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...
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ftdoajarticles:oai:doaj.org/article:3057004a340c466a8dd5e2065ce61eee 2023-05-15T15:15:58+02:00 NLRP3 controls Trypanosoma cruzi infection through a caspase-1-dependent IL-1R-independent NO production. Virginia M Gonçalves Kely C Matteucci Carina L Buzzo Bruna H Miollo Danny Ferrante Ana C Torrecilhas Mauricio M Rodrigues Jose M Alvarez Karina R Bortoluci 2013-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0002469 https://doaj.org/article/3057004a340c466a8dd5e2065ce61eee EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3789781?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002469 https://doaj.org/article/3057004a340c466a8dd5e2065ce61eee PLoS Neglected Tropical Diseases, Vol 7, Iss 10, p e2469 (2013) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2013 ftdoajarticles https://doi.org/10.1371/journal.pntd.0002469 2022-12-31T06:05:41Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 7 10 e2469 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Virginia M Gonçalves Kely C Matteucci Carina L Buzzo Bruna H Miollo Danny Ferrante Ana C Torrecilhas Mauricio M Rodrigues Jose M Alvarez Karina R Bortoluci NLRP3 controls Trypanosoma cruzi infection through a caspase-1-dependent IL-1R-independent NO production. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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 |
Article in Journal/Newspaper |
author |
Virginia M Gonçalves Kely C Matteucci Carina L Buzzo Bruna H Miollo Danny Ferrante Ana C Torrecilhas Mauricio M Rodrigues Jose M Alvarez Karina R Bortoluci |
author_facet |
Virginia M Gonçalves Kely C Matteucci Carina L Buzzo Bruna H Miollo Danny Ferrante Ana C Torrecilhas Mauricio M Rodrigues Jose M Alvarez Karina R Bortoluci |
author_sort |
Virginia M Gonçalves |
title |
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_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_sort |
nlrp3 controls trypanosoma cruzi infection through a caspase-1-dependent il-1r-independent no production. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2013 |
url |
https://doi.org/10.1371/journal.pntd.0002469 https://doaj.org/article/3057004a340c466a8dd5e2065ce61eee |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 7, Iss 10, p e2469 (2013) |
op_relation |
http://europepmc.org/articles/PMC3789781?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002469 https://doaj.org/article/3057004a340c466a8dd5e2065ce61eee |
op_doi |
https://doi.org/10.1371/journal.pntd.0002469 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
7 |
container_issue |
10 |
container_start_page |
e2469 |
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1766346290069766144 |