Elucidating Sources and Roles of Granzymes A and B during Bacterial Infection and Sepsis

Arias, Maykel; Bagüés, María Pilar Jiménez de; Aguiló, Nacho; Menao, Sebastián; Hervás-Stubbs, Sandra; Martino, Alba De; Alcaraz, Ana; Simon, Markus M.; Froelich, Christopher J.; Pardo, Julián

doi:10.1016/j.celrep.2014.06.012

Cited by 57 publications

(67 citation statements)

References 40 publications

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“…Thus, gzms played little, if any, role in the control of local infection and subsequent dissemination to distant organs. In agreement, gzmA -/- mice did not present differences in Listeria monocytogenes growth [19] or in bacteraemia and dissemination after Brucella microti infection [20] when compared to WT mice.…”

Section: Discussionsupporting

confidence: 50%

“…In this respect, it is worth mentioning, however, that we cannot exclude possible compensatory mechanisms by other gzms, such as gzmM and gzmK, taking part in the results obtained in the gzmAxB -/- mice [15,27,28]. Previous studies reported the reduced mortality of gzmB -/- mice during polymicrobial peritonitis [29] and of gzmA -/- mice during B. microti sepsis [20], suggesting differential roles of gzms depending on the primary site of infection and/or the causative pathogen. Of note and relevant for the responsiveness to Gram-negative bacteria, earlier reports on the role of gzms in LPS-induced shock are partially contradictory.…”

Section: Discussionmentioning

confidence: 96%

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Granzymes A and B Regulate the Local Inflammatory Response during Klebsiella pneumoniae Pneumonia

García‐Laorden

Stroo²,

Blok³

et al. 2016

J Innate Immun

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Klebsiella pneumoniae is a common cause of hospital-acquired pneumonia. Granzymes (gzms), mainly found in cytotoxic lymphocytes, have been implicated as mediators of infection and inflammation. We here sought to investigate the role of gzmA and gzmB in the host response to K. pneumoniae-induced airway infection and sepsis. For this purpose, pneumonia was induced in wild-type (WT) and gzmA-deficient (gzmA^-/-), gzmB^-/- and gzmAxB^-/- mice by intranasal infection with K. pneumoniae. In WT mice, gzmA and gzmB were mainly expressed by natural killer cells. Pneumonia was associated with reduced intracellular gzmA and increased intracellular gzmB levels. Gzm deficiency had little impact on antibacterial defence: gzmA^-/- and gzmAxB^-/- mice transiently showed modestly higher bacterial loads in the lungs but not in distant organs. GzmB^-/- and, to a larger extent, gzmAxB^-/- mice displayed transiently increased lung inflammation, reflected in the semi-quantitative histology scores and levels of pro-inflammatory cytokines and chemokines. Most differences between gzm-deficient and WT mice had disappeared during late-stage pneumonia. Gzm deficiency did not impact on distant organ injury or survival. These results suggest that gzmA and gzmB partly regulate local inflammation during early pneumonia but eventually play an insignificant role during pneumosepsis by the common human pathogen K. pneumoniae.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 96%

Granzymes A and B Regulate the Local Inflammatory Response during Klebsiella pneumoniae Pneumonia

García‐Laorden

Stroo²,

Blok³

et al. 2016

J Innate Immun

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“…2). Indeed, GZMA-deficient mice resist sepsis without compromising other protective functions like Tc cellmediated elimination of infected macrophages (102). However, caspase-1 activation does not lead to macrophage cell death in these conditions as in the case of pyroptosis induced by bacterial infection.…”

Section: Other Modalities Of Cell Deathmentioning

confidence: 99%

How Do Cytotoxic Lymphocytes Kill Cancer Cells?

Martínez-Lostao

Anel

Pardo

2015

Clinical Cancer Research

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538

394

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In the past few years, cancer immunotherapy has emerged as a safe and effective alternative for treatment of cancers that do not respond to classical treatments, including those types with high aggressiveness. New immune modulators, such as cytokines, blockers of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1(programmed cell death protein 1)/PD-L1 (programmed death-ligand 1), and interaction or adoptive cell therapy, have been developed and approved to treat solid and hematologic carcinomas. In these scenarios, cytotoxic lymphocytes (CL), mainly cytotoxic T cells (Tc) and natural killer (NK) cells, are ultimately responsible for killing the cancer cells and eradicating the tumor. Extensive studies have been conducted to assess how Tc and NK cells get activated and recognize the cancer cell. In contrast, few studies have focused on the effector molecules used by CLs to kill cancer cells during cancer immunosurveillance and immunotherapy. In this article, the two main pathways involved in CL-mediated tumor cell death, granule exocytosis (perforin and granzymes) and death ligands, are briefly introduced, followed by a critical discussion of the molecules involved in cell death during cancer immunosurveillance and immunotherapy. This discussion also covers unexpected consequences of proinflammatory and survival effects of granzymes and death ligands and recent experimental evidence indicating that perforin and granzymes of CLs can activate nonapoptotic pathways of cell death, overcoming apoptosis defects and chemoresistance. The consequences of apoptosis versus other modalities of cell death for an effective treatment of cancer by modulating the patient immune system are also briefly discussed.

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“…B. microti , a new species originally isolated from the common vole and later on from the red fox and from soil (Scholz et al, 2008a,b, 2009; Al Dahouk et al, 2012), is the first one found to be highly pathogenic in mice (Jiménez de Bagüés et al, 2011; Arias et al, 2014). In addition, it is able to cause sepsis in C57BL/6 mice (Arias et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, it is able to cause sepsis in C57BL/6 mice (Arias et al, 2014). These results suggest that B. microti is an emergent pathogen that represents a biologically relevant tool to study Brucella pathogenesis and host immunity in mouse models.…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptors 2 and 4 Cooperate in the Control of the Emerging Pathogen Brucella microti

Arias

Santiago

Costas-Ramon

et al. 2017

Front. Cell. Infect. Microbiol.

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Toll-like receptors (TLRs) recognize pathogen-derived molecules and play a critical role during the host innate and adaptive immune response. Brucella spp. are intracellular gram-negative bacteria including several virulent species, which cause a chronic zoonotic infection in a wide range of mammalian hosts known as brucellosis. A new Brucella species, Brucella microti, was recently isolated from wild rodents and found to be highly pathogenic in mice. Using this species-specific model, it was previously found that CD8+ T cells are required to control this infection. In order to find out the role of TLR-mediated responses in the control of this pathogen, the course of infection of B. microti was analyzed over 3 weeks in wild-type (WT) and TLR knock out (KO) mice including TLR2−/−, TLR4−/−, TLR9−/−, TLR2×4−/− and TLR2×4×9−/−. WT and single TLR2, TLR4 and TLR9 KO mice similarly control infection in liver and spleen. In contrast, bacterial clearance was delayed in TLR2×4−/− and TLR2×4×9−/− mice at 7 and 14 days post-infection. This defect correlated with impaired maturation and pro-inflammatory cytokine production in B. microti-infected dendritic cells from TLR2×4−/− and TLR2×4×9−/− mice. Finally, it was found that Tc cells from TLR2×4−/− and TLR2×4×9−/− mice showed reduced ability to inhibit growth of B. microti in macrophages, suggesting the involvement of TLR2 and 4 in the generation of specific Tc cells. Our findings indicate that TLR2 and TLR4 are required to control B. microti infection in mice and that this effect could be related to its participation in the maturation of dendritic cells and the generation of specific CD8+ Tc cells.

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Elucidating Sources and Roles of Granzymes A and B during Bacterial Infection and Sepsis

Cited by 57 publications

References 40 publications

Granzymes A and B Regulate the Local Inflammatory Response during <b><i>Klebsiella pneumoniae</i></b> Pneumonia

Granzymes A and B Regulate the Local Inflammatory Response during <b><i>Klebsiella pneumoniae</i></b> Pneumonia

How Do Cytotoxic Lymphocytes Kill Cancer Cells?

Toll-Like Receptors 2 and 4 Cooperate in the Control of the Emerging Pathogen Brucella microti

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