Trypanosoma brucei gambiense, transmitted by the tsetse fly, is the main causative agent of Human African trypanosomosis in West Africa and poses a significant health risk to 70 million people. Disease progression varies depending on host immunity, but usually begins with a haemo-lymphatic phase, followed by parasite invasion of the central nervous system. In the current study, the tropism of T. b. gambiense 1135, causing a low level chronic ‘silent’ infection, was monitored in a murine model using bioluminescence imaging and PCR. A tropism to the reproductive organs, in addition to the central nervous system, after 12–18 months of infection was observed. Bioluminescent analysis of healthy females crossed with infected males showed that 50%, 62.5% and 37.5% of the female mice were subsequently positive for parasites in their ovaries, uteri and brain respectively. Although PCR confirmed the presence of parasites in the uterus of one of these mice, the blood of all mice was negative by PCR and LAMP. Subsequently, bioluminescent imaging of the offspring of infected female mice crossed with healthy males indicated parasites were present in the reproductive organs of both male (80%) and female (60%) offspring. These findings imply that transmission of T. b. gambiense 1135 occurs horizontally, most probably via sexual contact, and vertically in a murine model, which raises the possibility of a similar transmission in humans. This has wide reaching implications. Firstly, the observations made in this study are likely to be valid for wild animals acting as a reservoir for T. b. gambiense. Also, the reproductive organs may act as a refuge for parasites during drug treatment in a similar manner to the central nervous system. This could leave patients at risk of a relapse, ultimately allowing them to act as a reservoir for subsequent transmission by tsetse and possibly, horizontally and vertically.
References
[1]
Brun R, Blum J, Chappuis F, Burri C (2010) Human African trypanosomiasis. Lancet 375: 148–159. doi: 10.1016/S0140-6736(09)60829-1. pmid:19833383
[2]
Simarro PP, Jannin J, Cattand P (2008) Eliminating human African trypanosomiasis: where do we stand and what comes next? PLoS Med 5: e55. doi: 10.1371/journal.pmed.0050055. pmid:18303943
[3]
Franco JR, Simarro PP, Diarra A, Jannin JG (2014) Epidemiology of human African trypanosomiasis. Clin Epidemiol 6: 257–275. doi: 10.2147/CLEP.S39728. pmid:25125985
[4]
Simarro PP, Cecchi G, Franco JR, Paone M, Diarra A, et al. (2012) Estimating and mapping the population at risk of sleeping sickness. PLoS Negl Trop Dis 6: e1859. doi: 10.1371/journal.pntd.0001859. pmid:23145192
[5]
Simarro PP, Franco JR, Cecchi G, Paone M, Diarra A, et al. (2012) Human African trypanosomiasis in non-endemic countries (2000–2010). J Travel Med 19: 44–53. doi: 10.1111/j.1708-8305.2011.00576.x. pmid:22221811
[6]
Sudarshi D, Brown M (2015) Human African trypanosomiasis in non-endemic countries. Clin Med 15: 70–73. doi: 10.7861/clinmedicine.15-1-70
[7]
Jamonneau V, Ilboudo H, Kabore J, Kaba D, Koffi M, et al. (2012) Untreated human infections by Trypanosoma brucei gambiense are not 100% fatal. PLoS Negl Trop Dis 6: e1691. doi: 10.1371/journal.pntd.0001691. pmid:22720107
[8]
Pentreath VW, Kennedy PGE (2004) Pathogenesis of Human African Trypanosomiasis. In: Maudlin I, Holmes PH, Miles MA, editors. The Trypanosomiases. Wallingford: CAB International. pp. 283–299.
[9]
Wengert O, Kopp M, Siebert E, Stenzel W, Hegasy G, et al. (2014) Human African trypanosomiasis with 7-year incubation period: clinical, laboratory and neuroimaging findings. Parasitol Int 63: 557–560. doi: 10.1016/j.parint.2014.02.003. pmid:24613272
[10]
Checchi F, Filipe JA, Barrett MP, Chandramohan D (2008) The natural progression of Gambiense sleeping sickness: what is the evidence? PLoS Negl Trop Dis 2: e303. doi: 10.1371/journal.pntd.0000303. pmid:19104656
[11]
Checchi F, Filipe JA, Haydon DT, Chandramohan D, Chappuis F (2008) Estimates of the duration of the early and late stage of gambiense sleeping sickness. BMC Infect Dis 8: 16. doi: 10.1186/1471-2334-8-16. pmid:18261232
[12]
Wastling SL, Picozzi K, Wamboga C, VONW B, Amongi-Accup C, et al. (2011) Latent Trypanosoma brucei gambiense foci in Uganda: a silent epidemic in children and adults? Parasitology 138: 1480–1487. doi: 10.1017/S0031182011000230. pmid:21554841
[13]
Ilboudo H, Bras-Goncalves R, Camara M, Flori L, Camara O, et al. (2014) Unravelling human trypanotolerance: IL8 is associated with infection control whereas IL10 and TNFalpha are associated with subsequent disease development. PLoS Pathog 10: e1004469. doi: 10.1371/journal.ppat.1004469. pmid:25375156
[14]
Wastling SL, Welburn SC (2011) Diagnosis of human sleeping sickness: sense and sensitivity. Trends Parasitol 27: 394–402. doi: 10.1016/j.pt.2011.04.005. pmid:21659003
[15]
Deborggraeve S, Lejon V, Ekangu RA, Mumba Ngoyi D, Pati Pyana P, et al. (2011) Diagnostic accuracy of PCR in gambiense sleeping sickness diagnosis, staging and post-treatment follow-up: a 2-year longitudinal study. PLoS Negl Trop Dis 5: e972. doi: 10.1371/journal.pntd.0000972. pmid:21364966
[16]
Sternberg JM, Gierlinski M, Bieler S, Ferguson MA, Ndung'u JM (2014) Evaluation of the diagnostic accuracy of prototype rapid tests for human African trypanosomiasis. PLoS Negl Trop Dis 8: e3373. doi: 10.1371/journal.pntd.0003373. pmid:25521120
[17]
Jamonneau V, Camara O, Ilboudo H, Peylhard M, Koffi M, et al. (2015) Accuracy of individual rapid tests for serodiagnosis of gambiense sleeping sickness in West Africa. PLoS Negl Trop Dis 9: e0003480. doi: 10.1371/journal.pntd.0003480. pmid:25642701
[18]
Koffi M, Solano P, Denizot M, Courtin D, Garcia A, et al. (2006) Aparasitemic serological suspects in Trypanosoma brucei gambiense human African trypanosomiasis: a potential human reservoir of parasites? Acta Trop 98: 183–188. pmid:16723098 doi: 10.1016/j.actatropica.2006.04.001
[19]
Meltzer E, Leshem E, Steinlauf S, Michaeli S, Sidi Y, et al. (2012) Human African trypanosomiasis in a traveler: diagnostic pitfalls. Am J Trop Med Hyg 87: 264–266. doi: 10.4269/ajtmh.2012.11-0512. pmid:22855756
[20]
Lejon V, Bentivoglio M, Franco JR (2013) Human African trypanosomiasis. Handb Clin Neurol 114: 169–181. doi: 10.1016/B978-0-444-53490-3.00011-X. pmid:23829907
[21]
Bucheton B, MacLeod A, Jamonneau V (2011) Human host determinants influencing the outcome of Trypanosoma brucei gambiense infections. Parasite Immunol 33: 438–447. doi: 10.1111/j.1365-3024.2011.01287.x. pmid:21385185
[22]
Balyeidhusa AS, Kironde FA, Enyaru JC (2012) Apparent lack of a domestic animal reservoir in Gambiense sleeping sickness in northwest Uganda. Vet Parasitol 187: 157–167. doi: 10.1016/j.vetpar.2011.12.005. pmid:22245071
[23]
Simo G, Asonganyi T, Nkinin SW, Njiokou F, Herder S (2006) High prevalence of Trypanosoma brucei gambiense group 1 in pigs from the Fontem sleeping sickness focus in Cameroon. Vet Parasitol 139: 57–66. pmid:16567049 doi: 10.1016/j.vetpar.2006.02.026
[24]
Njiokou F, Laveissiere C, Simo G, Nkinin S, Grebaut P, et al. (2006) Wild fauna as a probable animal reservoir for Trypanosoma brucei gambiense in Cameroon. Infect Genet Evol 6: 147–153. pmid:16236560 doi: 10.1016/j.meegid.2005.04.003
[25]
Hamill LC, Kaare MT, Welburn SC, Picozzi K (2013) Domestic pigs as potential reservoirs of human and animal trypanosomiasis in Northern Tanzania. Parasit Vectors 6: 322. doi: 10.1186/1756-3305-6-322. pmid:24499540
[26]
Funk S, Nishiura H, Heesterbeek H, Edmunds WJ, Checchi F (2013) Identifying transmission cycles at the human-animal interface: the role of animal reservoirs in maintaining gambiense human african trypanosomiasis. PLoS Comput Biol 9: e1002855. doi: 10.1371/journal.pcbi.1002855. pmid:23341760
[27]
Lindner AK, Priotto G (2010) The unknown risk of vertical transmission in sleeping sickness—a literature review. PLoS Negl Trop Dis 4: e783. doi: 10.1371/journal.pntd.0000783. pmid:21200416
[28]
Rocha G, Martins A, Gama G, Brandao F, Atouguia J (2004) Possible cases of sexual and congenital transmission of sleeping sickness. Lancet 363: 247. doi: 10.1016/s0140-6736(03)15345-7
[29]
Giroud C, Ottones F, Coustou V, Dacheux D, Biteau N, et al. (2009) Murine Models for Trypanosoma brucei gambiense disease progression—from silent to chronic infections and early brain tropism. PLoS Negl Trop Dis 3: e509. doi: 10.1371/journal.pntd.0000509. pmid:19721701
[30]
Masiga DK, Smyth AJ, Hayes P, Bromidge TJ, Gibson WC (1992) Sensitive detection of trypanosomes in tsetse flies by DNA amplification. Int J Parasitol 22: 909–918. pmid:1459784 doi: 10.1016/0020-7519(92)90047-o
[31]
Solano P, Jamonneau V, N'Guessan P, N'Dri L, Dje NN, et al. (2002) Comparison of different DNA preparation protocols for PCR diagnosis of Human African Trypanosomosis in Cote d'Ivoire. Acta Trop 82: 349–356. pmid:12039674 doi: 10.1016/s0001-706x(02)00029-3
[32]
Jamonneau V, Solano P, Garcia A, Lejon V, Dje N, et al. (2003) Stage determination and therapeutic decision in human African trypanosomiasis: value of polymerase chain reaction and immunoglobulin M quantification on the cerebrospinal fluid of sleeping sickness patients in Cote d'Ivoire. Trop Med Int Health 8: 589–594. pmid:12828540 doi: 10.1046/j.1365-3156.2003.01079.x
[33]
Wuyts N, Chokesajjawatee N, Panyim S (1994) A simplified and highly sensitive detection of Trypanosoma evansi by DNA amplification. Southeast Asian J Trop Med Public Health 25: 266–271. pmid:7855639
[34]
Bringaud F, Biteau N, Zuiderwijk E, Berriman M, El-Sayed NM, et al. (2004) The ingi and RIME non-LTR retrotransposons are not randomly distributed in the genome of Trypanosoma brucei. Mol Biol Evol 21: 520–528. pmid:14694076 doi: 10.1093/molbev/msh045
[35]
Njiru ZK, Mikosza AS, Matovu E, Enyaru JC, Ouma JO, et al. (2008) African trypanosomiasis: sensitive and rapid detection of the sub-genus Trypanozoon by loop-mediated isothermal amplification (LAMP) of parasite DNA. Int J Parasitol 38: 589–599. pmid:17991469 doi: 10.1016/j.ijpara.2007.09.006
Ashman PU, Seed JR (1974) The effects of photoperiod and a Trypanosoma brucei gambiense infection on the reproductive organs of male Microtus montanus. J Reprod Fertil 40: 51–60. pmid:4416242 doi: 10.1530/jrf.0.0400051
[39]
Claes F, Vodnala SK, van Reet N, Boucher N, Lunden-Miguel H, et al. (2009) Bioluminescent imaging of Trypanosoma brucei shows preferential testis dissemination which may hamper drug efficacy in sleeping sickness. PLoS Negl Trop Dis 3: e486. doi: 10.1371/journal.pntd.0000486. pmid:19621071
[40]
Rodrigues CM, Olinda RG, Silva TM, Vale RG, da Silva AE, et al. (2013) Follicular degeneration in the ovaries of goats experimentally infected with Trypanosoma vivax from the Brazilian semi-arid region. Vet Parasitol 191: 146–153. doi: 10.1016/j.vetpar.2012.08.001. pmid:22921989
[41]
Martinez-Garcia F, Regadera J, Mayer R, Sanchez S, Nistal M (1996) Protozoan infections in the male genital tract. J Urol 156: 340–349. pmid:8683676 doi: 10.1097/00005392-199608000-00003
[42]
Boersma A, Noireau F, Hublart M, Boutignon F, Lemesre JL, et al. (1989) Gonadotropic axis and Trypanosoma brucei gambiense infection. Ann Soc Belg Med Trop 69: 127–135. pmid:2802809 doi: 10.1016/0035-9203(89)90647-0
[43]
Ehrhardt S, Lippert U, Burchard GD, Sudeck H (2006) Orchitis as an unusual manifestation of human African trypanosomiasis. J Infect 52: e31–33. pmid:15936085 doi: 10.1016/j.jinf.2005.04.018
[44]
Pyana PP, Ngay Lukusa I, Mumba Ngoyi D, Van Reet N, Kaiser M, et al. (2011) Isolation of Trypanosoma brucei gambiense from cured and relapsed sleeping sickness patients and adaptation to laboratory mice. PLoS Negl Trop Dis 5: e1025. doi: 10.1371/journal.pntd.0001025. pmid:21526217
[45]
Brun R, Schumacher R, Schmid C, Kunz C, Burri C (2001) The phenomenon of treatment failures in Human African Trypanosomiasis. Trop Med Int Health 6: 906–914. pmid:11703845 doi: 10.1046/j.1365-3156.2001.00775.x
[46]
Sekhar GN, Watson CP, Fidanboylu M, Sanderson L, Thomas SA (2014) Delivery of antihuman African trypanosomiasis drugs across the blood-brain and blood-CSF barriers. Adv Pharmacol 71: 245–275. doi: 10.1016/bs.apha.2014.06.003. pmid:25307219
Melendez RD, Forlano M, Figueroa W (1993) Perinatal infection with Trypanosoma vivax in a calf in Venezuela. J Parasitol 79: 293–294. pmid:8459344 doi: 10.2307/3283524
[49]
Griffin L (1983) Congenital transmission of Trypanosoma congolense in mice. J Comp Pathol 93: 489–492. pmid:6886090 doi: 10.1016/0021-9975(83)90036-1
[50]
Silva TM, Olinda RG, Rodrigues CM, Camara AC, Lopes FC, et al. (2013) Pathogenesis of reproductive failure induced by Trypanosoma vivax in experimentally infected pregnant ewes. Vet Res 44: 1. doi: 10.1186/1297-9716-44-1. pmid:23289625
[51]
Brun R, Hecker H, Lun ZR (1998) Trypanosoma evansi and T. equiperdum: distribution, biology, treatment and phylogenetic relationship (a review). Vet Parasitol 79: 95–107. pmid:9806490 doi: 10.1016/s0304-4017(98)00146-0
[52]
Kemmerling U, Bosco C, Galanti N (2010) Infection and invasion mechanisms of Trypanosoma cruzi in the congenital transmission of Chagas' disease: a proposal. Biol Res 43: 307–316. pmid:21249302 doi: 10.4067/s0716-97602010000300007
[53]
Sanchez LV, Ramirez JD (2013) Congenital and oral transmission of American trypanosomiasis: an overview of physiopathogenic aspects. Parasitology 140: 147–159. doi: 10.1017/S0031182012001394. pmid:23010131
[54]
Balasegaram M, Chappuis F, Karunakara U, Priotto G, Ruiz JA (2005) Sleeping sickness: a practical manual for the treament and control of human African trypanosomiasis. Paris: Medecins Sans Frontieres.
[55]
Steinmann P, Stone CM, Sutherland CS, Tanner M, Tediosi F (2015) Contemporary and emerging strategies for eliminating human African trypanosomiasis due to Trypanosoma brucei gambiense: review. Trop Med Int Health 20: 707–718. doi: 10.1111/tmi.12483. pmid:25694261
