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American trypanosomiasis and Chagas disease: Sexual transmission

Open AccessPublished:January 18, 2019DOI:https://doi.org/10.1016/j.ijid.2019.01.021

      Highlights

      • Trypanosoma cruzi infection can be transmitted sexually from males and females to naïve mates.
      • T. cruzi parasites were detected in semen ejaculates from individuals with Chagas disease by nucleic acid techniques.
      • Semen aliquots from humans with Chagas disease instilled into the vagina of naïve female mice resulted in T. cruzi infections.
      • Breeding T. cruzi-infected male and female mice vertically transmitted the infection to progeny mice.

      Abstract

      Objective

      To contribute to the discussion on the research findings indicating the sexual transmission of American trypanosomiasis and Chagas disease in humans.

      Methods

      A review of the literature was performed to investigate the routes of transmission of Trypanosoma cruzi parasites and to evaluate the distribution of Chagas disease, which is now found across five continents.

      Results

      The epidemiological profile of American trypanosomiasis, which is still considered a neglected disease of the poor people of Latin America, has changed over time. A family-based study demonstrated that the blood protozoan T. cruzi can be transmitted sexually from infected males and females to naïve mates.

      Conclusions

      Evidence that Chagas disease can be transmitted sexually, coupled with the migration of individuals with Chagas disease to previously non-endemic countries and increased travel to endemic countries, has implications for public health. Improved screening of blood supplies and prenatal care are required to prevent congenital spread.

      Graphical abstract

      Keywords

      American trypanosomiasis, also known as Chagas disease, is endemic to people in rural areas of South America, where the Trypanosoma cruzi parasites are sympatric to the hematophagous triatomine insect vectors (
      • Prata A.
      Clinical and epidemiological aspects of Chagas disease.
      ,
      • Coura J.R.
      • Viñas P.A.
      Chagas disease: a new worldwide challenge.
      ,
      • Teixeira A.R.L.
      • Gomes C.
      • Rosa A.C.
      • Araujo P.F.
      • Anunciação C.E.
      • Silveira-Lacerda E.
      • et al.
      Prevention and control of Chagas disease—an overview.
      ). The migration of T. cruzi-infected people to the Northern Hemisphere and of travelers to endemic countries have likely made American trypanosomiasis a global challenge, since these infections can be transmitted from mother to offspring (
      • Murcia L.
      • Carrilero B.
      • Munoz-Davila M.
      • Thomas M.
      • López M.
      • et al.
      Risk factors and primary prevention of congenital Chagas disease in a nonendemic country.
      ), by blood transfusion and donated organs, and by contamination of hospital and laboratory workers (
      • Teixeira A.
      • Hecht M.
      • Guimaro M.
      • Sousa A.
      • Nitz N.
      Pathogenesis of Chagas’ disease: parasite persistence and autoimmunity.
      ). Chagas disease is a social and economic burden, and specialized clinical centers in various countries have employed skilled personnel for the provision of health care to patients and their families (
      • Repetto E.
      • Zachariah R.
      • Kumar A.
      • Angheben A.
      • Gobbi F.
      • et al.
      Neglect of a neglected disease in Italy: the challenge of access-to-care for Chagas disease in Bergamo area.
      ,
      • Grigorenko E.
      • Fisher C.
      • Patel S.
      • Chancey C.
      • Rios M.
      • et al.
      Multiplex screening for bloodborne viral, bacterial, and protozoan parasites using an OpenArray platform.
      ,
      • El Ghouzzi M.
      • Boiret E.
      • Wind F.
      • Brochard C.
      • Fittere S.
      • et al.
      Testing blood donors for Chagas disease in the Paris area, France: first results after 18 months of screening.
      ). The expertise stemming from these national centers is deemed important, because the problems associated with the emergence of Chagas disease can no longer be underestimated (
      • Hotez P.
      • Dumonteil E.
      • Woc-Colburn L.
      • Serpa J.
      • Bezek S.
      • et al.
      Chagas disease: “the new HIV/AIDS of the Americas”.
      ;
      • Teixeira A.
      • Hecht M.
      • Guimaro M.
      • Sousa A.
      • Nitz N.
      Pathogenesis of Chagas’ disease: parasite persistence and autoimmunity.
      ,
      • Teixeira A.
      • Vinaud M.
      • Castro A.
      Chagas disease: a global health problem.
      ;
      • Schmunis G.
      • Yadon Z.
      Chagas disease: a Latin American health problem becoming a world health problem.
      ).
      Acute T. cruzi infections are usually asymptomatic and unrecognized, although approximately 5% of infected children may show fever, headache, drowsiness, tachycardia, edema, and shortness of breath (
      • Pérez-Molina J.
      • Molina I.
      Chagas disease.
      ,
      • Teixeira A.
      • Hecht M.
      • Guimaro M.
      • Sousa A.
      • Nitz N.
      Pathogenesis of Chagas’ disease: parasite persistence and autoimmunity.
      ,
      • Teixeira A.
      • Nascimento R.
      • Sturm N.
      Evolution and pathology in Chagas disease.
      ). Morbidity and mortality in the acute phase of the infection are low, since an average of four deaths due to the acute disease have been recorded each year over the past three decades (
      • Andrade D.
      • Gollob K.
      • Dutra W.
      Acute Chagas disease: new global challenges for an old neglected disease.
      ). The chronic intermediate phase of lifelong T. cruzi infection ensues in the absence of clinical manifestations. However, approximately 30% of chronically infected people develop Chagas disease. Chronic Chagas disease kills people due to megaviscera and heart failure (
      • Coura J.R.
      • Viñas P.A.
      Chagas disease: a new worldwide challenge.
      ,
      • Prata A.
      Clinical and epidemiological aspects of Chagas disease.
      ); polyneuropathy and neuroendocrine syndromes are more rarely seen (
      • Pérez-Molina J.
      • Molina I.
      Chagas disease.
      ,
      • Teixeira A.
      • Hecht M.
      • Guimaro M.
      • Sousa A.
      • Nitz N.
      Pathogenesis of Chagas’ disease: parasite persistence and autoimmunity.
      ).
      Several studies have shown the course of T. cruzi infections and the pathological consequences upon inoculation of a few parasites into dogs (
      • Marsden P.D.
      • Hagstrom J.W.C.
      Experimental Trypanosoma cruzi infection in beagle puppies. The effect of variations in the dose and source of infecting trypanosomes and the route of inoculation on the course of the infection.
      ,
      • Lana M.
      • Tafuri W.L.
      • Caliari M.V.
      • Bambirra E.A.
      • Chiari C.
      • Rios V.H.
      Fase crônica cardíaca fibrosante da tripanossomíase cruzi experimental no cão.
      ), primates (
      • Falasca C.A.
      • Gili M.
      • Grana D.
      • Gomez E.
      • Zoppi J.
      • Mareso E.
      Chronic myocardial damage in experimental T. cruzi infection of a new world primate, Cebus sp. monkey.
      ), and rabbits (
      • Lauria-Pires L.
      Effects of superinfections in the experimental Chagas’ disease with genetically characterized Trypanosoma cruzi stocks and clones.
      ). In addition, a family-based study was performed to identify chronically infected individuals with low parasite loads (
      • Araujo P.
      • Almeida A.
      • Pimentel C.
      • Silva A.
      • Sousa A.
      • et al.
      Sexual transmission of American trypanosomiasis in humans: a new potential pandemic route for Chagas parasites.
      ). Nuclear DNA PCR (nDNA-PCR), Southern hybridization, cloning, and sequencing of a specific 188-nucleotide (nt) telomere repeat was used to validate the diagnosis of all T. cruzi infections. The use of these techniques assures high sensitivity and specificity for the diagnosis of Chagas parasites (
      • Almeida A.B.
      • Araújo P.F.
      • Bernal F.M.
      • Rosa A.C.
      • Valente S.A.
      • Teixeira A.R.L.
      Sexual transmission of American trypanosomes from males and females to naive mates.
      ). The in-house nDNA-PCR technology was able to detect as few as 1/10 of the total (270 fg) DNA of a single diploid T. cruzi only (
      • Araujo P.F.
      A genetic, immunological, and parasitological study of the Trypanosoma cruzi infections in families from Para Estate, Brazil. Ph.D. Thesis.
      ,
      • Hecht M.
      • Nitz N.
      • Araujo P.
      • Sousa A.
      • Cássia A.
      • et al.
      Inheritance of DNA transferred from American trypanosomes to human hosts.
      ,
      • Castro E.
      Chagas disease: lessons from routine donation testing.
      ). In the family-based study, the diagnosis of sexually transmitted Chagas disease was confirmed by nDNA-PCR detecting the T. cruzi 188-nt telomere sequence in blood samples obtained on three different occasions 1 year apart (
      • Araujo P.
      • Almeida A.
      • Pimentel C.
      • Silva A.
      • Sousa A.
      • et al.
      Sexual transmission of American trypanosomiasis in humans: a new potential pandemic route for Chagas parasites.
      ).
      In a research protocol approved by the Faculty of Medicine Ethics Committee for Human and Laboratory Animal Research, semen samples were obtained from nDNA-PCR-positive male volunteers with the 188-nt telomere sequence present in their ejaculate. The instillation of aliquots of this semen from Chagas-positive donors into the vaginas of female mice and into the peritoneal cavity of male mice resulted in T. cruzi infections. Pathological examinations revealed parasite amastigote nests in the heart, skeletal muscle, vas deferens, and uterine tube (Figure 1).
      Figure 1
      Figure 1The infectivity of Chagas patient ejaculate shown upon instillation of nDNA-PCR-positive semen aliquots into the vagina of naïve female mice and peritoneal cavity of naïve male mice. Notice the clumps of Trypanosoma cruzi amastigotes (arrows) in the heart (top left), skeletal muscle (top right), lumen of the vas deferens (bottom left), and in the epithelial cells of the uterine tube (bottom right). The circle shows a dividing amastigote. Bars, 10 μm. Reprinted with permission from the author and the publisher (
      • Araujo P.
      • Almeida A.
      • Pimentel C.
      • Silva A.
      • Sousa A.
      • et al.
      Sexual transmission of American trypanosomiasis in humans: a new potential pandemic route for Chagas parasites.
      ).
      A word of caution is required, because ELISA and indirect immunofluorescence (IIF) assays fail to detect T. cruzi antibodies in a majority of chagasic subjects (
      • Almeida A.B.
      • Araújo P.F.
      • Bernal F.M.
      • Rosa A.C.
      • Valente S.A.
      • Teixeira A.R.L.
      Sexual transmission of American trypanosomes from males and females to naive mates.
      ). In the absence of specific antibody, the immune tolerance present in a majority of the study family subjects was a consequence of the sexual transmission of T. cruzi infection to the early embryo before development of the immune system. In this regard, the diagnosis of a majority of the progeny from Chagas parents could not be accomplished with the immunoassays. In contrast, the presence of T. cruzi antibody in a minority of chagasic individuals indicates that T. cruzi parasites reached the fetus with a mature immune system (
      • Almeida A.B.
      • Araújo P.F.
      • Bernal F.M.
      • Rosa A.C.
      • Valente S.A.
      • Teixeira A.R.L.
      Sexual transmission of American trypanosomes from males and females to naive mates.
      ,
      • Araujo P.
      • Almeida A.
      • Pimentel C.
      • Silva A.
      • Sousa A.
      • et al.
      Sexual transmission of American trypanosomiasis in humans: a new potential pandemic route for Chagas parasites.
      ,
      • Guimaro M.
      • Alves R.
      • Rose E.
      • Sousa A.
      • Cássia A.
      • et al.
      Inhibition of Chagas-like heart disease by bone marrow transplantation.
      ,
      • Teixeira A.
      • Gomes C.
      • Nitz N.
      • Sousa A.
      • Alves R.
      • Guimaro M.
      • et al.
      Trypanosoma cruzi in the chicken model: Chagas-like heart disease in the absence of parasitism.
      ). Therefore, employment of immunoassays alone could underdiagnose congenital cases of Chagas disease. In consideration of this and for the safety of health facilities, nucleic acid techniques should be employed to discard blood contaminated with the T. cruzi 188-nt telomere sequence and from patients with Chagas disease.
      The investigations in the mouse model showed T. cruzi forms expelled through semen ejaculates (Figure 2), and a further experimental study suggested that males and females could transmit the Chagas parasites present either in semen ejaculate or in vaginal fluid (
      • Araujo P.
      • Almeida A.
      • Pimentel C.
      • Silva A.
      • Sousa A.
      • et al.
      Sexual transmission of American trypanosomiasis in humans: a new potential pandemic route for Chagas parasites.
      ,
      • Teixeira A.
      • Roters F.
      • Mott K.
      Acute Chagas disease.
      ).
      Figure 2
      Figure 2Trypanosoma cruzi in semen ejaculate from a chagasic male mouse. The arrows show: (A) amastigotes; (B) trypomastigote. The figure, with modification, is reprinted with permission from the author and the publisher (
      • Alarcon M.
      • Moreno E.
      • Colasante C.
      • Yarbuh A.
      • Cáceres K.
      • et al.
      Presencia de epimastigotes de Trypanosoma cruzi en el plasma seminal de ratones com infeccíon aguda.
      ).
      Moreover, T. cruzi-infected male and female mice sexually transmitted Trypanosoma parasites to naïve mouse mates in three series of independent experiments (
      • Araujo P.
      • Almeida A.
      • Pimentel C.
      • Silva A.
      • Sousa A.
      • et al.
      Sexual transmission of American trypanosomiasis in humans: a new potential pandemic route for Chagas parasites.
      ,
      • Rios A.
      • Ribeiro M.
      • Sousa A.
      • Pimentel P.
      • Hagström L.
      • Andrade R.
      • et al.
      Can sexual transmission support the enzootic cycle of Trypanosoma cruzi?.
      ): chagasic male and female mice bred naïve female and male founders (F0) that generated F1 progeny, and further breeding generated F2 progeny with nDNA-PCR positive for the 188-nt telomere repeat sequence, thus showing vertically acquired T. cruzi infections. The breeding experiments confirmed the absence of T. cruzi antibody in 78% of F1 and F2 progeny mice, and pathology revealed T. cruzi amastigote nests in the reproductive system (
      • Araujo P.
      • Almeida A.
      • Pimentel C.
      • Silva A.
      • Sousa A.
      • et al.
      Sexual transmission of American trypanosomiasis in humans: a new potential pandemic route for Chagas parasites.
      ,
      • Almeida A.B.
      • Araújo P.F.
      • Bernal F.M.
      • Rosa A.C.
      • Valente S.A.
      • Teixeira A.R.L.
      Sexual transmission of American trypanosomes from males and females to naive mates.
      ). Several studies have corroborated the sexual transmission of T. cruzi infections from male and female mice to naïve mouse mates (
      • Rios A.
      • Ribeiro M.
      • Sousa A.
      • Pimentel P.
      • Hagström L.
      • Andrade R.
      • et al.
      Can sexual transmission support the enzootic cycle of Trypanosoma cruzi?.
      ,
      • Ribeiro M.
      • Nitz N.
      • Santana C.
      • Moraes A.
      • Hagström L.
      • Andrade R.
      • et al.
      Sexual transmission of Trypanosoma cruzi in murine model.
      ,
      • Martin D.L.
      • Lowe K.R.
      • McNeill T.
      • Thiele E.A.
      • Roellig D.M.
      • Zajdowicz J.
      Potential sexual transmission of Trypanosoma cruzi in mice.
      ,
      • Araujo P.F.
      A genetic, immunological, and parasitological study of the Trypanosoma cruzi infections in families from Para Estate, Brazil. Ph.D. Thesis.
      ).
      In conclusion, (1) the sexual transmission of T. cruzi infections is a potential threat to public health worldwide; (2) specialized clinical centers are needed, because the emergence of Chagas disease can no longer be underestimated; (3) nDNA-PCR confirmed by Southern hybridization, cloning, and sequencing should be used to establish the diagnosis of all T. cruzi infections; (4) a high throughput digital platform is needed for the diagnosis of Chagas disease, epidemiological investigations, and to prevent blood contamination; (5) a robust education, information, and communication program should be implemented to prevent sexually transmitted T. cruzi infections and Chagas disease; (6) the perspective is that the control of Chagas disease requires international solidarity.

      Funding source

      The work received financial support from the National Research Council /CNPq, Brazil.

      Ethical approval

      Not applicable.

      Conflict of interest

      The authors declare that no conflict of interest exists.

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