The Division of Infectious Diseases has numerous specialized laboratories. Doctors and laboratory personnel conduct research in infectious diseases such as those due to HIV, Streptococcus pneumoniae, Neisseria meningitidis, hemorrhagic E. coli 0157:H7, Salmonella and bacteria resistant to multiple antibiotics (e.g. Klebsiella and Pseudomonas). In September 2002, a newly renovated BSL-3 (Bio-safety Level 3) laboratory became part of the Division.
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Harrison Laboratory The mission of our Public Heath Infectious Disease Laboratory (PHIDL), a component of the Infectious Diseases Epidemiology Research Unit, is to conduct molecular epidemiologic research and to provide laboratory services and expertise in molecular epidemiology. The two main focus areas of the laboratory are nosocomial infections and diseases caused by community-acquired bacterial pathogens. Ongoing PHIDL projects include studies of 1) the transmission of vancomycin-resistant Enterococcus, Pseudomonas aeruginosa, and Clostridium difficile within hospitals; 2) the molecular clones of Neisseria meningitidis causing invasive disease; 3) community transmission of drug resistant Streptococcus pneumoniae; 4) novel molecular subtyping methods for Escherichia coli 0157:H7, Salmonella, and C. difficile; and characterization of integrons in strains of multi-drug resistant Salmonella enterica. The main methods used in the laboratory include pulsed field gel electrophoresis (PFGE), restriction endonuclease analysis (REA), multi-locus sequence typing (MLST), and multiple-locus variable number tandem repeat analysis (MLVA). In addition, PHIDL provides training in molecular epidemiology to masters and doctoral students, infectious diseases fellows, and visiting international scientists. To visit Dr. Harrison's biography page, please click here. Laboratory personnel descriptions are included below.
Mellors Laboratory The goal of our research is to improve the treatment and outcome of patients with HIV-1 infection. This includes the design and evaluation of new antiretroviral compounds, both in vitro and in clinical trials, and basic studies to determine the genetic, biochemical and structural mechanisms of antiretroviral drug resistance. HIV-1 drug resistance is a major obstacle to effective long-term treatment of patients with HIV-1 infection. Drug resistance has developed to most antiretrovirals and is largely responsible for treatment failure, clinical disease progression and death despite treatment. Effective strategies are urgently needed to prevent the emergence of drug-resistant HIV and to treat patients in whom drug-resistant virus is present. Laboratory personnel detect and characterize HIV-1 variants that are resistant to new or existing antiretrovirals. Resistant viral variants are either selected in cell culture or identified in samples from treated patients and characterized in terms of biological properties (replication fitness), cross-resistance to other antiretroviral drugs classes, and the genetic, biochemical changes and structural changes in HIV-1 reverse transcriptase (RT), protease or integrase that are responsible for drug resistance. This line of research elucidates the mechanisms of drug action and drug resistance, identifies alternative drug therapies for resistant virus, and helps devise strategies to prevent the development of drug resistance. Other interests of this laboratory include HIV-1 viral load as a prognostic marker and identifying mechanisms of antiretroviral treatment failure other than drug resistance. To visit Dr. Mellors' biography page, please click here. Laboratory personnel descriptions are included below.
Paterson Laboratory Our research focuses on the mechanisms of resistance and molecular epidemiology of bacteria resistant to multiple antibiotics. This research is intrinsically linked to clinical epidemiologic studies on antibiotic resistance. Traditionally, epidemiologic studies have sought risk factors for infections with antibiotic resistant organisms. However, such an approach neglects the potential clonality of resistant organisms or the fact that resistance to an antibiotic may be mediated by different mechanisms in different patients. Therefore, organisms collected during clinical studies are subjected in our laboratory to pulsed field gel electrophoresis (PFGE) and investigation into the mechanisms of antibiotic resistance. Recent examples include investigation of ertapenem resistance in Klebsiella pneumoniae. Investigations have included antibiotic susceptibility testing, pulsed field gel electrophoresis, examination of outer membrane proteins, PCR for detection of ESBLs and AmpC enzymes and plasmid analysis. This has complemented our assessment of clinical risk factors for ertapenem resistance. The laboratory has recently recruited a pharmacist with experience in pharmacodynamic assessment of antimicrobials. This will lead the way to expansion of our work into the relationships between pharmacodynamic parameters and development of antibiotic resistance. To visit Dr. Paterson's biography page, please click here. Laboratory personnel descriptions are included below.
Sluis-Cremer Laboratory Our research focuses on: Nonnucleoside reverse transcriptase inhibitor (NNRTI) induced conformational changes in HIV-1 reverse transcriptase (RT). Recent studies have shown that NNRTI can modulate the inter-subunit interactions between the 66kDa and 51kDa polypeptides of RT. The molecular mechanisms by which this occurs, and the impact that this has on RT enzyme functioning is not known. In light of this, the specific aims of this project are to: (1) determine the mechanisms by which NNRTI modulate the inter-subunit interactions and intra-subunit conformational changes of HIV-1 RT; and (2) define the molecular interactions in the HIV-1 RT dimer interface and to evaluate the consequences of altering the intrinsic dimeric stability on enzymatic activity. HIV-1 RT dimerization as an antiviral target. HIV-1 reverse transcriptase is a heterodimeric enzyme consisting of a 66-kDa subunit (p66) and a p66-derived 51-kDa subunit (p51). The DNA polymerase and ribonuclease H (RNase H) activities of the enzyme are entirely dependent on the heterodimeric structure of the enzyme, suggesting that inhibition of the subunit-subunit assembly of RT provides an alternative target for HIV-1 inhibition. The specific aims of this project are: (1) to develop, optimize and validate an HTS assay for RT dimerization; and (2) to screen chemical libraries to identify compounds that inhibit RT dimerization. Molecular mechanisms of HIV-1 RT resistance to nucleoside reverse transcriptase inhibitors (NRTI): Although NRTI therapy is initially quite effective in reducing the viral load in HIV-1 infected individuals, the viral burden inevitably rebounds despite continued therapy, due to the appearance of drug-resistant strains of HIV. The primary objectives of this project are to understand the molecular (phenotypic) mechanisms by which drug-resistant HIV-1 RT provides resistance to NRTI such as 3?-azido-3?deoxythymidine (AZT) by utilizing appropriate in vitro biochemical models and molecular modeling. To visit Dr. Sluis-Cremer's biography page, please click here. Laboratory personnel descriptions are included below.
Special Pathogens Laboratory The Special Pathogens Laboratory is located in the VA Medical Center, and is under the direction of Janet E. Stout, Ph.D. The primary focus of the research performed in this laboratory is the clinical and environmental microbiology of Legionella spp. and the epidemiology of Legionnaires' disease. Clinical studies are performed to evaluate new methods for the diagnosis and treatment of Legionnaires' disease. Environmental studies include evaluation of new methods for controlling Legionella in water systems, and the study of Legionella in a model water system. Molecular epidemiology studies are performed to identify community and hospital sources of this infection. Our goal is to prevent future disease through awareness and proactive monitoring. To visit Dr. Stout's biography page, please click here. Laboratory personnel descriptions are included below.
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