Hendra virus (HeV) and Nipah virus (NiV) are emerging zoonotic paramyxoviruses responsible for repeated outbreaks in Australia, South Asia, India and Bangladesh. HeV and NiV are closely related and share similar genomic sequence and organization (21) as well as significant antigenic homology (10). The henipaviruses are also distinguished among the paramyxoviruses by their broad species tropism and highly pathogenic nature (reviewed in 4). The genus Henipavirus was created in 2002 to accommodate these 2 novel and closely related specimens among the Paramyxoviridae family of negative sense RNA viruses.
HeV was first identified in 1994 as the etiologic agent of a severe and often fatal acute respiratory disease among horses during two nearly simultaneous yet independent outbreaks in Queensland, Australia (reviewed in 20, 21). During the course of these epidemics, HeV was also transmitted to three human caretakers, two of which died. A few years later, a large multi-state outbreak of severe encephalitis among pig farmers occurred in peninsular Malaysia resulting in the recognition and discovery of NiV in 1998-1999 (reviewed in 14, 19). Here, NiV was primarily transmitted to humans from infected pigs resulting in some 265 cases of human infection with 105 deaths during this initial outbreak. In addition to pigs, several other animals were also infected including dogs, cats and horses. Acute clinical NiV disease in humans typically develops within 2 weeks of infection with the onset of fever, cough, headache, drowsiness, and myalgia (15, 55). Essentially similar findings have been observed in cases of HeV infection, and several animal models have been reported which display varying aspects of pathology that are reflective of human infections (reviewed in 4). Viral infection predominates in the respiratory system and subsequently spreads to multiple organ systems via a hematogenous route (reviewed in 21). Mortality is the result of severe pulmonary pathology and/or viral encephalitis.
Since these initial outbreaks, both viruses have repeatedly re-emerged. HeV outbreaks have occurred in Australia in 1994, 1999, 2004, 2006, 2007 and 2008, always involving horses. There have been three additional confirmed human infections, one in 2004 and two in 2008 with one fatality in the most recent outbreak (reviewed in 19) (1, 2, 40). NiV has caused outbreaks involving hundreds of human cases since its discovery with 9 recognized occurrences in Bangladesh and India since 2001, the most recent in 2008 (reviewed in 19) (3, 26, 30). Several of these recent NiV outbreaks have been associated with higher case fatality rates (~75%), increased incidence of acute respiratory distress syndrome along with neurological disease, and evidence of person-to-person transmission with direct transmission of the virus from natural reservoirs to humans via contaminated food sources (24, 26, 36).
The preponderance of evidence has implicated frugivorous bat species commonly known as flying foxes (order Chiroptera, family Pteropodidae, genus Pteropus) as the principle host reservoir of the henipaviruses (reviewed in 4). These bats are widely distributed throughout South Asia, Oceania, and as far west as Madagascar (22). Serological studies have shown evidence of henipavirus specific antibody or other indications of infection among several bat species from various geographic locations (reviewed in 4). Most recently, serologic evidence of henipaviruses in bats has been demonstrated in West Africa and China, bringing the total number of species to 24 from 10 genera of bats (27, 35). Evidence to date suggests that there are at least three distinct lineages of NiV: Malaysia, Bangladesh (25) and Cambodia (47) (reviewed in 21). It likely that when henipavirus isolates are obtained and characterized from the recently identified reservoirs in Madagascar and China there will be some additions to the NiV or HeV lineages or perhaps even one or more new viral species belonging to the henipavirus genus. These results indicate that the henipaviruses or henipa-like viruses are widespread and present a potentially significant zoonotic disease risk for a large human population. There are currently no approved therapeutics or vaccines available for the prevention or treatment of henipavirus infection and they are classified as biosafety level 4 (BSL-4) pathogens and select agents.
The Mechanism of Henipavirus Fusion: Examining the Relationships between the Attachment and Fusion Glycoproteins
- Received Date: 09 January 2009
- Accepted Date: 16 January 2009
Abstract: The henipaviruses, represented by Nipah virus and Hendra virus, are emerging zoonotic viral pathogens responsible for repeated outbreaks associated with high morbidity and mortality in Australia, Southeast Asia, India and Bangladesh. These viruses enter host cells via a class I viral fusion mechanism mediated by their attachment and fusion envelope glycoproteins; efficient membrane fusion requires both these glycoproteins in conjunction with specific virus receptors present on susceptible host cells. The henipavirus attachment glycoprotein interacts with a cellular B class ephrin protein receptor triggering conformational alterations leading to the activation of the viral fusion (F) glycoprotein. The analysis of monoclonal antibody (mAb) reactivity with G has revealed measurable alterations in the antigenic structure of the glycoprotein following its binding interaction with receptor. These observations only appear to occur with full-length native G glycoprotein, which is a tetrameric oligomer, and not with soluble forms of G (sG), which are disulfide-linked dimers. Single amino acid mutations in a heptad repeat-like structure within the stalk domain of G can disrupt its association with F and subsequent membrane fusion promotion activity. Notably, these mutants of G also appear to confer a post- receptor bound conformation implicating the stalk domain as an important element in the G glycoprotein’s structure and functional relationship with F. Together, these observations suggest fusion is dependent on a specific interaction between the F and G glycoproteins of the henipaviruses. Further, receptor binding induces measurable changes in the G glycoprotein that appear to be greatest in respect to the interactions between the pairs of dimers comprising its native tetrameric structure. These receptor-induced conformational changes may be associated with the G glycoprotein’s promotion of the fusion activity of F