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NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production
Open accessAbstract
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.
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“Remarkably, the master regulator Caspase, which is a family of protease enzymes, is associated mainly with regulating the reduction of the load of intracellular parasites, induction of nitric oxide production, increasing the level of CD4 and CD8+ T-cells, secretion of IFNγ, and control of trypanosome infection by macrophages (Gonçalves et al., 2013).”
From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Gonçalves et al., 2013
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Cryopyrin activates the inflammasome in response to toxins and ATP
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Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants
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The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses
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Sensing and reacting to microbes through the inflammasomes
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Man, S. M., Karki, R., & Kanneganti, T. (2017) · Immunological Reviews · doi:10.1111/imr.12534 · Cited by 1,684
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Transcriptome Remodeling in Trypanosoma cruzi and Human Cells during Intracellular Infection
Li, Y., Tomko, S. S., Okrah, K., Belew, A. T., Choi, J., Caradonna, K. L., Padmanabhan, P. K., Ndegwa, D. M., Temanni, M.-R., Bravo, H. C., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005511 · Cited by 160
Metadata
- Authors
- Gonçalves, V. M., Matteucci, K. C., Buzzo, C. L., Miollo, B. H., Ferrante, D., Torrecilhas, A. C., Rodrigues, M. M., Alvarez, J. M., & Bortoluci, K. R.
- Affiliations
- Universidade Federal de São Paulo (BR)
- Instituto de Ciências Ambientais, Químicas e Farmacêuticas (BR)
- Corresponding author
- Bortoluci, Karina R.
- Venue
- PLoS Neglected Tropical Diseases
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-10-03
- Volume
- 7
- Issue
- 10
- Pages
- e2469
- ISSN
- 1935-2727 (ISSN-L)
- 1935-2735
- PMC
- PMC3789781
- OpenAlex
- W2140577495
- Cited by
- 123
- References
- 68
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 15 · 2019: 14 · 2018: 17 · 2017: 12 · 2016: 14 · 2015: 6 · 2014: 14
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS neglected tropical diseases (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Americanae (AECID Library) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (08/50958-8)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Trypanosoma cruzi, Chagas disease, NLRP3 inflammasome, caspase-1, nitric oxide production, IL-1β, cathepsin B, innate immunity, MyD88, IL-18, parasitemia control
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, Disease Models, Animal, Female, Gene Expression Regulation, Nitric Oxide, Trypanosoma cruzi, Chagas Disease, Mice, Knockout, Caspase 1, Mice, Interleukin-1beta, Host-Pathogen Interactions
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