Jul 19, 2005 (CIDRAP News) Two groups have independently published the identity of the human protein that facilitates infection by the Nipah and Hendra viruses. First recognized in the mid-1990s, these two emerging infectious animal diseases, which are transmissible to humans, are considered possible bioterror agents.
In 1994, 15 horses and two humans near Brisbane, Australia, presented with fatal acute respiratory disease. The etiologic agent was named Hendra virus (HeV) and classified in a new genus of the viral family Paramyxoviridae.
A Malaysian outbreak of respiratory infections among pigs in 1998 spread to nearly 370 people in the form of a viral encephalitis, killing 105. The identified viral pathogen, named Nipah virus (NiV), was also classified as a paramyxovirus.
Though the viral proteins responsible for attachment were identified, no one had yet found the receptor that allows Nipah and Hendra viruses to enter host cells. The new studies point to a cell surface protein, Ephrin-B2, as the mechanism for entry. The protein is present in humans, horses, pigs, bats, and other mammals a finding consistent with the wide range of animals susceptible to Nipah and Hendra infection.
A team led by Christopher Broder, PhD, at the Uniformed Services University of the Health Sciences (USUHS) utilized a microarray screen to narrow down the possible receptors. Working independently, Benhur Lee, MD, and colleagues at the University of CaliforniaLos Angeles (UCLA) identified the receptor using an immunoprecipitation strategy.
Proceedings of the National Academy of Sciences published the USUHS group's findings online Jul 5. The authors had previously identified a human cell line not susceptible to infection by NiV or HeV. Using microchips embedded with thousands of candidate genes, they compared genes expressed in this resistant cell line to those in cell lines susceptible to viral infection. Twenty-one candidate genes were expressed only in the susceptible cell lines and from this group, the researchers identified the 10 genes expressed most strongly in the susceptible cells. These were transfected individually into the resistant cell line; only Ephrin-B2 caused the resistant cells to become susceptible to infection.
The UCLA group's findings are detailed in a Jul 6 online publication in Nature. Dr. Lee and colleagues utilized the NiV attachment glycoprotein (G) responsible for host cell fusion in an immunoprecipitation assay. They found that G pulled down a 48kD protein from the surface of susceptible, but not resistant, cells. Using trypsin digestion and mass spectrometry, they identified the protein as Ephrin-B2.
Both groups highlighted the close concordance between patterns of Ephrin-B2 expression and sites of infection. "EphrinB2 is essential for vasculogenesis and axonal guidance, and is expressed on endothelial cells, neurons and smooth muscle cells surrounding small arteries and arteriolesan expression pattern highly concordant with the known cellular tropism of NiV," the Nature report says.
The two groups also pointed out the conserved nature of the Ephrin family of cell surface proteins and noted that this could explain the broad range of species susceptible to infection by Nipah and Hendra viruses. Observing that NiV and HeV have been documented in flying foxes, the PNAS article says, "It will be of interest to determine whether [Ephrin-B2] serves as the virus receptor in these natural animal hosts."
As the PNAS article notes, "There are presently no vaccines or approved therapeutics for NiV or HeV infection." Knowing both the viral and cell proteins involved in fusion will allow scientists to develop vaccines and treatments for these two important emerging infectious diseases.
Both studies were funded by the National Institute of Allergy and Infectious Diseases (NIAID).
Negrete OA, Levroney EL, Aguilar HC, et al. EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus. (Letter) Nature 2005 (published online Jul 6) [Abstract]
Bonaparte MI, Dimitrov AS, Bossart KN, et al. Ephrin-B2 ligand is a functional receptor for Hendra virus and Nipah virus. Proc Natl Acad Sci 2005 (published online Jul 5) [Full text]
NIAID press release
CIDRAP Overview on Nipah virus