Granulysin: killer lymphocyte safeguard against microbes

Dotiwala, Farokh; Lieberman, Judy

doi:10.1016/j.coi.2019.04.013

Cited by 53 publications

(53 citation statements)

References 61 publications

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“…One pending aspect is how CD8+ cells can contribute to decreased colonization. A possible mechanism could involve the induction of cytotoxic T-lymphocytes (CTL) that kill extracellular bacteria, presumably by granulysin and granzymes [62] (Figure 6). On the other hand, because SIP is an agonist of TLR2 and TLR4, it remains unclear whether rL.…”

Section: Discussionmentioning

confidence: 99%

Mucosal Vaccination with Lactococcus lactis-Secreting Surface Immunological Protein Induces Humoral and Cellular Immune Protection against Group B Streptococcus in a Murine Model

et al. 2020

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Group B Streptococcus (GBS) is the primary etiological agent of sepsis and meningitis in newborns and is associated with premature birth and stillbirth. The development of a licensed vaccine is one of the pending challenges for the World Health Organization. Previously, we showed that oral immunization with surface immune protein (SIP) decreases vaginal colonization of GBS and generates functional opsonizing antibodies, which was determined by opsonophagocytic assays (OPA) in vitro. We also showed that the protein has an adjuvant vaccine profile. Therefore, an oral vaccine based on SIP may be an attractive alternative to employ in the development of new vaccines against GBS. Lactococcus lactis is a highlighted oral vaccine probiotic inducer of the mucosal immune response. This bacterium could serve as an antigen-delivering vehicle for the development of an edible vaccine and has been used in clinical trials. In this study, we showed that an oral vaccine with a recombinant L. lactis strain secreting SIP from GBS (rL. lactis-SIP) can induce protective humoral and cellular immunity in an experimental model of GBS vaginal colonization in C57BL/6 mice. Mice immunized with rL. lactis-SIP were protected against clinical symptoms and bacterial colonization after GBS vaginal colonization. Our rL. lactis-SIP vaccine also induces an increase of immunoglobulin G (IgG) and immunoglobulin A (IgA) specifically against SIP. The adoptive transfer of serum from vaccinated mice to naïve mice generated protection against GBS vaginal colonization. Moreover, the rL. lactis-SIP strain induces the activation of SIP-specific T cells, which could decrease GBS vaginal colonization and generate protective antibodies when transferred to other mice. Our experimental observations strongly support the notion that rL. lactis-SIP induces protective humoral and cellular immunity and could be considered as a novel alternative in the development of vaccines for GBS.

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Section: Discussionmentioning

confidence: 99%

Mucosal Vaccination with Lactococcus lactis-Secreting Surface Immunological Protein Induces Humoral and Cellular Immune Protection against Group B Streptococcus in a Murine Model

et al. 2020

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“…Recognition of iRetics also stimulated CD8 + T cells to secrete IFN-γ. iRetic lysis and parasite killing depended on CD8 + T cell release of cytotoxic granules and their contents, especially the death-inducing proteases (granzymes) and an antimicrobial peptide granulysin (GNLY), which preferentially permeabilizes cholesterol-poor membranes of bacteria, fungi and parasites rather than host cell membranes [6]. Unlike P. vivax iRetics, P. falciparuminfected RBCs do not express HLA-I, are not recognized by patient CD8 + T cells (manuscript in preparation) and are not thought to contribute to immune protection in erythrocytic P. falciparum infection [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Contributions of IFN-γ and granulysin to the clearance of Plasmodium yoelii blood stage

et al. 2020

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P. vivax-infected Retics (iRetics) express human leukocyte antigen class I (HLA-I), are recognized by CD8 + T cells and killed by granulysin (GNLY) and granzymes. However, how Plasmodium infection induces MHC-I expression on Retics is unknown. In addition, whether GNLY helps control Plasmodium infection in vivo has not been studied. Here, we examine these questions using rodent infection with the P. yoelii 17XNL strain, which has tropism for Retics. Infection with P. yoelii caused extramedullary erythropoiesis, reticulocytosis and expansion of CD8 + CD44 + CD62L-IFN-γ-producing T cells that form immune synapses with iRetics. We now provide evidence that MHC-I expression by iRetic is dependent on IFN-γinduced transcription of IRF-1, MHC-I and β2-microglobulin (β2-m) in erythroblasts. Consistently, CTLs from infected wild type (WT) mice formed immune synapses with iRetics in an IFN-γ-and MHC-I-dependent manner. When challenged with P. yoelii 17XNL, WT mice cleared parasitemia and survived, while IFN-γ KO mice remained parasitemic and all died. β2-m KO mice that do not express MHC-I and have virtually no CD8 + T cells had prolonged parasitemia, and 80% survived. Because mice do not express GNLY, GNLY-transgenic mice can be used to assess the in vivo importance of GNLY. Parasite clearance was accelerated in GNLY-transgenic mice and depletion of CD8 + T cells ablated the GNLY-mediated resistance to P. yoelii. Altogether, our results indicate that in addition to previously described mechanisms, IFN-γ promotes host resistance to the Retic-tropic P. yoelii 17XNL strain by promoting MHC-I expression on iRetics that become targets for CD8 + cytotoxic T lymphocytes and GNLY.

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“…Interestingly, in a mouse model of Legionella infection, cytolytic proteins did not appear to contribute to the MAIT cell protective role [36]. However, because cytolytic proteins are structurally and functionally divergent in mammals [39] and Gnly is absent in rodents [40], prudence should be exercised in interpreting the mechanism underlying MAIT cell mediated antimicrobial activity in murine models. Collectively, our findings indicate that MAIT cells mediate antimicrobial activity through the cytolytic protein-dependent pathway, which may contribute to the protection of the human host against bacterial infections.…”

Section: Discussionmentioning

confidence: 97%

“…As Gnly is similarly expressed late by activated cytotoxic T cells following activation [41], Gnly + MAIT cells in blood may represent an antigen-imprinted and -experienced MAIT cell subset that may respond to bacterial infection faster. While Gnly is broadly antimicrobial, it also has strong pro-inflammatory and chemotactic activity, and has been implicated in several inflammatory diseases [40]. Thus, the strict differential and temporal regulation of cytotoxicity and antimicrobial activity may also afford some protection against MAIT cell-mediated immunopathology that can occur in certain bacterial infections [42,43].…”

Section: Discussionmentioning

confidence: 99%

Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance inEscherichia coli

Boulouis

Sia

Gulam

et al. 2020

Preprint

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One Sentence Summary: Potent antimicrobial activity of human MAIT cells overcomes carbapenem-resistance in control of Escherichia coli Category of manuscript: Research Article. Abstract word count: 220 References: 69 Display items: 6 figures, 7 supplementary figures, 3 supplementary tables. Word count incl. main text, references, and figure legends: 10041. 3 Abstract Mucosa-associated invariant T (MAIT) cells are abundant antimicrobial T cells in humans, and recognize antigens derived from the microbial riboflavin biosynthetic pathway presented by the MHC-Ib-related protein (MR1). However, the mechanisms responsible for MAIT cell antimicrobial activity are not fully understood, and the efficacy of these mechanisms against antibiotic resistant bacteria has not been explored. Here, we show that MAIT cells mediate MR1restricted antimicrobial activity against E. coli clinical strains in a manner dependent on the activity of cytolytic proteins, but independent of production of pro-inflammatory cytokines or induction of apoptosis in infected cells. The combined action of the pore-forming antimicrobial protein granulysin and the serine protease granzyme B released in response to TCR-mediated recognition of MR1-presented antigen is essential to mediate control against both cell-associated and free-living E. coli. Furthermore, MAIT cell-mediated bacterial control extend to multidrugresistant E. coli primary clinical isolates additionally resistant to carbapenems, a class of last resort antibiotics. Notably, high levels of granulysin and granzyme B in the MAIT cell secretomes directly damage bacterial cells by increasing their permeability, rendering initially resistant E. coli susceptible to the bactericidal activity of carbapenems. These findings define the role of cytolytic effector proteins in MAIT cell-mediated antimicrobial activity, and indicate that granulysin and granzyme B synergize to restore carbapenem bactericidal activity and overcome carbapenem resistance in E. coli. 4 [Main Text: ] Introduction Mucosa-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in mucosal tissues, the liver, lungs and gastrotintestinal tract, and in peripheral blood [1]. MAIT cells are mostly CD8α + [2, 3], express a semi-invariant T cell receptor (TCR), and recognize antigens in complex with the MHC-Ib-related protein (MR1) [4]. MR1 displays an extraordinary level of evolutionary conservation among placental and marsupial mammals [5], strongly supporting the notion that MR1 and MAIT cells perform critical functions in the immune system. The MR1presented antigens recognized by MAIT cells are derivatives of intermediates in the microbial synthesis of vitamin B 2 (riboflavin) and are produced by many bacteria [6-8]. Riboflavin is a critical component in a wide variety of bacterial cellular processes [9]. MAIT cells are thus able to recognize and respond to a broad set of bacteria [10]. Following TCR-mediated recognition of MR1-presented bacterial riboflavin metabolite antigens, MAIT cells rapidly media...

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Granulysin: killer lymphocyte safeguard against microbes

Cited by 53 publications

References 61 publications

Mucosal Vaccination with Lactococcus lactis-Secreting Surface Immunological Protein Induces Humoral and Cellular Immune Protection against Group B Streptococcus in a Murine Model

Mucosal Vaccination with Lactococcus lactis-Secreting Surface Immunological Protein Induces Humoral and Cellular Immune Protection against Group B Streptococcus in a Murine Model

Contributions of IFN-γ and granulysin to the clearance of Plasmodium yoelii blood stage

Human MAIT cell cytolytic effector proteins synergize to overcome carbapenem resistance inEscherichia coli

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