are pathogenic for humans, causing, respectively, human Geiger A, Bossard G, Sereno D, African trypanosomiasis (HAT or sleeping sickness), Chagas’ disease, and cutaneous, mucocuta- Pissarra J, Lemesre J-L, neaous, and visceral Leishmaniasis (VL). These infectious eukaryotic parasites have been described Vincendeau P and Holzmuller P and identified over a century ago; however, as of today, no vaccines are available and the availability of (2016) Escaping Deleterious Immune Response in Their Hosts: Lessons effective prophylactic and therapeutic drugs remains limited. It is estimated that more than 20mil lion from Trypanosomatids. people are infected and that 100,000 people die each year of trypanosomiasis or Chagas’ disease (1). Front. Immunol. 7:212. Annually, cutaneous leishmaniasis affects around 1 million people, whereas VL is responsible for doi: 10.3389/fimmu.2016.00212 around 500,000 cases annually resulting in over 50,000 deaths (2). Frontiers in Immunology | www.frontiersin.org 1 May 2016 | Volume 7 | Article 212 Geiger et al. Immune Evasion of Trypanosomatids Tsetse flies (Glossina spp.) transmit HAT-causing South American countries affecting about 7–12 million people, trypanosomes. Regarding mortality, it ranks 9th out of 25 and putting at risk 60–80 million others (20, 21). Three hundred human infectious and parasitic diseases in Africa (3) and is thousand new cases are reported to occur each year, and 21,000 estimated to cause the loss of 1.5 million disability-adjusted life patients die annually (22). Once a host has become infected, the years per year (4). It is responsible for major setbacks in social, parasite is internalized in the cells of the innate immune system, agricultural, and economic development in Africa (5) and and the infection develops progressively. Similarly to HAT, two constitutes a severe burden for poor rural populations to whom forms of the Chagas’ disease can be distinguished. The acute form healthcare access is extremely difficult6 ( ) [reviewed in Geiger is marked by (a) the presence of T. cruzi trypomastigotes in the et al. (7)]. The real number of infected people is most probably blood stream, (b) high fever, and (c) a severe hepatomegaly. By underestimated as it results from a mathematical extrapolation contrast, in the case of the chronic form of the disease, there are of data recorded from only partial epidemiological surveys (5, far fewer parasites present in the blood stream, and the other 8). In addition, wars, social conflicts and struggles, the presence symptoms are also less severe. The chronic form can also be of trypanosome-infected domestic animals, and climate change “silent” that is, in the absence of any symptom, the infection may are recognized as factors favoring HAT development and spread remain undiagnosed. Nevertheless, 10–20 years later, 5–10% of (9–11). Thus, although the number estimated cases is fewer than these people will develop anatomical and functional abnormali- 10,000, this disabling and fatal disease is classified among the ties at their esophagus and their colon, while ~30% will develop group of poverty-promoting infectious diseases. myocarditis, leading to heart failure or sudden death (23). Two distinct forms of HAT exist which are (a) caused by Leishmaniasis is estimated to affect 12 million people in 98 two distinct trypanosome subspecies, (b) transmitted by two countries, while ~350 million live in disease-risk areas (24), and distinct tsetse fly vector species, and (c) widespread in two presents an incidence of around 2 million cases per year. Despite distinct geographic areas. The chronic form, caused by T. brucei more than 500,000 new VL cases per year causing the death of gambiense, is transmitted by Glossina palpalis sp., and distributed more than 50,000 patients (24, 25), this disease is classified among in western and central Africa, while the acute form, caused by the neglected tropical diseases. In 2010, WHO estimated the T. brucei rhodesiense is transmitted by Glossina morsitans sp., and disease to cause the loss of around 2.4 million disability-adjusted restricted to East Africa. Despite these differences, the infection life years per year (24) [reviewed in Geiger et al. (7)]. caused by either the chronic or the acute forms of the disease Leishmania spp. are transmitted by sandflies belonging to the evolve similarly in two distinct clinical phases. During the first genera Phlebotomus and Lutzomyia. They induce several forms phase (stage 1 or hemato-lymphatic stage), the trypanosomes are of disease in humans, ranging from localized cutaneous lesions present and multiply in the blood and in the lymph nodes; dur- to VL. VL, the most severe form of Leishmaniasis, is caused ing this phase the patients exhibit intermittent fever, headache, by parasites of the Leishmania donovani complex (Leishmania and joint pain. Stage 2 (meningo-encephalitic stage) begins once donovani, Leishmania infantum, and Leishmania chagasi) [see the trypanosomes have invaded the central nervous system (CNS); it review by Gupta et al. (26)]. Once the mammal host is infected, is characterized by severe neurological disorders (12) [reviewed the parasite differentiates intracellularly inside MFs and dissemi- in Ref. (13)]. The two HAT forms differ in the rapidity of their nates from the skin to the spleen, liver, and bone marrow MFs respective transition from stage 1 to stage 2: several months or (27). Most patients infected with L. donovani and L. infantum even several years for the chronic form, a few months or even develop asymptomatic chronic latent infections. However, ~10% a few weeks for the acute form. In addition, the severity of the of infected people develop fever, severe hepatosplenomegaly, latter is much higher than that of the former. The disease is pancytopenia, cachexia, and a hyper gamma-globulinemia lead- generally fatal when not treated. Today, despite the emergence ing to the death if untreated (28, 29). of some new drug candidates (14, 15) or drug combinations (16), In this review, the authors aimed to summarize the mechanisms the available chemotherapy remains limited and often generates trypanosomatids use to escape their host deleterious immune severe side effects or even the development of resistant trypano- responses. It will focus on the aspects of the parasite–host–vector some strains (5, 17). Also, inefficient T. b. gambiense case detec- life cycle; on the host innate immunity and the key steps allow- tion, chronic infections that are never treated and a long stage ing trypanosomatids to invade their hosts; on the deregulation 1 period are important contributors for stable human to human of antigen-presenting cells (APCs); on the disruption of specific transmission in endemic areas. In contrast, for T.