Immunology and Infectious Disease Commons^™

Topical Lipophilic Epigallocatechin-3-Gallate On Herpes Labialis: A Phase Ii Clinical Trial Of Averteax Formula, Man Zhao, Rong Zheng, Jinyan Jiang, Douglas Dickinson, Baiping Fu, Tin-Chun Chu, Lee Lee, Hanna Pearl, Stephen Hsu

Tin-Chun Chu, Ph.D.

Objectives The aim of this study was to clinically evaluate a topical proprietary formulation containing lipophilic catechins (AverTeaX) on recurrent herpes labialis. Methods A double blind, placebo-controlled, randomized trial with 40 participants initially in two groups. Results Compared to the vehicle group, AverTeaX applied topically 6-8 times daily resulted in a significant reduction of clinical episode duration (median 4.5 days, range 1-11 days vs. 9 days, range 2-11 days, p=0.003) and shortened blistering/ulceration stages within an episode from a median of 3 (range 0-6) days to 1 (range 0-3) day (p=0.0003). Median quality of life scores based on a multi-question …

Inhibition Of Sterile Danger Signals, Uric Acid And Atp, Prevents Inflammasome Activation And Protects From Alcoholic Steatohepatitis In Mice., Arvin Iracheta-Vellve, Jan Petrasek, Abhishek Satishchandran, Benedek Gyongyosi, Banishree Saha, Karen Kodys, Katherine Fitzgerald, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Background & Aims: The inflammasome is a well-characterized inducer of inflammation in alcoholic steatohepatitis (ASH). Inflammasome activation requires two signals for mature interleukin (IL)-1β production. Here we asked whether metabolic danger signals trigger inflammasome activation in ASH.

Results:The sterile danger signals, ATP and uric acid, were increased in the serum and liver of alcohol-fed mice. Depletion of uric acid or ATP, or lack of ATP signaling attenuated ASH and prevented inflammasome activation and its major downstream cytokine, IL-1β. Pharmacological depletion of uric acid with allopurinol provided significant protection from alcohol-induced inflammatory response, steatosis and liver damage, and additional protection was …

Metabolic Danger Signals, Uric Acid And Atp, Mediate Inflammatory Cross-Talk Between Hepatocytes And Immune Cells In Alcoholic Liver Disease., Jan Petrasek, Arvin Iracheta-Vellve, Banishree Saha, Abhishek Satishchandran, Karen Kodys, Katherine Fitzgerald, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

Inflammation defines the progression of ALD from reversible to advanced stages. Translocation of bacterial LPS to the liver from the gut is necessary for alcohol-induced liver inflammation. However, it is not known whether endogenous, metabolic danger signals are required for inflammation in ALD. Uric acid and ATP, 2 major proinflammatory danger signals, were evaluated in the serum of human volunteers exposed to a single dose of ethanol or in supernatants of primary human hepatocytes exposed to ethanol. In vitro studies were used to evaluate the role of uric acid and ATP in inflammatory cross-talk between hepatocytes and immune cells. The …

Positive Selection Drives Preferred Segment Combinations During Influenza Virus Reassortment, Konstantin Zeldovich, Ping Liu, Nicholas Renzette, Matthieu Foll, Serena Pham, Sergey Venev, Glen Gallagher, Daniel Bolon, Evelyn Kurt-Jones, Jeffrey Jensen, Daniel Caffrey, Celia Schiffer, Timothy Kowalik, Jennifer Wang, Robert Finberg

Celia A. Schiffer

Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 …

Alcohol And Hcv: Implications For Liver Cancer, Gyongyi Szabo, Banishree Saha, Terence Bukong

Gyongyi Szabo

Liver cancers are one of the deadliest known malignancies which are increasingly becoming a major public health problem in both developed and developing countries. Overwhelming evidence suggests a strong role of infection with hepatitis B and C virus (HBV and HCV), alcohol abuse, as well as metabolic diseases such as obesity and diabetes either individually or synergistically to cause or exacerbate the development of liver cancers. Although numerous etiologic mechanisms for liver cancer development have been advanced and well characterized, the lack of definite curative treatments means that gaps in knowledge still exist in identifying key molecular mechanisms and pathways …

A Novel Human Radixin Peptide Inhibits Hepatitis C Virus Infection At The Level Of Cell Entry, Terence Bukong, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

Hepatitis C virus infection of hepatocytes is a multistep process involving the interaction between viral and host cell molecules. Recently, we identified ezrin-moesin-radixin proteins and spleen tyrosine kinase (SYK) as important host therapeutic targets for HCV treatment development. Previously, an ezrin hinge region peptide (Hep1) has been shown to exert anti-HCV properties in vivo, though its mechanism of action remains limited. In search of potential novel inhibitors of HCV infection and their functional mechanism we analyzed the anti-HCV properties of different human derived radixin peptides. Sixteen different radixin peptides were derived, synthesized and tested. Real-time quantitative PCR, cell toxicity assay, …

The Genetics Of Hepatitis C Virus Underlie Its Ability To Escape Humoral Immunity, Jay Kolls, Gyongyi Szabo

Gyongyi Szabo

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, and efforts to develop therapeutic vaccine strategies have been limited by immune escape due to HCV variants that are resistant to current vaccines or HCV variants that rapidly acquire new resistance-conferring mutations. Recently, the crystal structure of the viral envelope protein E2 region was resolved as well as how E2 docks to the host CD81 protein; therefore, antibodies that block this interaction should prevent viral entry into host cells. In this issue of the JCI, Bailey and colleagues show that immune escape of HCV can occur by naturally …

Antiviral Activity Of Theaflavin Digallate Against Herpes Simplex Virus Type 1, Aline De Oliveira, Derek Prince, Chih-Yu Lo, Lee Lee, Tin-Chun Chu

Tin-Chun Chu, Ph.D.

Tea is the second most consumed drink in the world. The beneficial effects of tea have been mostly attributed to its catechin content. Black tea is derived from the leaves of Camellia sinensis plant, and it is rich in theaflavin polyphenols, in particular theaflavin (TF1), theaflavin-3-monogallate (TF2A), theaflavin-3′-monogallate (TF2B), and theaflavin-3,3′-digallate (TF3). Vero and A549 cells were used to evaluate the effect of purified individual black tea theaflavins as anti-herpes simplex virus 1 agents. With the rise of HSV resistant strains, there is a critical need to develop novel antiherpesviral treatments. Results of the cytotoxicity assay tested by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium] …

Alcohol-Induced Mir-27a Regulates Differentiation And M2 Macrophage Polarization Of Normal Human Monocytes, Banishree Saha, Johanna Bruneau, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

Alcohol abuse is a leading cause of liver disease characterized by liver inflammation, fatty liver, alcoholic hepatitis, or liver cirrhosis. Immunomodulatory effects of alcohol on monocytes and macrophages contribute to alcoholic liver disease. Alcohol use, an independent risk factor for progression of hepatitis C virus (HCV) infection-mediated liver disease, impairs host defense and alters cytokine production and monocyte/macrophage activation. We hypothesized that alcohol and HCV have synergistic effects on the phenotype and function of monocytes. Our data show that acute alcohol binge drinking in healthy volunteers results in increased frequency of CD16(+) and CD68(+) and M2-type (CD206(+), dendritic cell [DC]-SIGN(+)-expressing …

Influenza Virus Drug Resistance: A Time-Sampled Population Genetics Perspective, Matthieu Foll, Yu Poh, Nicholas Renzette, Anna Admetlla, Claudia Bank, Hyunjin Shim, Anna Malaspinas, Gregory Ewing, Ping Liu, Daniel Wegmann, Daniel Caffrey, Konstantin Zeldovich, Daniel Bolon, Jennifer Wang, Timothy Kowalik, Celia Schiffer, Robert Finberg, Jeffrey Jensen

Celia A. Schiffer

The challenge of distinguishing genetic drift from selection remains a central focus of population genetics. Time-sampled data may provide a powerful tool for distinguishing these processes, and we here propose approximate Bayesian, maximum likelihood, and analytical methods for the inference of demography and selection from time course data. Utilizing these novel statistical and computational tools, we evaluate whole-genome datasets of an influenza A H1N1 strain in the presence and absence of oseltamivir (an inhibitor of neuraminidase) collected at thirteen time points. Results reveal a striking consistency amongst the three estimation procedures developed, showing strongly increased selection pressure in the presence …

Hiv-1 Protease-Substrate Coevolution In Nelfinavir Resistance, Madhavi Kolli, Aysegul Ozen, Nese Yilmaz, Celia Schiffer

Celia A. Schiffer

Resistance to various human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) challenges the effectiveness of therapies in treating HIV-1-infected individuals and AIDS patients. The virus accumulates mutations within the protease (PR) that render the PIs less potent. Occasionally, Gag sequences also coevolve with mutations at PR cleavage sites contributing to drug resistance. In this study, we investigated the structural basis of coevolution of the p1-p6 cleavage site with the nelfinavir (NFV) resistance D30N/N88D protease mutations by determining crystal structures of wild-type and NFV-resistant HIV-1 protease in complex with p1-p6 substrate peptide variants with L449F and/or S451N. Alterations of residue …