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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Pathogenesis and Diagnosis of Hepatitis A Virus and Other Biodefense Agents

Principal Investigator: Gerardo Kaplan, PhD
Office / Division / Lab: OBRR / DETTD / LEP


General Overview

Hepatitis viruses are important human pathogens that cause severe liver disease worldwide.

Hepatitis A virus (HAV) causes acute hepatitis in humans, and as a potential agent of bioterrorism (BT) it poses a threat to the safety of the blood supply. Ebola virus is a Filovirus that causes a severe hemorrhagic disease in humans. There is currently no licensed treatment or vaccine to prevent Filovirus infection, which mortality rate can reach 90% of infected individuals, Early diagnosis and quarantine are the main tools to control Filovirus outbreaks.

Tests to screen blood donations and diagnose viral infection for hepatitis viruses are widely used. Nevertheless, hepatitis virus infections and the potential release of BT agents remain a serious public health problem in the United States. Understanding how these human pathogens cause disease is of paramount importance for detecting, treating, and preventing infection. The use of rapid and highly sensitive tests will have a major impact on public health by reducing the levels of illness and death due to hepatitis viruses and BT agents.

To accomplish our research goals, we use state-of-the-art techniques to detect viruses, adapt viruses to growth in cell culture, and develop animal models of hepatitis to study the course of the disease.

CBER regulates tests and vaccines used to detect and prevent infections, and our mission-oriented research in HAV and BT agents gives us expertise in these areas; it also helps us to develop materials FDA needs to evaluate the safety and effectiveness of such products submitted by industry for Agency approval.


Scientific Overview

The major obstacle to the development and preclinical assessment of reagents and tests to diagnose hepatitis virus infections is the inability of most hepatitis viruses to grow in cell cultures.

We have recently developed a cell culture system to grow wild type HAV, and have introduced an antibiotic selectable marker into the HAV genome. Since the biology of HAV is poorly understood, we study the role of the hepatitis A virus receptor 1 in pathogenesis of HAV in animal models.

We are also developing sensitive and cost-effective methods to detect hepatitis viruses and bioterrorism agents such as Ebola Virus and Marburg Virus in blood. We are currently developing rapid colorimetric tests that could be used at point-of-care and tests that will simultaneously detect multiple pathogens. In addition, we are developing monoclonal antibodies against Ebola virus as therapeutic agents and tools to diagnose and characterize in vitro the immune response to experimental vaccines.


Publications

Gastroenterology 2012 Jun;142(7):1516-25.e3
Binding of hepatitis A virus to its cellular receptor 1 inhibits T-regulatory cell functions in humans.
Manangeeswaran M, Jacques J, Tami C, Konduru K, Amharref N, Perrella O, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ, Perrella A, Kaplan GG

Virol J 2012 Jan 25;9:32
Induction of ebolavirus cross-species immunity using retrovirus-like particles bearing the Ebola virus glycoprotein lacking the mucin-like domain.
Ou W, Delisle J, Jacques J, Shih J, Price G, Kuhn JH, Wang V, Verthelyi D, Kaplan G, Wilson CA

J Virol Methods 2011 Jun;174(1-2):99-109
Development and characterization of rabbit and mouse antibodies against ebolavirus envelope glycoproteins.
Ou W, Delisle J, Konduru K, Bradfute S, Radoshitzky SR, Retterer C, Kota K, Bavari S, Kuhn JH, Jahrling PB, Kaplan G, Wilson CA

Vaccine 2011 Apr 5;29(16):2968-77
Ebola virus glycoprotein Fc fusion protein confers protection against lethal challenge in vaccinated mice.
Konduru K, Bradfute SB, Jacques J, Manangeeswaran M, Nakamura S, Morshed S, Wood SC, Bavari S, Kaplan GG

J Clin Invest 2011 Mar 1;121(3):1111-8
A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans.
Kim HY, Eyheramonho MB, Pichavant M, Gonzalez Cambaceres C, Matangkasombut P, Cervio G, Kuperman S, Moreiro R, Konduru K, Manangeeswaran M, Freeman GJ, Kaplan GG, Dekruyff RH, Umetsu DT, Rosenzweig SD

J Virol 2010 Aug;84(16):8342-7
Determinants in 3Dpol modulate the rate of growth of hepatitis A virus.
Konduru K, Kaplan GG

Virol J 2010 Feb 19;7:44
Increased susceptibility of Huh7 cells to HCV replication does not require mutations in RIG-I.
Feigelstock DA, Mihalik KB, Kaplan G, Feinstone SM

J Immunol 2010 Feb 15;184(4):1918-30
T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells.
DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT, Freeman GJ, Casasnovas JM

Virol J 2009 Nov 18;6:204
Hepatitis A virus (HAV) packaging size limit.
Konduru K, Nakamura SM, Kaplan GG

Virol J 2009 Oct 27;6:175
The interaction of hepatitis A virus (HAV) with soluble forms of its cellular receptor 1 (HAVCR1) share the physiological requirements of infectivity in cell culture.
Silberstein E, Konduru K, Kaplan GG

Virol J 2008 Dec 18;5:155
A simple and rapid Hepatitis A Virus (HAV) titration assay based on antibiotic resistance of infected cells: evaluation of the HAV neutralization potency of human immune globulin preparations.
Konduru K, Virata-Theimer ML, Yu MY, Kaplan GG

Immunity 2007 Dec;27(6):941-51
Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds.
Santiago C, Ballesteros A, Martínez-Muñoz L, Mellado M, Kaplan GG, Freeman GJ, Casasnovas JM

Immunity 2007 Dec;27(6):927-40
TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells.
Kobayashi N, Karisola P, Peña-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ

Biochem Biophys Res Commun 2007 May 18;356(4):1017-23
Microarray multiplex assay for the simultaneous detection and discrimination of hepatitis B, hepatitis C, and human immunodeficiency type-1 viruses in human blood samples.
Hsia CC, Chizhikov VE, Yang AX, Selvapandiyan A, Hewlett I, Duncan R, Puri RK, Nakhasi HL, Kaplan GG

J Virol 2007 Apr;81(7):3437-46
IgA is a natural ligand of the Hepatitis A virus cellular receptor 1, and their association enhances virus-receptor interactions.
Tami C, Silberstein E, Manangeeswaran M, Freeman GJ, Umetsu SE, Dekruyff RH, Umetsu DT, Kaplan GG

Immunity 2007 Mar;26(3):299-310
Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family.
Santiago C, Ballesteros A, Tami C, Martinez-Munoz L, Kaplan GG, Casasnovas JM

J Virol 2006 Feb;80(3):1352-60
Stable growth of wild-type hepatitis a virus in cell culture.
Konduru K, Kaplan GG

J Mol Diagn 2005 Oct;7(4):486-94
A multiplex polymerase chain reaction microarray assay to detect bioterror pathogens in blood.
Tomioka K, Peredelchuk M, Zhu X, Arena R, Volokhov D, Selvapandiyan A, Stabler K, Mellquist-Riemenschneider J, Chizhikov V, Kaplan G, Nakhasi H, Duncan R

J Virol 2005 Mar;79(5):2950-5
Growth of hepatitis a virus in a mouse liver cell line.
Feigelstock DA, Thompson P, Kaplan GG

Kidney Int 2004 May;65(5):1761-1773
Hepatitis A virus receptor blocks cell differentiation and is overexpressed in clear cell renal cell carcinoma.
Vila MR, Kaplan GG, Feigelstock D, Nadal M, Morote J, Porta R, Bellmunt J, Meseguer A

Arch Virol 2004 Apr;149(4):759-72
Rescue of Hepatitis A virus from cDNA-transfected but not virion RNA-transfected mouse Ltk- cells.
Lu JH, Dveksler G, Kaplan GG

 

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