title: Early double-negative thymocyte export in Trypanosoma cruzi infection is restricted by sphingosine receptors and associated with human chagas disease.
abstract: The protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironmental and lymphoid compartments. Acute infection results in severe atrophy of the organ and early release of immature thymocytes into the periphery. To date, the pathophysiological effects of thymic changes promoted by parasite-inducing premature release of thymocytes to the periphery has remained elusive. Herein, we show that sphingosine-1-phosphate (S1P), a potent mediator of T cell chemotaxis, plays a role in the exit of immature double-negative thymocytes in experimental Chagas disease. In thymuses from T. cruzi-infected mice we detected reduced transcription of the S1P kinase 1 and 2 genes related to S1P biosynthesis, together with increased transcription of the SGPL1 sphingosine-1-lyase gene, whose product inactivates S1P. These changes were associated with reduced intrathymic levels of S1P kinase activity. Interestingly, double-negative thymocytes from infected animals expressed high levels of the S1P receptor during infection, and migrated to lower levels of S1P. Moreover, during T. cruzi infection, this thymocyte subset expresses high levels of IL-17 and TNF-α cytokines upon polyclonal stimulation. In vivo treatment with the S1P receptor antagonist FTY720 resulted in recovery the numbers of double-negative thymocytes in infected thymuses to physiological levels. Finally, we showed increased numbers of double-negative T cells in the peripheral blood in severe cardiac forms of human Chagas disease.
authors.affiliation: Laboratory on Thymus Research, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Ailin
authors.initials: A
authors.lastname: Lepletier
authors.affiliation: Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Liliane
authors.initials: L
authors.lastname: de Almeida
authors.affiliation: Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Santos
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Luzia
authors.initials: L
authors.lastname: da Silva Sampaio
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Bruno
authors.initials: B
authors.lastname: Paredes
authors.affiliation: Institute of Immunology, National University of Rosario, Rosario, Argentina.
authors.forename: Florencia Belén
authors.initials: FB
authors.lastname: González
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Célio Geraldo
authors.initials: CG
authors.lastname: Freire-de-Lima
authors.affiliation: Servicio de Clínica Médica, Hospital J.B. Iturraspe, Santa Fe, Argentina.
authors.forename: Juan
authors.initials: J
authors.lastname: Beloscar
authors.affiliation: Servicio de Clínica Médica, Hospital J.B. Iturraspe, Santa Fe, Argentina.
authors.forename: Oscar
authors.initials: O
authors.lastname: Bottasso
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Einicker-Lamas
authors.affiliation: Institute of Immunology, National University of Rosario, Rosario, Argentina.
authors.forename: Ana Rosa
authors.initials: AR
authors.lastname: Pérez
authors.affiliation: Laboratory on Thymus Research, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Wilson
authors.initials: W
authors.lastname: Savino
authors.affiliation: Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morrot
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D014355:Chagas Disease / Q000503:physiopathology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013601:T-Lymphocytes; D060168:Thymocytes / Q000378:metabolism*; D014349:Trypanosoma cruzi
chemical_list: D008246:Lysophospholipids; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; C556330:S1pr1 protein, mouse; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D013110:Sphingosine