The clinical manifestation of leishmaniases depends on parasite species, host genetic background, and immune response. Manifestations of human leishmaniases are highly variable, ranging from self-healing skin lesions to fatal visceral disease. The scope of standard model hosts is insufficient to mimic well the wide disease spectrum, which compels the introduction of new model animals for leishmaniasis research. In this article, we study the susceptibility of three Asian rodent species (Cricetulus griseus, Lagurus lagurus, and Phodopus sungorus) to Leishmania major and L. donovani. The external manifestation of the disease, distribution, as well as load of parasites and infectiousness to natural sand fly vectors, were compared with standard models, BALB/c mice and Mesocricetus auratus. No significant differences were found in disease outcomes in animals inoculated with sand fly- or culture-derived parasites. All Asian rodent species were highly susceptible to L. major. Phodopus sungorus showed the non-healing phenotype with the progressive growth of ulcerative lesions and massive parasite loads. Lagurus lagurus and C. griseus represented the healing phenotype, the latter with high infectiousness to vectors, mimicking best the character of natural reservoir hosts. Both, L. lagurus and C. griseus were also highly susceptible to L. donovani, having wider parasite distribution and higher parasite loads and infectiousness than standard model animals.

Department of Cell Biology Faculty of Science Charles University 12844 Prague Czech Republic

Department of Infection Biology Faculty of Infectious and Tropical Diseases London School of Hygiene and Tropical Medicine London WC1E 7HT UK

Department of Parasitology Faculty of Science Charles University 12844 Prague Czech Republic

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Alvar J., Vélez I.D., Bern C., Herrero M., Desjeux P., Cano J., Jannin J., den Boer M. Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE. 2012;7:e35671. doi: 10.1371/journal.pone.0035671. PubMed DOI PMC

Bern C., Maguire J.H., Alvar J. Complexities of assessing the disease burden attributable to leishmaniasis. PLoS Negl. Trop. Dis. 2008;2:e313. doi: 10.1371/journal.pntd.0000313. PubMed DOI PMC

Akhoundi M., Kuhls K., Cannet A., Votýpka J., Marty P., Delaunay P., Sereno D. A historical overview of the classification, evolution, and dispersion of Leishmania parasites and sandflies. PLoS Negl. Trop. Dis. 2016;10:e0004349. doi: 10.1371/journal.pntd.0004349. PubMed DOI PMC

Akilov O.E., Khachemoune A., Hasan T. Clinical manifestations and classification of Old World cutaneous leishmaniasis. Int. J. Dermatol. 2007;46:132–142. doi: 10.1111/j.1365-4632.2007.03154.x. PubMed DOI

Desjeux P. Leishmaniasis: Public health aspects and control. Clin. Dermatol. 1996;14:417–423. doi: 10.1016/0738-081X(96)00057-0. PubMed DOI

Loría-Cervera N.E., Andrade-Narváez J.F. Animal models for the study of leishmaniasis immunology. Rev. Inst. Med. Trop. Sao Paulo. 2014;56:1–11. doi: 10.1590/S0036-46652014000100001. PubMed DOI PMC

Guenet J.-L., Bonhomme F. Wild mice: An ever-increasing contribution to a popular mammalian model. Trends Genet. 2003;19:24–31. doi: 10.1016/S0168-9525(02)00007-0. PubMed DOI

Hommel M., Jaffe C.L., Travi B., Milon G. Experimental models for leishmaniasis and for testing anti-leishmanial vaccines. Ann. Trop. Med. Parasitol. 1995;89:55–73. doi: 10.1080/00034983.1995.11813015. PubMed DOI

Roque A.L.R., Cupolillo E., Marchevsky R.S., Jansen A.M. Thrichomys laurentius (Rodentia; Echimyidae) as a putative reservoir of Leishmania infantum and L. braziliensis: Patterns of experimental infection. PLoS Negl. Trop. Dis. 2010;4:e589. doi: 10.1371/journal.pntd.0000589. PubMed DOI PMC

Sosa-Bibiano E.I., Van Wynsberghe N.R., Canto-Lara S.B., Andrade-Narvaez F.J. Preliminary study towards a novel experimental model to study localized cutaneous leishmaniasis caused by Leishmania (Leishmania) mexicana. Rev. Inst. Med. Trop. Sao Paulo. 2012;54:165–170. doi: 10.1590/S0036-46652012000300009. PubMed DOI

Smyly H.J., Young C.W. The experimental transmission of leishmaniasis to animals. Proc. Soc. Exp. Biol. Med. 1924;21:354–356. doi: 10.3181/00379727-21-181. DOI

Young C.W., Smyly H.J., Brown C. Experimental kala azar in a hamster, Cricetulus griseus M.Edw. Am. J. Hyg. 1926;6:254–275.

Hindle E., Patton W.S. Reports from the Royal Society’s Kala Azar Commission in China. No. 2.—Experiments Bearing on the Susceptibility of the Striped Hamster (Cricetulus griseus) to Leishmania of Chinese Kala Azar. Proc. R. Soc. B Biol. Sci. 1926:374–379.

Meleney H.E. The Histopathology of Kala-Azar in the Hamster, Monkey, and Man. Am. J. Pathol. 1925;1:147–174. PubMed PMC

Lun Z.R., Wu M.-S., Chen Y.-F., Wang J.-Y., Zhou X.-N., Liao L.-F., Chen J.-P., Chow L.M.C., Chang K.P. Visceral leishmaniasis in China: An endemic disease under control. Clin. Microbiol. Rev. 2015;28:987–1004. doi: 10.1128/CMR.00080-14. PubMed DOI PMC

Volf P., Volfova V. Establishment and maintenance of sand fly colonies. J. Vector Ecol. 2011;36:1–9. doi: 10.1111/j.1948-7134.2011.00106.x. PubMed DOI

Sadlova J., Yeo M., Seblova V., Lewis M.D., Mauricio I., Volf P., Miles M. Visualisation of Leishmania donovani fluorescent hybrids during early stage development in the sand fly vector. PLoS ONE. 2011;6:e19851. doi: 10.1371/journal.pone.0019851. PubMed DOI PMC

Sadlova J., Seblova V., Votypka J., Warburg A., Volf P. Xenodiagnosis of Leishmania donovani in BALB/c mice using Phlebotomus orientalis: A new laboratory model. Parasite. Vector. 2015;8:158. doi: 10.1186/s13071-015-0765-x. PubMed DOI PMC

Alcolea P.J., Alonso A., Sánchez-Gorostiaga A., Moreno-Paz M., Gómez M., Ramos I., Parro V., Larraga V. Genome-wide analysis reveals increased levels of transcripts related with infectivity in peanut lectin non-agglutinated promastigotes of Leishmania infantum. Genomics. 2009;93:551–564. doi: 10.1016/j.ygeno.2009.01.007. PubMed DOI

Sadlova J., Price H.P.B., Smith A., Votypka J., Volf P., Smith D.F. The stage-regulated HASPB and SHERP proteins are essential for differentiation of the protozoan parasite Leishmania major in its sand fly vector, Phlebotomus papatasi. Cell. Microbiol. 2010;12:1765–1779. doi: 10.1111/j.1462-5822.2010.01507.x. PubMed DOI PMC

Dostálová A., Volf P. Leishmania development in sand flies: Parasite-vector interactions overview. Parasite. Vector. 2012;5:276. doi: 10.1186/1756-3305-5-276. PubMed DOI PMC

Seblova V., Volfova V., Dvorak V., Pruzinova K., Votypka J., Kassahun A., Gebre-Michael T., Hailu A., Warburg A., Volf P. Phlebotomus orientalis sand flies from two geographically distant Ethiopian localities: Biology, genetic analyses and susceptibility to Leishmania donovani. PLoS Negl. Trop. Dis. 2013;7:e2187. doi: 10.1371/journal.pntd.0002187. PubMed DOI PMC

Jaouadi K., Haouas N., Chaara D., Gorcii M., Chargui N., Augot D., Pratlong F., Dedet J.-P., Ettlijani S., Mezhoud H., et al. First detection of Leishmania killicki (Kinetoplastida, Trypanosomatidae) in Ctenodactylus gundi (Rodentia, Ctenodactylidae), a possible reservoir of human cutaneous leishmaniasis in Tunisia. Parasite Vectors. 2011;4:159. doi: 10.1186/1756-3305-4-159. PubMed DOI PMC

Ghawar W., Bettaieba J., Salema S., Snoussia M.-A., Jaouadia K., Yazidia R., Ben-Salah A. Natural infection of Ctenodactylus gundi by Leishmania major in Tunisia. Acta Trop. 2018;177:89–93. doi: 10.1016/j.actatropica.2017.09.022. PubMed DOI

Davami M.H., Motazedian M.H., Kalantari M., Asgari Q., Mohammadpour I., Sotoodeh-Jahromi A., Solhjoo K., Pourahmad M. Molecular survey on detection of leishmania infection in rodent reservoirs in Jahrom District, Southern Iran. J. Arthropod. Borne. Dis. 2014;8:139–146. PubMed PMC

Parhizkari M., Motazedian M.H., Asqari Q., Mehrabani D. The PCR-based detection of Leishmania major in Mus musculus and other rodents caught in southern Iran: A guide to sample selection. Ann. Trop. Med. Parasitol. 2011;105:319–323. doi: 10.1179/136485911X12987676649827. PubMed DOI PMC

Mohebali M., Kanari M.N., Kanani A., Edrissian H., Anvari S., Nadim A. Cricetulus migratorius (gray hamster), another possible animal reservoir of Kala-Azar in Meshkin-Shahr, Iran. Iran. J. Public Health. 1995;24:27–30.

Mohebali M., Moradi-Asl E., Rassi Y. Geographic distribution and spatial analysis of Leishmania infantum infection in domestic and wild animal reservoir hosts of zoonotic visceral leishmaniasis in Iran: A systematic review. J. Vector Borne Dis. 2018;55:173–183. PubMed

Bradley R.D. Family Cricetidae. In: Wilson D.E., Lacher T.E., Mittermeier R.A., editors. Handbook of the Mammals of the World. Rodents II. Volume 7. Lynx Edicions; Barcelona, Spain: 2017. pp. 181–313.

Ashford R.W. Leishmaniasis reservoirs and their significance in control. Clin. Dermatol. 1996;14:523–532. doi: 10.1016/0738-081X(96)00041-7. PubMed DOI

McCall L.I., Zhang W.W., Matlashewski G. Determinants for the development of visceral leishmaniasis disease. PLoS Pathog. 2013;9:e1003053. doi: 10.1371/journal.ppat.1003053. PubMed DOI PMC

Loeuillet C., Bañuls A., Hide M. Study of Leishmania pathogenesis in mice: Experimental considerations. Parasit. Vector. 2016;9:144. doi: 10.1186/s13071-016-1413-9. PubMed DOI PMC

Aslan H., Dey R., Meneses C., Castrovinci P., Bezerra Jeronimo S.M., Oliva G., Fischer L., Duncan R.C., Nakhasi H.L., Valenzuela J.G., et al. A new model of progressive visceral leishmaniasis in hamsters by natural transmission via bites of vector sand flies. JID. 2013;207:1328–1338. doi: 10.1093/infdis/jis932. PubMed DOI PMC

Rogers M.E., Ilg T., Nikolaev A.V., Ferguson M.A.J., Bates P.A. Transmission of cutaneous leishmaniasis by sand flies is enhanced by regurgitation of fPPG. Nature. 2004;430:463–467. doi: 10.1038/nature02675. PubMed DOI PMC

Wilson H.R., Dieckmann B.S., Childs G.E. Leishmania braziliensis and Leishmania mexicana: Experimental cutaneous infections in golden hamsters. Exp. Parasitol. 1979;47:270–283. doi: 10.1016/0014-4894(79)90079-1. PubMed DOI

Martín-Martín I., Jiménez M., González E., Eguiluz C., Molina R. Natural transmission of Leishmania infantum through experimentally infected Phlebotomus perniciosus highlights the virulence of Leishmania parasites circulating in the human visceral leishmaniasis outbreak in Madrid, Spain. Vet. Res. 2015;46:138. doi: 10.1186/s13567-015-0281-1. PubMed DOI PMC

Lestinova T., Rohousova I., Sima M., de Oliveira C.I., Volf P. Insights into the sand fly saliva: Blood-feeding and immune interactions between sand flies, hosts, and Leishmania. PLoS Negl. Trop. Dis. 2017;11:1–26. doi: 10.1371/journal.pntd.0005600. PubMed DOI PMC

Silverman J.M., Clos J., Horakova E., Wang A.Y., Wiesgigl M., Kelly I., Lynn M.A., McMaster W.R., Foster L.J., Levings M.K., et al. Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells. J. Immunol. 2010;185:5011–5022. doi: 10.4049/jimmunol.1000541. PubMed DOI

Kimblin N., Peters N., Debrabant A., Secundino N., Egen J., Lawyer P., Fay M.P., Kamhawi S., Sacks D. Quantification of the infectious dose of Leishmania major transmitted to the skin by single sand flies. Proc. Natl. Acad. Sci. USA. 2008;105:10125–10130. doi: 10.1073/pnas.0802331105. PubMed DOI PMC

Maia C., Seblova V., Sadlova J., Votypka J., Volf P. Experimental transmission of Leishmania infantum by two major vectors: A comparison between a viscerotropic and a dermotropic strain. PLoS Negl. Trop. Dis. 2011;5:e1181. doi: 10.1371/journal.pntd.0001181. PubMed DOI PMC

Secundino N.F.C., De Freitas V.C., Monteiro C.C., Pires A.-C.A.M., David B.A., Pimenta P.F.P. The transmission of Leishmania infantum chagasi by the bite of the Lutzomyia longipalpis to two different vertebrates. Parasite. Vector. 2012;5:20. doi: 10.1186/1756-3305-5-20. PubMed DOI PMC

Doehl J.S.P., Sadlova J., Aslan H., Pruzinova K., Metangmo S., Votypka J., Kamhawi S., Volf P., Smith D.F. Leishmania HASP and SHERP genes are required for in vivo differentiation, parasite transmission and virulence attenuation in the host. PLoS Pathog. 2017;13:e1006130. doi: 10.1371/journal.ppat.1006130. PubMed DOI PMC

Belkaid Y., Kamhawi S., Modi G., Valenzuela J., Noben-Trauth N., Rowton E., Ribeiro J., Sack D.L. Development of a natural model of cutaneous leishmaniasis: Powerful effects of vector saliva and saliva preexposure on the long-term outcome of Leishmania major infection in the mouse ear dermis. J. Exp.Med. 1998;188:1941–1953. doi: 10.1084/jem.188.10.1941. PubMed DOI PMC

Belkaid Y., Mendez S., Lira R., Kadambi N., Milon G., Sacks D. A natural model of Leishmania major infection reveals a prolonged phase of parasite amplification in the skin before the onset of lesion formation and immunity. J. Immunol. 2000;165:969–977. doi: 10.4049/jimmunol.165.2.969. PubMed DOI

Ong H.B., Clare S., Roberts A.J., Wilson M.E., Wright G.J. Establishment, optimisation and quantitation of a bioluminescent murine infection model of visceral leishmaniasis for systematic vaccine screening. Sci Rep. 2020;10:4689. doi: 10.1038/s41598-020-61662-3. PubMed DOI PMC

Carrión J., Nieto A., Iborra S., Iniesta V., Soto M., Folgueira C., Abanades D.R., Requena J.M., Alonso C. Immunohistological features of visceral leishmaniasis in BALB/c mice. Parasite Immunol. 2006;28:173–183. doi: 10.1111/j.1365-3024.2006.00817.x. PubMed DOI

Conter C.C., Camila Alves Mota C.A., dos Santos B.A., de Souza Braga L., de Souza Terrona M., Navasconia T.R., Bekner Silva Fernandes A.C., Galhardo Demarchi I., Reinhold de Castroa K.R., Alessi Aristides S.M., et al. Experimental Parasitology PCR primers designed for new world Leishmania: A systematic review. Exp. Parasitol. 2019;207:107773. doi: 10.1016/j.exppara.2019.107773. PubMed DOI

Conter C.C., Neitzke-Abreu H.C., Bocchi Pedroso R., Campana Lonardoni K.V., Verzignassi Silveira T.G., Alessi Aristides S.M. Detection of Leishmania (Viannia) DNA in leucocytes from the blood of patients with cutaneous leishmaniasis. Rev. Soc. Bras. Med. Trop. 2015;48:626–628. doi: 10.1590/0037-8682-0052-2015. PubMed DOI

Fagundes A., Schubach A., de Paula C.C., Bogio A., de Fátima Antonio L., Botelho Schiavoni P., de Souza Monteiro V., de Fátima Madeira M., Pereira Quintella L., Valete-Rosalino C.M., et al. Evaluation of polymerase chain reaction in the routine diagnosis for tegumentary leishmaniasis in a referral centre. Mem. Inst. Oswaldo Cruz. 2010;105:109–112. doi: 10.1590/S0074-02762010000100018. PubMed DOI

Sadlova J., Vojtkova B., Hrncirova K., Lestinova T., Spitzova T., Becvar T., Votypka J., Bates P., Volf P. Host competence of African rodents Arvicanthis neumanni, A. niloticus and Mastomys natalensis for Leishmania major. Int. J. Parasitol. Parasites Wildl. 2019;8:118–126. doi: 10.1016/j.ijppaw.2019.01.004. PubMed DOI PMC

Neumann N.F., Gyurek L.L., Gammie L., Finch G.R., Belosevic M. Comparison of animal infectivity and nucleic acid staining for assessment of Cryptosporidium parvum viability in water. Appl. Environ. Microbiol. 2000;66:406–412. doi: 10.1128/AEM.66.1.406-412.2000. PubMed DOI PMC

Staalsoe T., Giha H.A., Dodoo D., Theander T.G., Hviid L. Detection of antibodies to variant antigens on Plasmodium falciparum -infected erythrocytes by flow cytometry. Cytology. 1999;336:329–336. PubMed

Di Giorgio C.D.I., Ridoux O., Delmas F., Azas N., Gasquet M., Diseases T. Flow cytometric detection of Leishmania parasites in human monocyte-derived macrophages: Application to antileishmanial-drug testing. Antimicrob. Agents Chemother. 2000;44:3074–3078. doi: 10.1128/AAC.44.11.3074-3078.2000. PubMed DOI PMC

Barbieri C.L., Giorgio S., Merjan A.J.C., Figueiredo E.N. Glycosphingolipid antigens of Leishmania (Leishmania) amazonensis amastigotes identified by use of a monoclonal antibody. Infect. Immun. 1993;61:2131–2137. doi: 10.1128/IAI.61.5.2131-2137.1993. PubMed DOI PMC

Schmid I., Uittenbogaart C., Jamieson B.D. Live-cell assay for detection of apoptosis by dual-laser flow cytometry using Hoechst 33342 and 7-amino-actinomycin D. Nat. Protoc. 2007;2:187–190. doi: 10.1038/nprot.2006.458. PubMed DOI

Thalhofer C.J., Graff J.W., Love-Homan L., Hickerson S.M., Noah Craft N., Beverley S.M., Wilson M.E. In vivo imaging of transgenic Leishmania parasites in a live host. J. Vis. Exp. 2010;41:3–9. PubMed PMC

Melo G.D., Goyard S., Lecoeur H., Rouault E., Pescher P., Fiette L., Boissonnas A., Minoprio P., Lang T. New insights into experimental visceral leishmaniasis: Real-time in vivo imaging of Leishmania donovani virulence. PLoS Negl. Trop. Dis. 2017;11:1–18. doi: 10.1371/journal.pntd.0005924. PubMed DOI PMC

Melby P.C., Chandrasekar B., Zhao W., Coe J.E. The hamster as a model of human visceral leishmaniasis: Progressive disease and impaired generation of nitric oxide in the face of a prominent Th1-like cytokine response. J. Immunol. 2001;166:1912–1920. doi: 10.4049/jimmunol.166.3.1912. PubMed DOI

Nieto A., Domínguez-Bernal G., Orden J.A., La Fuente R.D., Madrid-Elena N., Carrión J. Mechanisms of resistance and susceptibility to experimental visceral leishmaniosis: BALB/c mouse versus syrian hamster model. Vet. Res. 2011;42:39. doi: 10.1186/1297-9716-42-39. PubMed DOI PMC

Wilson M.E., Innes D.J., de Sousa A., Pearson R.D. Early histopathology of experimental infection with Leishmania donovani in hamsters. J. Parasitol. 1987;73:55–63. doi: 10.2307/3282344. PubMed DOI

das Dores Moreira N., Vitoriano-Souya J., Rooatt B.M., de Abreu Vieira P.M., Coura-Vital W., de Oliveira Cardoso J.M., Rezende M.T., Ker H.G., Giunchetti R.C., Carneiro C.M., et al. Clinical, hematological and biochemical alterations in hamster (Mesocricetus auratus) experimentally infected with Leishmania infantum through different routes of inoculation. Parasit. Vector. 2016;9:181. doi: 10.1186/s13071-016-1464-y. PubMed DOI PMC

Gomes R., Teixeira C., Teixeira M.J., Oliveira F., Menezes M.J., Silva C., de Oliveira C.I., Miranda J.C., Elnaiem D.E., Kamhawi S., et al. Immunity to a salivary protein of a sand fly vector protects against the fatal outcome of visceral leishmaniasis in a hamster model. Proc. Natl. Acad. Sci. USA. 2008;105:7845–7850. doi: 10.1073/pnas.0712153105. PubMed DOI PMC

Sacks D., Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat. Rev. Immunol. 2002;2:845–858. doi: 10.1038/nri933. PubMed DOI

Murray H.W., Masur H., Keithly J.S. Cell-mediated immune response in experimental visceral leishmaniasis. I. Correlation between resistance to Leishmania donovani and lymphokine-generating capacity. J. Immunol. 1982;129:344–350. PubMed

Rocha F.J.S., Schleicher U., Mattner J., Alber G., Bogdan C. Cytokines, signaling pathways, and effector molecules required for the control of Leishmania (Viannia) braziliensis in mice. Infect. Immun. 2007;75:3823–3832. doi: 10.1128/IAI.01335-06. PubMed DOI PMC

De Moura T.R., Novais F.O., Oliveira F., Clarencio J., Noronha A., Barral A., Brodskyn C., de Oliveira C.I. Toward a novel experimental model of infection to study american cutaneous leishmaniasis caused by Leishmania braziliensis. Infect. Immun. 2005;73:5827–5834. doi: 10.1128/IAI.73.9.5827-5834.2005. PubMed DOI PMC

Wilson M.E., Jeronimo S.M.B., Pearson R.D. Immunopathogenesis of infection with the visceralizing Leishmania species. Microb. Pathog. 2005;38:147–160. doi: 10.1016/j.micpath.2004.11.002. PubMed DOI

The Working Group on Research Priorities for Development of Leishmaniasis Vaccines. Nery Costa C.H., Peters N.C., Maruyama S.R., de Brito E.C., Jr., Santos I.K. Vaccines for the leishmaniases: Proposal for a research agenda. PLoS Negl. Trop. Dis. 2011;5:e943. doi: 10.1371/journal.pntd.0000943. PubMed DOI PMC

Steppe lemmings and Chinese hamsters as new potential animal models for the study of the Leishmania subgenus Mundinia (Kinetoplastida: Trypanosomatidae)

Host competence of Algerian Gerbillus amoenus for Leishmania major

Infectiousness of Asymptomatic Meriones shawi, Reservoir Host of Leishmania major