Pathogenesis and Diagnosis of Hepatitis A Virus and Other Biodefense Agents

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

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Overview

Public Health Issue: Hepatitis viruses are important human pathogens that cause severe liver disease worldwide. Hepatitis A virus (HAV) causes acute hepatitis in humans and is a category B NIAID biodefense priority pathogen. Bioterrorism (BT) agents pose a threat to the safety of the blood supply. Tests to screen blood donations and diagnose viral infection for hepatitis viruses have been developed and are widely used. However, hepatitis virus infections and the potential release of BT agents remain a serious public health problem in the United States. Understanding how these human pathoges cause disease is of paramount importance to detect, treat, and prevent infection. Use of rapid and highly sensitive tests will have a major impact in public health reducing the morbidity and mortality due to hepatitis viruses and BT agents.

Regulatory Contribution: Development and evaluation of blood tests that use new technologies to control and eradicate hepatitis viruses and BT agents.

Research Approach: Most hepatitis viruses do not grow in cell culture, presenting a major problem for the development and preclinical assessment of reagents and tests to diagnose hepatitis virus infections. We have recently developed a cell culture system to grow wild type HAV, and have introduced a 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. We are also developing sensitive and cost-effective methods to detect hepatitis viruses and bioterrorism agents in blood. Finally, we are developing monoclonal antibodies against Ebola virus as therapeutic agents and tools to diagnose and characterize the immune response to experimental vaccines.

Mission Relevance & Outcomes: The availability of cell lines susceptible to HAV infection and monoclonal antibodies against Ebola virus will allow the development and preclinical evaluation of rapid and highly sensitive tests to diagnose infections, and, thus, increase the safety of the US blood supply.

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Publications

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

Transfusion 2006 Oct;46(10):1829-35
Quantification of hepatitis B virus genomes and infectivity in human serum samples.
Hsia CC, Purcell RH, Farshid M, Lachenbruch PA, Yu MY

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