Publications by authors named "E Navarrete-De Gálvez"

150 Publications

Biological relevance of Granzymes A and K during sepsis.

Theranostics 2021 17;11(20):9873-9883. Epub 2021 Oct 17.

Instituto de Carboquímica ICB-CSIC, 50018, Zaragoza, Spain.

Recent findings suggest that the serine protease Granzyme K (GzmK) may act as a proinflammatory mediator. However, its role in sepsis is unknown. Here we aim to understand the role of GzmK in a mouse model of bacterial sepsis and compare it to the biological relevance of Granzyme A (GzmA). Sepsis was induced in WT, GzmA and GzmK mice by an intraperitoneal injection of 2x10 CFU from . Mouse survival was monitored during 5 days. Levels of IL-1α, IL-1β, TNFα and IL-6 in plasma were measured and bacterial load in blood, liver and spleen was analyzed. Finally, profile of cellular expression of GzmA and GzmK was analyzed by FACS. GzmA and GzmK are not involved in the control of bacterial infection. However, GzmA and GzmK deficient mice showed a lower sepsis score in comparison with WT mice, although only GzmA deficient mice exhibited increased survival. GzmA deficient mice also showed reduced expression of some proinflammatory cytokines like IL1-α, IL-β and IL-6. A similar result was found when extracellular GzmA was therapeutically inhibited in WT mice using serpinb6b, which improved survival and reduced IL-6 expression. Mechanistically, active extracellular GzmA induces the production of IL-6 in macrophages by a mechanism dependent on TLR4 and MyD88. These results suggest that although both proteases contribute to the clinical signs of -induced sepsis, inhibition of GzmA is sufficient to reduce inflammation and improve survival irrespectively of the presence of other inflammatory granzymes, like GzmK.
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http://dx.doi.org/10.7150/thno.59418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581435PMC
October 2021

A versatile genetic toolbox for Prevotella copri enables studying polysaccharide utilization systems.

EMBO J 2021 Oct 21:e108287. Epub 2021 Oct 21.

Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany.

Prevotella copri is a prevalent inhabitant of the human gut and has been associated with plant-rich diet consumption and diverse health states. The underlying genetic basis of these associations remains enigmatic due to the lack of genetic tools. Here, we developed a novel versatile genetic toolbox for rapid and efficient genetic insertion and allelic exchange applicable to P. copri strains from multiple clades. Enabled by the genetic platform, we systematically investigated the specificity of polysaccharide utilization loci (PULs) and identified four highly conserved PULs for utilizing arabinan, pectic galactan, arabinoxylan, and inulin, respectively. Further genetic and functional analysis of arabinan utilization systems illustrate that P. copri has evolved two distinct types of arabinan-processing PULs (PUL ) and that the type-II PUL is significantly enriched in individuals consuming a vegan diet compared to other diets. In summary, this genetic toolbox will enable functional genetic studies for P. copri in future.
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http://dx.doi.org/10.15252/embj.2021108287DOI Listing
October 2021

Klebsiella oxytoca causes colonization resistance against multidrug-resistant K. pneumoniae in the gut via cooperative carbohydrate competition.

Cell Host Microbe 2021 Nov 4;29(11):1663-1679.e7. Epub 2021 Oct 4.

Department of Microbial Immune Regulation, Helmholtz Center for Infection Research, Braunschweig, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany; Center for Individualized Infection Medicine, Hannover, Germany; German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany. Electronic address:

Gut colonization with multidrug-resistant (MDR) bacteria enhances the risk of bloodstream infections in susceptible individuals. We demonstrate highly variable degrees of ex vivo colonization resistance against a carbapenem-resistant Klebsiella pneumoniae strain in human feces samples and subsequently isolate diverse K. oxytoca strains from protected donors. Several of these K. oxytoca strains reduce gut colonization of MDR K. pneumoniae strains in antibiotic-treated and gnotobiotic mouse models. Comparative analysis of K. oxytoca strains coupled with CRISPR-Cas9-mediated deletion of casA, a protein essential for utilization of selected beta-glucosides, identified competition for specific carbohydrates as key in promoting colonization resistance. In addition to direct competition between K. oxytoca and K. pneumoniae, cooperation with additional commensals is required to reestablish full colonization resistance and gut decolonization. Finally, humanized microbiota mice generated from K. pneumoniae-susceptible donors are protected by K. oxytoca administration, demonstrating the potential of commensal K. oxytoca strains as next-generation probiotics.
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http://dx.doi.org/10.1016/j.chom.2021.09.003DOI Listing
November 2021

Cognate recognition of microbial antigens defines constricted CD4 T cell receptor repertoires in the inflamed colon.

Immunity 2021 11 27;54(11):2565-2577.e6. Epub 2021 Sep 27.

Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany. Electronic address:

Key aspects of intestinal T cells, including their antigen specificity and their selection by the microbiota and other intestinal antigens, as well as the contribution of individual T cell clones to regulatory and effector functions, remain unresolved. Here we tracked adoptively transferred T cell populations to specify the interrelation of T cell receptor repertoire and the gut antigenic environment. We show that dominant TCRα clonotypes were shared between interferon-γ- and interleukin-17-producing but not regulatory Foxp3 T cells. Identical TCRα clonotypes accumulated in the colon of different individuals, whereas antibiotics or defined colonization correlated with the expansion of distinct expanded T cell clonotypes. Our results demonstrate key aspects of intestinal CD4 T cell activation and suggest that few microbial species exert a dominant effect on the intestinal T cell repertoire during colitis. We speculate that dominant proinflammatory T cell clones might provide a therapeutic target in human inflammatory bowel disease.
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http://dx.doi.org/10.1016/j.immuni.2021.08.014DOI Listing
November 2021

Induction of IL-22-Producing CD4+ T Cells by Segmented Filamentous Bacteria Independent of Classical Th17 Cells.

Front Immunol 2021 8;12:671331. Epub 2021 Sep 8.

Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany.

The intestinal microbiota modulates IL-22 production in the intestine, including the induction of IL-22-producing CD4+ T helper cells. Which specific bacteria are responsible for the induction of these cells is less well understood. Here, we demonstrate through the use of novel gnotobiotic knock-in reporter mice that segmented filamentous bacteria (SFB), which are known for their ability to induce Th17 cells, also induce distinct IL-17A negative CD4+ T cell populations in the intestine. A subset of these cells instead produces IL-22 upon restimulation and also during enteric infections. Furthermore, they produce a distinct set of cytokines compared to Th17 cells including the differential expression of IL-17F and IFN-γ. Importantly, genetic models demonstrate that these cells, presumably Th22 cells, develop independently of intestinal Th17 cells. Together, our data identifies that besides Th17, SFB also induces CD4+ T cell populations, which serve as immediate source of IL-22 during intestinal inflammation.
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http://dx.doi.org/10.3389/fimmu.2021.671331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456099PMC
October 2021
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