ARENAVIRUS · Molecular mechanisms of arenavirus cell entry and antibody-mediated neutralization

Molecular mechanisms of arenavirus cell entry and antibody-mediated neutralization

Emerging infectious disease events are dominated by zoonoses: infections that are naturally transmissible from animals to humans or vice versa. A diverse and deadly group of exotic emerging viruses are the viral hemorrhagic fever (VHF) agents, including the rodent-borne mammalian arenaviruses (genus Mammarenavirus). The research carried out in the scope of the ‘ARENAVIRUS’ project focused on New World (NW) clade B arenaviruses responsible for hemorrhagic fever (HF) outbreaks in South America with high case fatality rates. These include Junin (JUNV), Machupo (MACV) and Guanarito (GTOV) viruses, which are responsible for HF outbreaks in rural areas of Argentina, Bolivia and Venezuela, respectively. Despite the significant threat to the public health and economy in the affected areas, there are no internationally approved drugs for preventing or treating NW arenavirus HF. To aid in rational, structure-based antiviral and vaccine design, the ‘ARENAVIRUS’ project is aimed at demonstrating the molecular mechanisms by which arenaviruses attach to human cells and are neutralized by the humoral immune response. A primary determinant of zoonotic spread of clade B arenaviruses is their ability to recognize the human transferrin receptor 1 (hTfR1) in addition to the TfR1 of their natural rodent hosts. Cellular targeting, attachment, and membrane fusion is directed by the trimeric multi-functional glycoprotein (GPC) spikes, which decorate arenaviral envelope surface. Each protomer in the trimer consists of: a myristoylated stable signal peptide (SSP), a receptor attachment subunit (GP1), and a transmembrane fusion subunit (GP2). Remarkably, despite conserved utilization of TfR1 during viral attachment, the sequence similarity at the receptor binding site across the NW arenavirus GP1s is low. Before the start date of the project, the Host Laboratory and others had solved the GP1 structure of the MACV alone (1) and in complex with TfR1 (2). However, due to the substantial residue-sequence variability, molecular requirements for arenavirus zoonosis remained unknown. The GPC spike also comprises the primary target for the host neutralizing immune response. As a preliminary work, the Researcher had demonstrated that the publicly available JUNV glycoprotein-specific neutralizing antibodies (raised by Sanchez et al. (3) and obtained from BEI Resources (Biodefense and Emerging Infections Research Resources Repository, NIAID, NIH)) specifically target the GP1 subunit. Therefore, NW arenavirus GP1s were selected as immunogens for raising novel (cross)neutralizing antibodies against pathogenic NW arenaviruses. 1. Bowden TA et al. (2009) Unusual molecular architecture of the machupo virus attachment glycoprotein, Journal of virology. 83, 8259-65. 2. Abraham J et al. (2010) Structural basis for receptor recognition by New World hemorrhagic fever arenaviruses, Nature structural & molecular biology. 17, 438-44. 3. Sanchez A, et al. (1989) Junin virus monoclonal antibodies: characterization and cross-reactivity with other arenaviruses. J Gen Virol 70 ( Pt 5):1125-1132.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз