A5048935070- Hepatitis C virus research
- Antibiotic Resistance in Bacteria
- Monoclonal and Polyclonal Antibodies Research
- Herpesvirus Infections and Treatments
- Cytomegalovirus and herpesvirus research
- Viral-associated cancers and disorders
- Galectins and Cancer Biology
- Glycosylation and Glycoproteins Research
- Hepatitis B Virus Studies
- Respiratory Support and Mechanisms
- Peptidase Inhibition and Analysis
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Protein purification and stability
- Bacterial Genetics and Biotechnology
- Cancer Mechanisms and Therapy
- Sepsis Diagnosis and Treatment
- Bacterial biofilms and quorum sensing
- Neuroinflammation and Neurodegeneration Mechanisms
- Genomics and Phylogenetic Studies
- Drug Transport and Resistance Mechanisms
- Immune cells in cancer
- Microbial Natural Products and Biosynthesis
- COVID-19 Clinical Research Studies
- Liver Disease Diagnosis and Treatment
Kaiser Permanente South San Francisco Medical Center
2014
Scripps Research Institute
2003-2006
Allergan (United States)
1991-2004
Washington University in St. Louis
1999-2003
The absence of a robust cell culture model hepatitis C virus (HCV) infection has severely limited analysis the HCV life cycle and development effective antivirals vaccines. Here we report establishment simple yet system based on JFH-1 molecular clone Huh-7-derived lines that allows production can be efficiently propagated in tissue culture. This provides powerful tool for host-virus interactions should facilitate discovery antiviral drugs vaccines this important human pathogen.
Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Our laboratory has previously demonstrated that high-level HCV replication during acute chimpanzees associated with the modulation multiple genes involved in lipid metabolism, drugs regulate cholesterol fatty acid biosynthesis subgenomic replicon Huh-7 cells. In this article, we demonstrate cells harboring replicating, full-length RNAs express elevated levels ATP citrate...
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, which can lead to the development cirrhosis and hepatocellular carcinoma. Current therapy patients with HCV includes treatment IFNα in combination ribavirin. Because most treated do not resolve infection, alternative essential. RNA interference (RNAi) recently discovered antiviral mechanism present plants animals that induces double-stranded degradation. Using selectable subgenomic replicon cell culture system, we...
Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC). HBV integration into the host genome has been reported, but its scale, impact and contribution to HCC development not clear. Here, we sequenced tumor nontumor genomes (>80× coverage) transcriptomes of four patients identified 255 sites. Increased sequencing 240× coverage revealed proportionally higher number Clonal expansion HBV-integrated hepatocytes was found specifically in samples. We observe...
In the past several years, a number of cellular proteins have been identified as candidate entry receptors for hepatitis C virus (HCV) by using surrogate models HCV infection. Among these, tetraspanin CD81 and scavenger receptor B type I (SR-BI), both which localize to specialized plasma membrane domains enriched in cholesterol, suggested be key players entry. current study, we used recently developed vitro infection system demonstrate that SR-BI are required authentic vitro, they function...
The recent development of a cell culture infection model for hepatitis C virus (HCV) permits the production infectious particles in vitro. In this report, we demonstrate that are present both within infected cells and supernatant. Kinetic analysis indicates intracellular constitute precursors secreted virus. Ultracentrifugation analyses indicate viral similar size (approximately 65 to 70 nm) but different buoyant density 1.15 1.20 g/ml) from extracellular 1.03 1.16 g/ml). These results HCV...
ABSTRACT While epidermal growth factor receptor (EGFR) has been shown to be important in the entry process for multiple viruses, including hepatitis C virus (HCV), molecular mechanisms by which EGFR facilitates HCV are not well understood. Using infectious cell culture model (HCVcc), we demonstrate that binding of HCVcc particles human hepatocyte cells induces activation is dependent on interactions between and CD81 but claudin 1. can also induced antibody mediated cross-linking CD81. In...
Abstract Background Hepatocellular carcinoma (HCC) is a heterogeneous disease with high mortality rate. Recent genomic studies have identified TP53 , AXIN1 and CTNNB1 as the most frequently mutated genes. Lower frequency mutations been reported in ARID1A ARID2 JAK1 . In addition, hepatitis B virus (HBV) integrations into human genome associated HCC. Results Here, we deep-sequence 42 HCC patients combination of whole genome, exome transcriptome sequencing to identify mutational landscape...
Pharmacokinetic (PK) testing of a humanized (κI, VH3 framework) and affinity matured anti-hepatitis C virus E2-glycoprotein (HCV-E2) antibody (hu5B3.κ1VH3.v3) in rats revealed unexpected fast clearance (34.9 mL/day/kg). This binds to the rat recycling receptor FcRn as expected for human IgG1 does not display non-specific binding baculovirus particles an assay that is correlated with cynomolgus monkey. The antigen expressed so target-dependent contribute PK. Removal maturation changes...
Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma. Glycan shielding has been proposed to be mechanism by which HCV masks broadly neutralizing epitopes on its viral glycoproteins. However, the role altered glycosylation in resistance antibodies not fully understood. Here, we have generated potent hu5B3.v3 MRCT10.v362 that, similar previously described AP33 HCV1, bind highly conserved linear epitope E2. We utilize combination vitro selections...
The bacteria Helicobacter pylori is a major human pathogen that infects over half of the world's population. Infection initiates series changes in gastric mucosa, beginning with atrophic gastritis and leading some patients to peptic ulcer disease, mucosa-associated lymphomas, adenocarcinoma. Although this cascade events clearly occurs, little known about role host immune response disease progression. We have utilized C57BL/6 felis mouse model critically analyze adaptive development...
Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and expressed on various innate immune types including microglia. We show here common missense variant (G78R, rs1859788) of PILRA the likely causal allele for confirmed Alzheimer's disease risk locus at 7q21 (rs1476679). The G78R alters interaction residues essential sialic acid engagement, resulting in >50% reduced binding several ligands novel...
ABSTRACT Gammaherpesviruses such as Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus are important human pathogens that establish long-term latent infections. Understanding of the initiation maintenance infections has implications for prevention treatment gammaherpesvirus-related diseases. Although much is known about gammaherpesvirus pathogenesis, it unclear how infectious dose a influences its ability to infection. To examine relationship between latency, we inoculated...
Significance Lipoprotein biosynthesis is crucial for Gram-negative bacterial viability and involves the activities of three essential integral membrane proteins embedded in inner (Lgt, LspA, Lnt). These enzymes function sequentially to produce mature triacylated lipoproteins, many which are then transported outer membrane. Lnt responsible catalyzing addition palmitate N terminus diacylated apolipoproteins. Despite a number studies that have biochemically characterized Escherichia coli Lnt,...
Angiopoietin-2 (Ang-2) is associated with vascular endothelial injury and permeability in the acute respiratory distress syndrome (ARDS) sepsis. Elevated circulating Ang-2 levels may identify critically ill patients distinct pathobiology amenable to targeted therapy. We hypothesized that plasma measured shortly after hospitalization among sepsis would be development of ARDS poor clinical outcomes. To test this hypothesis, we a cohort 757 sepsis, including 267 ARDS, enrolled emergency...
ABSTRACT Sequence analysis of the murine gammaherpesvirus 68 (γHV68) genome revealed an open reading frame (gene 4) which is homologous to a family proteins known as regulators complement activation (RCA proteins) (H. W. Virgin, P. Latreille, Wamsley, K. Hallsworth, E. Weck, A. J. Dal Canto, and S. H. Speck, Virol. 71:5894–5904, 1997). The predicted gene 4 product has homology other virally encoded RCA homologs, well complement-regulatory decay-accelerating factor membrane cofactor protein....
Chemokines are involved in recruitment and activation of hematopoietic cells sites infection inflammation. The M3 gene the γ-herpesvirus γHV68 encodes an abundant secreted protein that binds CC chemokines with high affinity. We report here this is essential for efficient induction lethal meningitis by γHV68. An mutant (γHV68-M3.stop) was 100-fold less virulent than wild-type or marker rescue control (γHV68-M3.MR) viruses after intracerebral inoculation. After inoculation, γHV68-M3.stop grew...
Pseudomonas aeruginosa causes life-threatening infections that are associated with antibiotic failure. Previously, we identified the G2637, an analog of arylomycin, targeting bacterial type I signal peptidase, which has moderate potency against P. aeruginosa. We hypothesized antibody-antibiotic conjugate (AAC) could increase its activity by colocalizing bacteria high local concentrations G2637 in intracellular environment phagocytes. Using a novel technology screening for hybridomas...
While antiviral antibody plays a key role in resistance to acute viral infection, the contribution of control latent virus infection is less well understood. Gammaherpesvirus 68 (gammaHV68) mice provides model suited defining contributions specific immune system components latency. B cells play critical regulating gammaHV68 latency, but mechanism(s) by which regulate latency not known. In experiments reported here, we determined effect passively transferred on established B-cell-deficient...
Lipoprotein diacylglyceryl transferase (Lgt) catalyzes the first step in biogenesis of Gram-negative bacterial lipoproteins which play crucial roles growth and pathogenesis. We demonstrate that Lgt depletion a clinical uropathogenic Escherichia coli strain leads to permeabilization outer membrane increased sensitivity serum killing antibiotics. Importantly, we identify G2824 as first-described inhibitor potently inhibits biochemical activity vitro is bactericidal against wild-type...
The application of phage display technology to mammalian proteins with multiple transmembrane regions has had limited success due the difficulty in generating these sufficient amounts and purity. We report here a method that can be easily generally applied sorting libraries multispan protein targets solubilized detergent. A key feature this approach is production biotinylated virions baculovirus vector allows library panning without prior purification target protein. obtained Fab fragments...
ABSTRACT Murein lipoprotein (Lpp) and peptidoglycan-associated (Pal) are major outer membrane lipoproteins in Escherichia coli . Their roles cell-envelope integrity have been documented E. laboratory strains, while Lpp has linked to serum resistance vitro , the underlying mechanism not established. Here, lpp pal mutants of uropathogenic strain CFT073 showed reduced survival a mouse bacteremia model, but only mutant was sensitive killing The peptidoglycan-bound form specifically required for...