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  1. Science & Research (Biologics)

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

  1. J Virol 2022 Sep;96(18):e0116621
    Enhanced in vitro and in vivo potency of a T cell epitope in the Ebola virus glycoprotein following amino acid replacement at HLA-A*02:01 binding positions.
    Chabot S, Gimie Y, Obeid K, Kim J, Meseda CA, Konduru K, Kaplan G, Sheng Fowler L, Weir JP, Peden K, Major ME
  2. PLoS One 2022 Feb 10;17(2):e0263732
    Tracking ebolavirus genomic drift with a resequencing microarray.
    Tiper I, Kourout M, Fisher C, Konduru K, Purkayastha A, Kaplan G, Duncan R
  3. Nat Microbiol 2020 Sep;5(9):1096-106
    Exosome mimicry by a HAVCR1-NPC1 pathway of endosomal fusion mediates hepatitis A virus infection.
    Costafreda MI, Abbasi A, Lu H, Kaplan G
  4. Adv Mater 2019 Jul;31(30):e1902331
    Ultrasensitive Ebola virus antigen sensing via 3D nanoantenna arrays.
    Zang F, Su Z, Zhou L, Konduru K, Kaplan G, Chou SY
  5. J Virol 2019 Jun;93(11):e02040-18
    Reply to Das et al., "TIM1 (HAVCR1): an essential 'receptor' or an 'accessory attachment factor' for hepatitis A virus?".
    Costafreda MI, Kaplan G
  6. J Virol 2018 May;92(9):e02065-17
    HAVCR1 (CD365) and its mouse ortholog are functional hepatitis A virus (HAV) cellular receptors that mediate HAV infection.
    Costafreda MI, Kaplan G
  7. J Virol Methods 2018 Apr;254:1-7
    High degree of correlation between Ebola virus BSL-4 neutralization assays and pseudotyped VSV BSL-2 fluorescence reduction neutralization test.
    Konduru K, Shurtleff AC, Bavari S, Kaplan G
  8. J Virol 2018 Mar;92(6):e01742-17
    Determinants in the IgV domain of human HAVCR1 (TIM-1) are required to enhance hepatitis C virus entry.
    Kachko A, Costafreda MI, Zubkova I, Jacques J, Takeda K, Wells F, Kaplan G, Major ME
  9. JAMA Intern Med 2017 Mar 1;177(3):430-2
    Evaluation of potencies of immune globulin products against hepatitis A.
    Tejada-Strop A, Costafreda MI, Dimitrova Z, Kaplan GG, Teo CG
  10. Curr Trends Immunol 2016;17:117-23
    Therapeutic potential of the heme oxygenase-1 inducer hemin against Ebola virus infection.
    Huang H, Konduru K, Solovena V, Zhou ZH, Kumari N, Takeda K, Nekhai S, Bavari S, Kaplan GG, Yamada KM, Dhawan S
  11. PLoS One 2016 Sep 13;11(9):e0162446
    Ebolavirus glycoprotein Fc fusion protein protects guinea pigs against lethal challenge.
    Konduru K, Shurtleff AC, Bradfute SB, Nakamura S, Bavari S, Kaplan G
  12. Traffic 2015 Nov;16(11):1193-207
    Distinct trafficking of cell surface and endosomal TIM-1 to the immune synapse.
    Echbarthi M, Zonca M, Mellwig R, Schwab Y, Kaplan GG, DeKruyff RH, Roda-Navarro P, Casasnovas JM
  13. J Biol Chem 2015 Feb 13;290(7):4422-31
    Induction and activation of latent TGF-beta1 is carried out by two distinct domains of pregnancy-specific glycoprotein 1 (PSG1).
    Ballesteros A, Mentink-Kane MM, Warren J, Kaplan GG, Dveksler GS
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