Publications by authors named "Jay Gunawardana"

16 Publications

  • Page 1 of 1

EBV-tissue positive primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity.

Blood 2020 Nov 17. Epub 2020 Nov 17.

Princess Alexandra Hospital, brisbane, Australia.

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression, e.g. post-transplant lymphoproliferative disorders (PTLD) or HIV (AIDS-related PCNSL). These cases are poorly characterized, have dismal outcome and are typically Epstein-Barr virus (EBV)-tissue positive. We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. 47 were EBV-tissue negative: 45 EBV(-) HIV(-) PCNSL, 2 EBV(-) HIV(+) PCNSL; and 44 were EBV-tissue positive: 23 EBV(+) HIV(+) PCNSL, 21 EBV(+) HIV(-) PCNSL. As with prior studies, EBV(-) HIV(-) PCNSL had frequent MYD88, CD79B and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin (COO) sub-type. In contrast, these mutations were absent in all EBV-tissue positive cases and ABC frequency was low. Furthermore, copy number loss in HLA-class I/II and antigen presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV(+) HIV(-) PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-tissue positive PCNSL in the immunosuppressed is immunobiologically distinct from EBV(-) HIV(-) PCNSL, and despite expressing an immunogenic virus retains the ability to present EBV-antigens. Results provide a framework for targeted treatment.
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http://dx.doi.org/10.1182/blood.2020008520DOI Listing
November 2020

Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma.

Cell Rep 2020 05 23;31(5):107522. Epub 2020 Apr 23.

Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Hospital of the Ludwig-Maximilians-University (LMU), Munich, Bavaria 81377, Germany; German Cancer Consortium (DKTK), Munich, Bavaria 81377, Germany; German Cancer Research Center (DKFZ), Heidelberg, Baden-Wuerttemberg 69120, Germany. Electronic address:

Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4 T cells in vitro. Tumors with hyperactive CTSS showed increased CD4 T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment.
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http://dx.doi.org/10.1016/j.celrep.2020.107522DOI Listing
May 2020

EBV microRNA-BHRF1-2-5p targets the 3'UTR of immune checkpoint ligands PD-L1 and PD-L2.

Blood 2019 12;134(25):2261-2270

Mater Research, University of Queensland, Brisbane, QLD, Australia.

Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphomas (DLBCLs) express high levels of programmed death ligand 1 (PD-L1) and PD-L2. MicroRNA (miR) regulation is an important mechanism for the fine-tuning of gene expression via 3'-untranslated region (3'UTR) targeting, and we have previously demonstrated strong EBV miR expression in EBV+ DLBCL. Whereas the EBV latent membrane protein-1 (LMP1) is known to induce PD-L1/L2, a potential counterregulatory role of EBV miR in the fine-tuning of PD-L1/L2 expression remains to be established. To examine this, a novel in vitro model of EBV+ DLBCL was developed, using the viral strain EBV WIL, which unlike common laboratory strains retains intact noncoding regions where several EBV miRs reside. This enabled interrogation of the relationship among EBV latency genes, cell of origin (COO), PD-L1, PD-L2, and EBV miRs. The model successfully recapitulated the full spectrum of B-cell differentiation, with 4 discrete COO phases: early and late germinal center B cells (GCBs) and early and late activated B cells (ABCs). Interestingly, PD-L1/L2 levels increased markedly during transition from late GCB to early ABC phase, after LMP1 upregulation. EBV miR-BamHI fragment H rightward open reading frame 1 (BHRF1)-2-5p clustered apart from other EBV miRs, rising during late GCB phase. Bioinformatic prediction, together with functional validation, confirmed EBV miR-BHRF1-2-5p bound to PD-L1 and PD-L2 3'UTRs to reduce PD-L1/L2 surface protein expression. Results indicate a novel mechanism by which EBV miR-BHRF1-2-5p plays a context-dependent counterregulatory role to fine-tune the expression of the LMP1-driven amplification of these inhibitory checkpoint ligands. Further identification of immune checkpoint-targeting miRs may enable potential novel RNA-based therapies to emerge.
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http://dx.doi.org/10.1182/blood.2019000889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923667PMC
December 2019

Reply to M. Sorigue.

J Clin Oncol 2020 02 9;38(6):648-649. Epub 2019 Dec 9.

Joshua W.D. Tobin, MD and Colm Keane, MD, Mater Research, University of Queensland, Brisbane, Queensland, AustraliaPrincess Alexandra Hospital, Brisbane, Queensland, Australia; Jay Gunawardana, PhD, Mater Research, University of Queensland, Brisbane, Queensland, Australia; and Maher K. Gandhi, MD, PhD, Mater Research, University of Queensland, Brisbane, Queensland, AustraliaPrincess Alexandra Hospital, Brisbane, Queensland, Australia.

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http://dx.doi.org/10.1200/JCO.19.02935DOI Listing
February 2020

Progression of Disease Within 24 Months in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune Infiltration.

J Clin Oncol 2019 12 28;37(34):3300-3309. Epub 2019 Aug 28.

Mater Research, University of Queensland, Brisbane, QLD, Australia.

Purpose: Understanding the immunobiology of the 15% to 30% of patients with follicular lymphoma (FL) who experience progression of disease within 24 months (POD24) remains a priority. Solid tumors with low levels of intratumoral immune infiltration have inferior outcomes. It is unknown whether a similar relationship exists between POD24 in FL.

Patients And Methods: Digital gene expression using a custom code set-five immune effector, six immune checkpoint, one macrophage molecules-was applied to a discovery cohort of patients with early- and advanced-stage FL (n = 132). T-cell receptor repertoire analysis, flow cytometry, multispectral immunofluorescence, and next-generation sequencing were performed. The immune infiltration profile was validated in two independent cohorts of patients with advanced-stage FL requiring systemic treatment (n = 138, rituximab plus cyclophosphamide, vincristine, prednisone; n = 45, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), with the latter selected to permit comparison of patients experiencing a POD24 event with those having no progression at 5 years or more.

Results: Immune molecules showed distinct clustering, characterized by either high or low expression regardless of categorization as an immune effector, immune checkpoint, or macrophage molecule. Low programmed death-ligand 2 (PD-L2) was the most sensitive/specific marker to segregate patients with adverse outcomes; therefore, PD-L2 expression was chosen to distinguish immune infiltration (ie, high PD-L2) FL biopsies from immune infiltration (ie, low PD-L2) tumors. Immune infiltration tissues were highly infiltrated with macrophages and expanded populations of T-cell clones. Of note, the immune infiltration subset of patients with FL was enriched for POD24 events (odds ratio [OR], 4.32; c-statistic, 0.81; = .001), validated in the independent cohorts (rituximab plus cyclophosphamide, vincristine, prednisone: OR, 2.95; c-statistic, 0.75; = .011; and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone: OR, 7.09; c-statistic, 0.88; = .011). Mutations were equally proportioned across tissues, which indicated that degree of immune infiltration is capturing aspects of FL biology distinct from its mutational profile.

Conclusion: Assessment of immune-infiltration by PD-L2 expression is a promising tool with which to help identify patients who are at risk for POD24.
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http://dx.doi.org/10.1200/JCO.18.02365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881104PMC
December 2019

The tumour microenvironment is immuno-tolerogenic and a principal determinant of patient outcome in EBV-positive diffuse large B-cell lymphoma.

Eur J Haematol 2019 Sep 24;103(3):200-207. Epub 2019 Jul 24.

Mater Research, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia.

Objective: Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV DLBCL) is a recently identified entity. Data regarding outcome to frontline immuno-chemotherapy are conflicting. Although the prognostic impact of the tumour microenvironment (TME) in EBV DLBCL is well-established, it remains untested whether the TME influences survival in EBV DLBCL. There are no data with new digital gene expression technologies that simultaneously interrogate the virus, B cells and the tumour microenvironment (TME).

Methods: We used the NanoString™ platform in a population-based cohort of 433 patients to establish if the technology could detect EBV in the tumour biopsies and to investigate the influence that EBV has on the complex tumour microenvironment of DLBCL.

Results: Incidence of EBV DLBCL was 6.9% with 5-year survival of 65% vs 82% in EBV DLBCL (P = 0.018). EBV tissues had similar expression of T-cell genes compared to EBV DLBCL but higher levels of the antigen-presenting molecule B2M. This was countered by elevated PD-L1, PD-L2, LAG3 and TIM3 immune checkpoints and a higher CD163/CD68 "M2" macrophage score.

Conclusion: In EBV DLBCL, the TME is immuno-tolerogenic and may explain the poor outcomes seen in this subtype of DLBCL.
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http://dx.doi.org/10.1111/ejh.13274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899834PMC
September 2019

Biology and therapy of primary mediastinal B-cell lymphoma: current status and future directions.

Br J Haematol 2019 04 10;185(1):25-41. Epub 2019 Feb 10.

Blood Cancer Research Group, Mater Research, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.

Primary mediastinal B-cell lymphoma (PMBCL) is a distinct disease closely related to classical nodular sclerosing Hodgkin lymphoma. Conventional diagnostic paradigms utilising clinical, morphological and immunophenotypical features can be challenging due to overlapping features with other B-cell lymphomas. Reliable diagnostic and prognostic biomarkers that are applicable to the conventional diagnostic laboratory are largely lacking. Nuclear factor kappa B (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signalling pathways are characteristically dysregulated in PMBCL and implicated in several aspects of disease pathogenesis, and the latter pathway in host immune evasion. The tumour microenvironment is manipulated by PMBCL tumours to avoid T-cell mediated destruction via strategies that include loss of tumour cell antigenicity, T-cell exhaustion and activation of suppressive T-regulatory cells. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) and DA-EPOCH-R (dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab) are the most common first-line immunochemotherapy regimens. End of treatment positron emission tomography scans are the recommended imaging modality and are being evaluated to stratify patients for radiotherapy. Relapsed/refractory disease has a relatively poor outcome despite salvage immunochemotherapy and subsequent autologous stem cell transplantation. Novel therapies are therefore being developed for treatment-resistant disease, targeting aberrant cellular signalling and immune evasion.
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http://dx.doi.org/10.1111/bjh.15778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594147PMC
April 2019

Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation.

Blood 2018 05 21;131(18):2036-2046. Epub 2018 Feb 21.

Department of Lymphoid Cancer Research, British Columbia Cancer Agency, Vancouver, Canada.

Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic mutations in 15 of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8, leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain of function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.
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http://dx.doi.org/10.1182/blood-2017-09-808907DOI Listing
May 2018

Correction for Massari et al., meningococcal porin PorB prevents cellular apoptosis in a Toll-like receptor 2- and NF-κB-independent manner.

Infect Immun 2015 Aug;83(8):3339

Evans BioMedical Research Center, Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118.

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http://dx.doi.org/10.1128/IAI.00627-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496629PMC
August 2015

Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma.

Nat Genet 2014 Apr 16;46(4):329-35. Epub 2014 Feb 16.

1] Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada. [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Classical Hodgkin lymphoma and primary mediastinal B cell lymphoma (PMBCL) are related lymphomas sharing pathological, molecular and clinical characteristics. Here we discovered by whole-genome and whole-transcriptome sequencing recurrent somatic coding-sequence mutations in the PTPN1 gene. Mutations were found in 6 of 30 (20%) Hodgkin lymphoma cases, in 6 of 9 (67%) Hodgkin lymphoma-derived cell lines, in 17 of 77 (22%) PMBCL cases and in 1 of 3 (33%) PMBCL-derived cell lines, consisting of nonsense, missense and frameshift mutations. We demonstrate that PTPN1 mutations lead to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Moreover, silencing of PTPN1 by RNA interference in Hodgkin lymphoma cell line KM-H2 resulted in hyperphosphorylation and overexpression of downstream oncogenic targets. Our data establish PTPN1 mutations as new drivers in lymphomagenesis.
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http://dx.doi.org/10.1038/ng.2900DOI Listing
April 2014

Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma.

Blood 2014 Mar 4;123(13):2062-5. Epub 2014 Feb 4.

Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada; and.

The pathogenesis of primary mediastinal large B-cell lymphoma (PMBCL) is incompletely understood. Recently, specific genotypic and phenotypic features have been linked to tumor cell immune escape mechanisms in PMBCL. We studied 571 B-cell lymphomas with a focus on PMBCL. Using fluorescence in situ hybridization here, we report that the programmed death ligand (PDL) locus (9p24.1) is frequently and specifically rearranged in PMBCL (20%) as compared with diffuse large B-cell lymphoma, follicular lymphoma, and Hodgkin lymphoma. Rearrangement was significantly correlated with overexpression of PDL transcripts. Utilizing high-throughput sequencing techniques, we characterized novel translocations and chimeric fusion transcripts involving PDLs at base-pair resolution. Our data suggest that recurrent genomic rearrangement events underlie an immune privilege phenotype in a subset of B-cell lymphomas.
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http://dx.doi.org/10.1182/blood-2013-10-535443DOI Listing
March 2014

Elevated circulating tissue factor procoagulant activity, factor VII, and plasminogen activator inhibitor-1 in childhood obesity: evidence of a procoagulant state.

Br J Haematol 2012 Aug 21;158(4):523-7. Epub 2012 May 21.

Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.

Childhood obesity is rapidly increasing in prevalence. We compared circulating membrane-bound tissue factor (FIII, F3) procoagulant activity (TF-PCA) and plasma markers of coagulation, fibrinolysis and endothelial dysfunction in 21 obese (10·1 ± 1·5 years, mean ± standard deviation) and 22 healthy weight children (9·9 ± 1·6 years), classified by Body Mass Index (BMI). TF-PCA and factor VII coagulant activity (FVII:C), plasminogen activator inhibitor (PAI-1, SERPINE1) and soluble vascular cell adhesion molecule 1 (sVCAM1) were higher in obese children. BMI correlated positively with TF-PCA, FVII:C, and PAI-1. Childhood obesity is associated with a procoagulant state and endothelial dysfunction. Studies are needed to assess whether weight reduction reverses these abnormalities.
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http://dx.doi.org/10.1111/j.1365-2141.2012.09160.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406232PMC
August 2012

Whole-blood tissue factor procoagulant activity is elevated in type 1 diabetes: effects of hyperglycemia and hyperinsulinemia.

Diabetes Care 2012 Jun 12;35(6):1322-7. Epub 2012 Mar 12.

Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.

Objective: To determine tissue factor procoagulant activity (TF-PCA) in patients with type 1 diabetes and to examine effects of hyperglycemia and hyperglycemia plus hyperinsulinemia on TF-PCA.

Research Design And Methods: We have determined circulating TF-PCA and other coagulation factors under basal (hyperglycemic) conditions, after acute correction of hyperglycemia, in response to 24 h of selective hyperglycemia, and in response to 24 h of hyperglycemia plus hyperinsulinemia in nine type 1 diabetic patients and in seven nondiabetic control subjects.

Results: As shown previously in patients with type 2 diabetes, basal TF-PCA and plasma coagulation factor VIIa (FVIIa) were higher in patients with type 1 diabetes than in nondiabetic control subjects. However, in contrast with type 2 diabetes, normalizing glucose did not decrease the elevated TF-PCA levels, and raising glucose or glucose plus insulin levels did not increase TF-PCA.

Conclusions: Patients with type 1 diabetes have elevated circulating TF-PCA and FVIIa levels and are in a procoagulant state that may predispose them to acute cardiovascular events. The mechanisms regulating TF-PCA in patients with type 1 and type 2 diabetes are different and should be further explored.
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http://dx.doi.org/10.2337/dc11-2114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357241PMC
June 2012

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma.

Blood 2012 Mar 30;119(9):1963-71. Epub 2011 Dec 30.

Centre for Lymphoid Cancer, British Columbia Cancer Agency, 675 W.10th Ave.,Vancouver, BC, Canada.

Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.
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http://dx.doi.org/10.1182/blood-2011-11-391474DOI Listing
March 2012

Meningococcal porin PorB prevents cellular apoptosis in a toll-like receptor 2- and NF-kappaB-independent manner.

Infect Immun 2010 Mar 22;78(3):994-1003. Epub 2009 Dec 22.

Evans BioMedical Research Center, Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Rm. 635, 650 Albany Street, Boston, MA 02118, USA.

Meningococcal porin PorB is an inhibitor of apoptosis induced via the intrinsic pathway in various cell types. This effect is attributed to prevention of mitochondrial depolarization and of subsequent release of proapoptotic mitochondrial factors. To determine whether apoptosis is globally inhibited by PorB, we compared the intrinsic and extrinsic pathways in HeLa cells. Interestingly, PorB does not prevent extrinsic apoptosis induced by tumor necrosis factor alpha plus cycloheximide, suggesting a unique mitochondrial pathway specificity. Several intracellular factors regulated by NF-kappaB, including members of the Bcl-2 family and of the inhibitor of apoptosis (IAP) family, play major roles in controlling apoptosis, and some of them are thought to contribute to the antiapoptotic effect of the gonococcal porin, PIB. However, most of the members of the Bcl-2 family and the IAP family are not induced by meningococcal PorB in HeLa cells, with the exception of Bfl-1/A1. Interestingly, PorB does not induce NF-kappaB activation in HeLa cells, likely due to a lack of Toll-like receptor 2 (TLR2) expression in these cells. Bfl-1/A1 expression is also regulated by CBF1, a nuclear component of the Notch signaling pathway, independent of NF-kappaB activation. Since HeLa cells are protected by PorB from intrinsic apoptosis events, regardless of TLR2 and NF-kappaB expression, the possibility of a contribution of alternative signaling pathways to this effect cannot be excluded. In this paper, we describe an initial dissection of the cascade of cellular events involved in the antiapoptotic effect of PorB in the absence of TLR2.
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http://dx.doi.org/10.1128/IAI.00156-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2825956PMC
March 2010

Meningococcal porin PorB binds to TLR2 and requires TLR1 for signaling.

J Immunol 2006 Feb;176(4):2373-80

Evans BioMedical Research Center, Division of Infectious Diseases, Department of Medicine, Boston University School of Medicine, MA 02118, USA.

TLR2 plays a key role in the initiation of the cellular innate immune responses by a wide range of bacterial products. TLRs signaling, including TLR2 and its coreceptors TLR1 and TLR6, is mediated by a number of specific ligands. Although many of the TLR-mediated cell signaling pathways have been elucidated in the past few years, the molecular mechanisms that lead to cell activation are still poorly understood. In this study, we investigate the interaction of PorB from Neisseria meningitidis with TLR2 and describe the direct binding of a bacterial protein to TLR2 for the first time. Using labeled PorB, we demonstrate its binding to TLR2 both in its soluble form in vitro, and when it is over-expressed on the surface of human embryonic kidney 293 cells. We also show that TLR2-mediated binding of PorB is directly related to cellular activation. In addition, using 293 cells expressing the chimeric TLR2/TLR1 and TLR2/TLR6 complexes, we report the selectivity of PorB binding to the TLR2/TLR1 heterodimer, which is required for initiating signaling in transfected 293 cells and in murine B cells. Together, these data provide new evidence that TLR2 recognizes PorB through direct binding, and that PorB-induced cell activation is mediated by a TLR2/TLR1 complex.
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http://dx.doi.org/10.4049/jimmunol.176.4.2373DOI Listing
February 2006