The New World clade B arenaviruses (NWA), particularly Junin (JUNV) and Machupo (MACV) are associated with outbreaks of viral hemorrhagic fever in South America. JUNV and MACV infections represent zoonoses from rodents and are both transmitted through aerosols;thus, the NWAs are potential bioterrorism agents. JUNV in particular is one of only three viruses included in the recent list of agents developed by the Department of Homeland Security that represent in their assessment the most significant bioterrorism threats faced by the US. Recently, transferrin receptor 1 (TfR1) was identified as a cellular receptor for the pathogenic New World arenaviruses. However, little is known about the steps subsequent to virus/TfR1 cell surface interaction and there is evidence that other molecules play a role in NWA entry. Moreover, although JUNV and MACV efficiently use TfR1 from their host rodent species for entry, they appear to only be pathogenic in infected humans. We propose several approaches to identify co-factors that support NWA infection as a means for better understanding the pathogenicity of these viruses in humans. These include cDNA expression, siRNA and chemical library screening, to identify genes and pathways that could serve as targets for therapeutic intervention of infection. All rely on the high-throughput, cell-based screening (HTCS) core at Penn, that will support projects in RCE Programs I and II. We also propose creating chimeric JUNV/MMTV hybrid viruses using the MMTV envelope and JUNV wild type and vaccine strain (candid #1) GP proteins to pseudotype JUNV and MMTV virus cores, respectively. These pseudotypes will provide us with a means of studying how arenavirus gene products cause pathogenicity. The chimeric viruses will be used for HTCS screens of NFicB and IRF3 reporter cells, to begin to uncover the activation pathways that lead to the cytokine storm. As there are currently no anti-virals in use for therapeutic or postinfection prophylactic treatment of the clade B arenaviruses, the identification of co-factors that participate in JUNV and MACV entry and perhaps contribute to pathogenesis has the potential to lead to the development of novel therapies for hemorrhagic fevers cause by these viruses.

Public Health Relevance

The studies proposed here will address how the New World hemorrhagic fever viruses infect different species and cell types and how this relates to their ability to cause disease. Since the S. American hemorrhagic fever viruses have been classified as Category A Priority Pathogens because of their lethality and potential use as bioterrorism agents, the results of these studies could lead the development of treatment or prevention therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057168-10
Application #
8442366
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$295,513
Indirect Cost
$35,877
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Champion, Anna E; Bandara, Aloka B; Mohapatra, Nrusingh et al. (2018) Further Characterization of the Capsule-Like Complex (CLC) Produced by Francisella tularensis Subspecies tularensis: Protective Efficacy and Similarity to Outer Membrane Vesicles. Front Cell Infect Microbiol 8:182
Bridge, Dacie R; Blum, Faith C; Jang, Sungil et al. (2017) Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways. Sci Rep 7:11057
Kaempfer, Raymond; Popugailo, Andrey; Levy, Revital et al. (2017) Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint. Receptors Clin Investig 4:
Molleston, Jerome M; Cherry, Sara (2017) Attacked from All Sides: RNA Decay in Antiviral Defense. Viruses 9:
Cifuentes-Muñoz, Nicolás; Sun, Weina; Ray, Greeshma et al. (2017) Mutations in the Transmembrane Domain and Cytoplasmic Tail of Hendra Virus Fusion Protein Disrupt Virus-Like-Particle Assembly. J Virol 91:
Sarute, Nicolás; Ross, Susan R (2017) New World Arenavirus Biology. Annu Rev Virol 4:141-158
Ramachandran, Girish; Aheto, Komi; Shirtliff, Mark E et al. (2016) Poor biofilm-forming ability and long-term survival of invasive Salmonella Typhimurium ST313. Pathog Dis 74:
Wahid, Rezwanul; Fresnay, Stephanie; Levine, Myron M et al. (2016) Cross-reactive multifunctional CD4+ T cell responses against Salmonella enterica serovars Typhi, Paratyphi A and Paratyphi B in humans following immunization with live oral typhoid vaccine Ty21a. Clin Immunol 173:87-95
Li, Huiguang; Hwang, Young; Perry, Kay et al. (2016) Structure and Metal Binding Properties of a Poxvirus Resolvase. J Biol Chem 291:11094-104
Chou, Yi-Ying; Cuevas, Christian; Carocci, Margot et al. (2016) Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor. J Virol 90:4494-4510

Showing the most recent 10 out of 375 publications