Cargando…

NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production

Trypanosoma cruzi (T. cruzi) is an intracellular protozoan parasite and the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people worldwide. Although the role of TLR and Nod1 in the control of T. cruzi infection is well-established, the involvement of infl...

Descripción completa

Detalles Bibliográficos
Autores principales: Gonçalves, Virginia M., Matteucci, Kely C., Buzzo, Carina L., Miollo, Bruna H., Ferrante, Danny, Torrecilhas, Ana C., Rodrigues, Mauricio M., Alvarez, Jose M., Bortoluci, Karina R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789781/
https://www.ncbi.nlm.nih.gov/pubmed/24098823
http://dx.doi.org/10.1371/journal.pntd.0002469
_version_ 1782286497765916672
author Gonçalves, Virginia M.
Matteucci, Kely C.
Buzzo, Carina L.
Miollo, Bruna H.
Ferrante, Danny
Torrecilhas, Ana C.
Rodrigues, Mauricio M.
Alvarez, Jose M.
Bortoluci, Karina R.
author_facet Gonçalves, Virginia M.
Matteucci, Kely C.
Buzzo, Carina L.
Miollo, Bruna H.
Ferrante, Danny
Torrecilhas, Ana C.
Rodrigues, Mauricio M.
Alvarez, Jose M.
Bortoluci, Karina R.
author_sort Gonçalves, Virginia M.
collection PubMed
description Trypanosoma cruzi (T. cruzi) is an intracellular protozoan parasite and the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people worldwide. Although the role of TLR and Nod1 in the control of T. cruzi infection is well-established, the involvement of inflammasomes remains to be elucidated. Herein, we demonstrate for the first time that T. cruzi infection induces IL-1β production in an NLRP3- and caspase-1-dependent manner. Cathepsin B appears to be required for NLRP3 activation in response to infection with T. cruzi, as pharmacological inhibition of cathepsin B abrogates IL-1β secretion. NLRP3(−/−) and caspase1(−/−) mice exhibited high numbers of T. cruzi parasites, with a magnitude of peak parasitemia comparable to MyD88(−/−) and iNOS(−/−) mice (which are susceptible models for T. cruzi infection), indicating the involvement of NLRP3 inflammasome in the control of the acute phase of T. cruzi infection. Although the inflammatory cytokines IL-6 and IFN-γ were found in spleen cells from NLRP3(−/−) and caspase1(−/−) mice infected with T. cruzi, these mice exhibited severe defects in nitric oxide (NO) production and an impairment in macrophage-mediated parasite killing. Interestingly, neutralization of IL-1β and IL-18, and IL-1R genetic deficiency demonstrate that these cytokines have a minor effect on NO secretion and the capacity of macrophages to control T. cruzi infection. In contrast, inhibition of caspase-1 with z-YVAD-fmk abrogated NO production by WT and MyD88(−/−) macrophages and rendered them as susceptible to T. cruzi infection as NLRP3(−/−) and caspase-1(−/−) macrophages. Taken together, our results demonstrate a role for the NLRP3 inflammasome in the control of T. cruzi infection and identify NLRP3-mediated, caspase-1-dependent and IL-1R-independent NO production as a novel effector mechanism for these innate receptors.
format Online
Article
Text
id pubmed-3789781
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-37897812013-10-04 NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production Gonçalves, Virginia M. Matteucci, Kely C. Buzzo, Carina L. Miollo, Bruna H. Ferrante, Danny Torrecilhas, Ana C. Rodrigues, Mauricio M. Alvarez, Jose M. Bortoluci, Karina R. PLoS Negl Trop Dis Research Article Trypanosoma cruzi (T. cruzi) is an intracellular protozoan parasite and the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people worldwide. Although the role of TLR and Nod1 in the control of T. cruzi infection is well-established, the involvement of inflammasomes remains to be elucidated. Herein, we demonstrate for the first time that T. cruzi infection induces IL-1β production in an NLRP3- and caspase-1-dependent manner. Cathepsin B appears to be required for NLRP3 activation in response to infection with T. cruzi, as pharmacological inhibition of cathepsin B abrogates IL-1β secretion. NLRP3(−/−) and caspase1(−/−) mice exhibited high numbers of T. cruzi parasites, with a magnitude of peak parasitemia comparable to MyD88(−/−) and iNOS(−/−) mice (which are susceptible models for T. cruzi infection), indicating the involvement of NLRP3 inflammasome in the control of the acute phase of T. cruzi infection. Although the inflammatory cytokines IL-6 and IFN-γ were found in spleen cells from NLRP3(−/−) and caspase1(−/−) mice infected with T. cruzi, these mice exhibited severe defects in nitric oxide (NO) production and an impairment in macrophage-mediated parasite killing. Interestingly, neutralization of IL-1β and IL-18, and IL-1R genetic deficiency demonstrate that these cytokines have a minor effect on NO secretion and the capacity of macrophages to control T. cruzi infection. In contrast, inhibition of caspase-1 with z-YVAD-fmk abrogated NO production by WT and MyD88(−/−) macrophages and rendered them as susceptible to T. cruzi infection as NLRP3(−/−) and caspase-1(−/−) macrophages. Taken together, our results demonstrate a role for the NLRP3 inflammasome in the control of T. cruzi infection and identify NLRP3-mediated, caspase-1-dependent and IL-1R-independent NO production as a novel effector mechanism for these innate receptors. Public Library of Science 2013-10-03 /pmc/articles/PMC3789781/ /pubmed/24098823 http://dx.doi.org/10.1371/journal.pntd.0002469 Text en © 2013 Gonçalves et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Gonçalves, Virginia M.
Matteucci, Kely C.
Buzzo, Carina L.
Miollo, Bruna H.
Ferrante, Danny
Torrecilhas, Ana C.
Rodrigues, Mauricio M.
Alvarez, Jose M.
Bortoluci, Karina R.
NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production
title NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production
title_full NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production
title_fullStr NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production
title_full_unstemmed NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production
title_short NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production
title_sort nlrp3 controls trypanosoma cruzi infection through a caspase-1-dependent il-1r-independent no production
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789781/
https://www.ncbi.nlm.nih.gov/pubmed/24098823
http://dx.doi.org/10.1371/journal.pntd.0002469
work_keys_str_mv AT goncalvesvirginiam nlrp3controlstrypanosomacruziinfectionthroughacaspase1dependentil1rindependentnoproduction
AT matteuccikelyc nlrp3controlstrypanosomacruziinfectionthroughacaspase1dependentil1rindependentnoproduction
AT buzzocarinal nlrp3controlstrypanosomacruziinfectionthroughacaspase1dependentil1rindependentnoproduction
AT miollobrunah nlrp3controlstrypanosomacruziinfectionthroughacaspase1dependentil1rindependentnoproduction
AT ferrantedanny nlrp3controlstrypanosomacruziinfectionthroughacaspase1dependentil1rindependentnoproduction
AT torrecilhasanac nlrp3controlstrypanosomacruziinfectionthroughacaspase1dependentil1rindependentnoproduction
AT rodriguesmauriciom nlrp3controlstrypanosomacruziinfectionthroughacaspase1dependentil1rindependentnoproduction
AT alvarezjosem nlrp3controlstrypanosomacruziinfectionthroughacaspase1dependentil1rindependentnoproduction
AT bortolucikarinar nlrp3controlstrypanosomacruziinfectionthroughacaspase1dependentil1rindependentnoproduction