Volker Briken

University of Maryland, College Park, Maryland, United States

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Publications (44)318.3 Total impact

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    ABSTRACT: The synthesis of acyclic cucurbit[n]uril dendrimers G1-G3 that bear four dendrons on their aromatic sidewalls via thiolate SN2 chemistry is reported. G1-G3 are polycationic and can bind to pEGFP plasmid DNA as shown by dynamic light scattering (DLS), gel electrophoresis, and scanning electron microscopy (SEM). The gene delivery ability of G1-G3 is presented.
    Organic Letters 11/2015; DOI:10.1021/acs.orglett.5b03145 · 6.36 Impact Factor
  • Swati Shah · Joe R Cannon · Catherine Fenselau · Volker Briken ·
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    ABSTRACT: The ESX-5 secretion system of Mycobacterium tuberculosis (Mtb) is important for bacterial virulence and the secretion of the large PE/PPE protein family that constitutes 10% of the Mtb genome. A four-gene region of ESX-5 is duplicated three times in the Mtb genome but the function of these duplicates is unknown. Here we investigated one of these duplicates, the esxI, esxJ, ppe15 and pe8 (ESX-5a) region. ESX-5a deletion mutant in the model system, M. marinum (Mm) background was deficient in the secretion of some members of the PE/PPE family of proteins. Surprisingly, we also identified other proteins that are not members this family, thus expanding the range ESX-5 secretion substrates. In addition, we demonstrate that ESX-5a is important for virulence of Mm in the zebrafish model. Furthermore, we show the role of the Mtb ESX-5a region in inflammasome activation but not in host cell death induction, which is different from the Mtb ESX-5 system. In conclusion, the ESX-5a region is non-redundant with its ESX-5 paralog and is necessary for secretion of a specific subset of proteins in Mtb and Mm that are important for bacterial virulence of Mm. Our findings point to a role for the three ESX-5 duplicate regions in the selection of substrates for secretion via ESX-5 and hence they provide the basis for a refined model of the molecular mechanism of this type VII secretion system. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Infection and immunity 08/2015; DOI:10.1128/IAI.00827-15 · 3.73 Impact Factor
  • Lalitha Srinivasan · Sarah Ahlbrand · Volker Briken ·
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    ABSTRACT: Mycobacterium tuberculosis (Mtb) has coevolved with humans for tens of thousands of years. It is thus highly adapted to its human host and has evolved multiple mechanisms to manipulate host immune responses to its advantage. One central host pathogen interaction modality is host cell death pathways. Host cell apoptosis is associated with a protective response to Mtb infection, whereas a necrotic response favors the pathogen. Consistently, Mtb inhibits host cell apoptosis signaling but promotes induction of programmed necrosis. The molecular mechanisms involved in Mtb-mediated host cell death manipulation, the consequences for host immunity, and the potential for therapeutic and preventive approaches will be discussed.
    Cold Spring Harbor Perspectives in Medicine 06/2014; 4(8). DOI:10.1101/cshperspect.a022459 · 9.47 Impact Factor
  • Liping Cao · Gaya Hettiarachchi · Volker Briken · Lyle Isaacs ·
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    ABSTRACT: Stay on target: The cucurbit[7]uril derivative 1, which bears a covalently attached biotin targeting ligand allows for the efficient delivery of oxaliplatin as its 1⋅oxaliplatin complex to cancer cells resulting in enhanced cytotoxicity relative to oxaliplatin alone.
    Angewandte Chemie International Edition 11/2013; 52(46). DOI:10.1002/anie.201305061 · 11.26 Impact Factor
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    Volker Briken · Sarah E Ahlbrand · Swati Shah ·
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    ABSTRACT: The production of IL-1β during the infection with Mycobacterium tuberculosis (Mtb) is important for successful host immune defense. In macrophages and dendritic cells the host cell inflammasome is crucial for generation of secreted IL-1β in response to Mtb infections. In these cell types Mtb infection only activates the NLRP3-inflammasome. New reports demonstrate that nitric oxide has an important function in the negative regulation of the NLRP3-inflammasome to reduce tissue damage during Mtb infections. The type I interferon, IFN-β, is induced after Mtb infections and can also suppress NLRP3-inflammasome activation. In contrast, IFN-β increases activity of the AIM2-inflammasome after infection with intracellular pathogens such as Francisella tularensis and Listeria monocytogenes. Recent results demonstrate that non-tuberculous mycobacteria but not virulent Mtb induce the AIM2-inflammasome in an IFN-β dependent matter. Indeed, Mtb inhibits AIM2-inflammasome activation via its ESX-1 secretion system. This novel immune evasion mechanism may help Mtb to allow the induction of low levels of IFN-β to suppress the NLRP3-inflammasome without activating the AIM2-inflammasome.
    Frontiers in Cellular and Infection Microbiology 10/2013; 3:62. DOI:10.3389/fcimb.2013.00062 · 3.72 Impact Factor
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    ABSTRACT: Mycobacterium tuberculosis extracellular DNA gains access to the host cell cytosol via the ESX-1 secretion system. It is puzzling that this extracellular DNA of M. tuberculosis does not induce activation of the absent in melanoma 2 (AIM2) inflammasome because AIM2 recognizes cytosolic DNA. In this study, we show that nonvirulent mycobacteria such as Mycobacterium smegmatis induce AIM2 inflammasome activation, which is dependent on their strong induction of IFN-β production. In contrast, M. tuberculosis, but not an ESX-1-deficient mutant, inhibits the AIM2 inflammasome activation induced by either M. smegmatis or transfected dsDNA. The inhibition does not involve changes in host cell AIM2 mRNA or protein levels but led to decreased activation of caspase-1. We furthermore demonstrate that M. tuberculosis inhibits IFN-β production and signaling, which was partially responsible for the inhibition of AIM2 activation. In conclusion, we report a novel immune evasion mechanism of M. tuberculosis that involves the ESX-1-dependent, direct or indirect, suppression of the host cell AIM2 inflammasome activation during infection.
    The Journal of Immunology 08/2013; 191(7). DOI:10.4049/jimmunol.1301331 · 4.92 Impact Factor
  • Gaya Hettiarachchi · Da Ma · Duc Nguyen · Lyle Isaacs · Volker Briken ·

    Cancer Research 08/2013; 73(8 Supplement):4347-4347. DOI:10.1158/1538-7445.AM2013-4347 · 9.33 Impact Factor
  • Volker Briken ·
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    ABSTRACT: The topic of host cell death response upon Mycobacterium tuberculosis (Mtb) infection has been a controversial one [1]. Recent findings demonstrate that one of the important confounding factors was most likely the fact that while Mtb inhibits host cell apoptosis induction early during the infection it clearly induces a necrotic form of cell death during later infection stages [2, 3]. This bi-phasic intracellular lifestyle in regard to host cell death manipulation is emerging as a common theme shared with other facultative and obligate intracellular bacterial pathogens such as Chlamydia and Legionella [4-6]. Accordingly, the list of discovered bacterial proteins involved in host cell apoptosis inhibition is growing [7, 8]. At the same time it is clearly beneficial for the resistance of the host to overcome the bacterial apoptosis block during the early stage of the infection [9-11]. Hence, host cell components have evolved to recognize intracellular pathogens and mediate host cell apoptosis induction if necessary [12]. There have been several reviews on the various aspects of the host cell death response upon Mtb infection [1, 3, 13-15]. Thus in this chapter I will focus on the pathogen side of the equation and describe the tremendous progress that has been made in the identification and characterization of Mtb genes involved in manipulation of host cell death pathways.
    Advances in Experimental Medicine and Biology 03/2013; 783:93-102. DOI:10.1007/978-1-4614-6111-1_5 · 1.96 Impact Factor
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    Volker Briken ·
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    ABSTRACT: The uptake of apoptotic cells by phagocytes is defined as efferocytosis. In this issue of Cell Host & Microbe, Martin et al. (2012) and Yang et al. (2012) report that macrophage- and neutrophil-mediated efferocytosis of apoptotic cells containing mycobacteria is an innate antibacterial effector mechanism.
    Cell host & microbe 09/2012; 12(3):261-3. DOI:10.1016/j.chom.2012.08.008 · 12.33 Impact Factor
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    ABSTRACT: Interleukin-1β (IL-1β) is important for host resistance against Mycobacterium tuberculosis (Mtb) infections. The response of the dendritic cell inflammasome during Mtb infections has not been investigated in detail. Here we show that Mtb infection of bone marrow-derived dendritic cells (BMDCs) induces IL-1β secretion and that this induction is dependent upon the presence of functional ASC and NLRP3 but not NLRC4 or NOD2. The analysis of cell death induction in BMDCs derived from these knock-out mice revealed the important induction of host cell apoptosis but not necrosis, pyroptosis or pyronecrosis. Furthermore, NLRP3 inflammasome activation and apoptosis induction were both reduced in BMDCs infected with the esxA deletion mutant of Mtb demonstrating the importance of a functional ESX-1 secretion system. Surprisingly, caspase-1/11-deficient BMDCs still secreted residual levels of IL-1βand IL-18 upon Mtb infection which was abolished in cells infected with the esxA Mtb mutant. Altogether we demonstrate the partially caspase-1/11-independent, but NLRP3- and ASC-dependent IL-1β secretion in Mtb-infected BMDCs. These findings point towards a potential role of DCs in the host innate immune response to mycobacterial infections via their capacity to induce IL-1β and IL-18 secretion.
    PLoS ONE 07/2012; 7(7):e40722. DOI:10.1371/journal.pone.0040722 · 3.23 Impact Factor
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    ABSTRACT: The solubility characteristics of 40-70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents-acyclic cucurbituril-type containers-which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container-drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery.
    Nature Chemistry 04/2012; 4(6):503-10. DOI:10.1038/nchem.1326 · 25.33 Impact Factor
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    Robert Blomgran · Ludovic Desvignes · Volker Briken · Joel D Ernst ·
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    ABSTRACT: Mycobacterium tuberculosis promotes its replication by inhibiting the apoptosis of infected macrophages. A proapoptotic M. tuberculosis mutant lacking nuoG, a subunit of the type I NADH dehydrogenase complex, exhibits attenuated growth in vivo, indicating that this virulence mechanism is essential. We show that M. tuberculosis also suppresses neutrophil apoptosis. Compared to wild-type, the nuoG mutant spread to a larger number of lung phagocytic cells. Consistent with the shorter lifespan of infected neutrophils, infection with the nuoG mutant resulted in fewer bacteria per infected neutrophil, accelerated bacterial acquisition by dendritic cells, earlier trafficking of these dendritic cells to lymph nodes, and faster CD4 T cell priming. Neutrophil depletion abrogated accelerated CD4 T cell priming by the nuoG mutant, suggesting that inhibiting neutrophil apoptosis delays adaptive immunity in tuberculosis. Thus, pathogen modulation of apoptosis is beneficial at multiple levels, and enhancing phagocyte apoptosis promotes CD4 as well as CD8 T cell responses.
    Cell host & microbe 01/2012; 11(1):81-90. DOI:10.1016/j.chom.2011.11.012 · 12.33 Impact Factor
  • Volker Briken · David M Mosser ·

    Journal of leukocyte biology 11/2011; 90(5):839-41. DOI:10.1189/jlb.0411203 · 4.29 Impact Factor
  • Gaya Hettiarachchi · Da Ma · Duc Nguyen · Lyle Isaacs · Volker Briken ·

    Cancer Research 07/2011; 71(8 Supplement):4429-4429. DOI:10.1158/1538-7445.AM2011-4429 · 9.33 Impact Factor
  • Gaya Hettiarachchi · Duc Nguyen · Jing Wu · Derick Lucas · Da Ma · Lyle Isaacs · Volker Briken ·

    Cancer Research 01/2011; 70(8 Supplement):5528-5528. DOI:10.1158/1538-7445.AM10-5528 · 9.33 Impact Factor
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    ABSTRACT: This essay describes how the use of a concept inventory has enhanced professional development and curriculum reform efforts of a faculty teaching community. The Host Pathogen Interactions (HPI) teaching team is composed of research and teaching faculty with expertise in HPI who share the goal of improving the learning experience of students in nine linked undergraduate microbiology courses. To support evidence-based curriculum reform, we administered our HPI Concept Inventory as a pre- and postsurvey to approximately 400 students each year since 2006. The resulting data include student scores as well as their open-ended explanations for distractor choices. The data have enabled us to address curriculum reform goals of 1) reconciling student learning with our expectations, 2) correlating student learning with background variables, 3) understanding student learning across institutions, 4) measuring the effect of teaching techniques on student learning, and 5) demonstrating how our courses collectively form a learning progression. The analysis of the concept inventory data has anchored and deepened the team's discussions of student learning. Reading and discussing students' responses revealed the gap between our understanding and the students' understanding. We provide evidence to support the concept inventory as a tool for assessing student understanding of HPI concepts and faculty development.
    CBE life sciences education 12/2010; 9(4):408-16. DOI:10.1187/cbe.10-05-0069 · 1.89 Impact Factor
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    ABSTRACT: The HIV pandemic raised the potential for facultative-pathogenic mycobacterial species like, Mycobacterium kansasii, to cause disseminating disease in humans with immune deficiencies. In contrast, non-pathogenic mycobacterial species, like M. smegmatis, are not known to cause disseminating disease even in immunocompromised individuals. We hypothesized that this difference in phenotype could be explained by the strong induction of an innate immune response by the non-pathogenic mycobacterial species. A comparison of two rapid-growing, non-pathogenic species (M. smegmatis and M. fortuitum) with two facultative-pathogenic species (M. kansasii and M. bovis BCG) demonstrated that only the non-pathogenic bacteria induced strong apoptosis in human THP-1 cells and murine bone marrow-derived macrophages (BMDM) and dendritic cells (BMDD). The phospho-myo-inositol modification of lipoarabinomannan (PI-LAM) isolated from non-pathogenic species may be one of the cell wall components responsible for the pro-inflammatory activity of the whole bacteria. Indeed, PI-LAM induces high levels of apoptosis and IL-12 expression compared to the mannosyl modification of LAM isolated from facultative-pathogenic mycobacteria. The apoptosis induced by non-pathogenic M. smegmatis was dependent upon caspase-3 activation and TNF secretion. Consistently, BALB/c BMDM responded by secreting large amounts of TNF upon infection with non-pathogenic but not facultative-pathogenic mycobacteria. Interestingly, C57Bl/6 BMDM do not undergo apoptosis upon infection with non-pathogenic mycobacteria despite the fact that they still induce an increase in TNF secretion. This suggests that the host cell signaling pathways are different between these two mouse genotypes and that TNF is necessary but not sufficient to induce host cell apoptosis. These results demonstrate a much stronger induction of the innate immune response by non-pathogenic versus facultative-pathogenic mycobacteria as measured by host cell apoptosis, IL-12 and TNF cytokine induction. These observations lend support to the hypothesis that the strong induction of the innate immune response is a major reason for the lack of pathogenicity in fast-growing mycobacteria.
    BMC Microbiology 09/2010; 10(1):237. DOI:10.1186/1471-2180-10-237 · 2.73 Impact Factor
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    Gaya Hettiarachchi · Duc Nguyen · Jing Wu · Derick Lucas · Da Ma · Lyle Isaacs · Volker Briken ·
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    ABSTRACT: Many drug delivery systems are based on the ability of certain macrocyclic compounds - such as cyclodextrins (CDs) - to act as molecular containers for pharmaceutical agents in water. Indeed beta-CD and its derivatives have been widely used in the formulation of hydrophobic pharmaceuticals despite their poor abilities to act as a molecular container (e.g., weak binding (K(a)<10(4) M(-1)) and their challenges toward chemical functionalization. Cucurbit[n]urils (CB[n]) are a class of molecular containers that bind to a variety of cationic and neutral species with high affinity (K(a)>10(4) M(-1)) and therefore show great promise as a drug delivery system. In this study we investigated the toxicology, uptake, and bioactivity of two cucurbit[n]urils (CB[5] and CB[7]) and three CB[n]-type containers (Pentamer 1, methyl hexamer 2, and phenyl hexamer 3). All five containers demonstrated high cell tolerance at concentrations of up to 1 mM in cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the CB[7] molecular container was efficiently internalized by macrophages indicating their potential for the intracellular delivery of drugs. Bioactivity assays showed that the first-line tuberculosis drug, ethambutol, was as efficient in treating mycobacteria infected macrophages when loaded into CB[7] as when given in the unbound form. This result suggests that CB[7]-bound drug molecules can be released from the container to find their intracellular target. Our study reveals very low toxicity of five members of the cucurbit[n]uril family of nanocontainers. It demonstrates the uptake of containers by cells and intracellular release of container-loaded drugs. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.
    PLoS ONE 05/2010; 5(5):e10514. DOI:10.1371/journal.pone.0010514 · 3.23 Impact Factor
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    ABSTRACT: The capacity of infected cells to undergo apoptosis upon insult with a pathogen is an ancient innate immune defense mechanism. Consequently, the ability of persisting, intracellular pathogens such as the human pathogen Mycobacterium tuberculosis (Mtb) to inhibit infection-induced apoptosis of macrophages is important for virulence. The nuoG gene of Mtb, which encodes the NuoG subunit of the type I NADH dehydrogenase, NDH-1, is important in Mtb-mediated inhibition of host macrophage apoptosis, but the molecular mechanism of this host pathogen interaction remains elusive. Here we show that the apoptogenic phenotype of MtbDeltanuoG was significantly reduced in human macrophages treated with caspase-3 and -8 inhibitors, TNF-alpha-neutralizing antibodies, and also after infection of murine TNF(-/-) macrophages. Interestingly, incubation of macrophages with inhibitors of reactive oxygen species (ROS) reduced not only the apoptosis induced by the nuoG mutant, but also its capacity to increase macrophage TNF-alpha secretion. The MtbDeltanuoG phagosomes showed increased ROS levels compared to Mtb phagosomes in primary murine and human alveolar macrophages. The increase in MtbDeltanuoG induced ROS and apoptosis was abolished in NOX-2 deficient (gp91(-/-)) macrophages. These results suggest that Mtb, via a NuoG-dependent mechanism, can neutralize NOX2-derived ROS in order to inhibit TNF-alpha-mediated host cell apoptosis. Consistently, an Mtb mutant deficient in secreted catalase induced increases in phagosomal ROS and host cell apoptosis, both of which were dependent upon macrophage NOX-2 activity. In conclusion, these results serendipitously reveal a novel connection between NOX2 activity, phagosomal ROS, and TNF-alpha signaling during infection-induced apoptosis in macrophages. Furthermore, our study reveals a novel function of NOX2 activity in innate immunity beyond the initial respiratory burst, which is the sensing of persistent intracellular pathogens and subsequent induction of host cell apoptosis as a second line of defense.
    PLoS Pathogens 04/2010; 6(4):e1000864. DOI:10.1371/journal.ppat.1000864 · 7.56 Impact Factor
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    ABSTRACT: As a group of faculty with expertise and research programs in the area of host-pathogen interactions (HPI), we are concentrating on students' learning of HPI concepts. As such we developed a concept inventory to measure level of understanding relative to HPI after the completion of a set of microbiology courses (presently eight courses). Concept inventories have been useful tools for assessing student learning, and our interest was to develop such a tool to measure student learning progression in our microbiology courses. Our teaching goal was to create bridges between our courses which would eliminate excessive overlap in our offerings and support a model where concepts and ideas introduced in one course would become the foundation for concept development in successive courses. We developed our HPI concept inventory in several phases. The final product was an 18-question, multiple-choice concept inventory. In fall 2006 and spring 2007 we administered the 18-question concept inventory in six of our courses. We collected pre- and postcourse surveys from 477 students. We found that students taking pretests in the advanced courses retained the level of understanding gained in the general microbiology prerequisite course. Also, in two of our courses there was significant improvement on the scores from pretest to posttest. As we move forward, we will concentrate on exploring the range of HPI concepts addressed in each course and determine and/or create effective methods for meaningful student learning of HPI aspects of microbiology.
    12/2009; 10(1):43-50. DOI:10.1128/jmbe.v10.98

Publication Stats

2k Citations
318.30 Total Impact Points


  • 2007-2014
    • University of Maryland, College Park
      • Department of Cell Biology & Molecular Genetics
      Maryland, United States
  • 2008-2013
    • Loyola University Maryland
      • Department of Biology
      Baltimore, Maryland, United States
  • 2010
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
  • 2000-2006
    • Albert Einstein College of Medicine
      • Department of Microbiology & Immunology
      New York City, New York, United States
  • 1998-2002
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Institut de Génétique Moléculaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
  • 1997
    • Institut Curie
      Lutetia Parisorum, Île-de-France, France