Structural and functional analyses reveal promiscuous and species specific use of ephrin receptors by Cedar virus.

Cedar virus (CedV) is a bat-borne henipavirus related to Nipah virus (NiV) and Hendra virus (HeV), zoonotic agents of fatal human disease. CedV receptor-binding protein (G) shares only ∼30% sequence identity with those of NiV and HeV, although they can all use ephrin-B2 as an entry receptor. We demonstrate that CedV also enters cells through additional B- and A-class ephrins (ephrin-B1, ephrin-A2, and ephrin-A5) and report the crystal structure of the CedV G ectodomain alone and in complex with ephrin-B1 or ephrin-B2. The CedV G receptor-binding site is structurally distinct from other henipaviruses, underlying its capability to accommodate additional ephrin receptors. We also show that CedV can enter cells through mouse ephrin-A1 but not human ephrin-A1, which differ by 1 residue in the key contact region. This is evidence of species specific ephrin receptor usage by a henipavirus, and implicates additional ephrin receptors in potential zoonotic transmission.

Matrix proteins of Nipah and Hendra viruses interact with beta subunits of AP-3 complexes.

UNLABELLED: Paramyxoviruses and other negative-strand RNA viruses encode matrix proteins that coordinate the virus assembly process. The matrix proteins link the viral glycoproteins and the viral ribonucleoproteins at virus assembly sites and often recruit host machinery that facilitates the budding process. Using a co-affinity purification strategy, we have identified the beta subunit of the AP-3 adapter protein complex, AP3B1, as a binding partner for the M proteins of the zoonotic paramyxoviruses Nipah virus and Hendra virus. Binding function was localized to the serine-rich and acidic Hinge domain of AP3B1, and a 29-amino-acid Hinge-derived polypeptide was sufficient for M protein binding in coimmunoprecipitation assays. Virus-like particle (VLP) production assays were used to assess the relationship between AP3B1 binding and M protein function. We found that for both Nipah virus and Hendra virus, M protein expression in the absence of any other viral proteins led to the efficient production of VLPs in transfected cells, and this VLP production was potently inhibited upon overexpression of short M-binding polypeptides derived from the Hinge region of AP3B1. Both human and bat (Pteropus alecto) AP3B1-derived polypeptides were highly effective at inhibiting the production of VLPs. VLP production was also impaired through small interfering RNA (siRNA)-mediated depletion of AP3B1 from cells. These findings suggest that AP-3-directed trafficking processes are important for henipavirus particle production and identify a new host protein-virus protein binding interface that could become a useful target in future efforts to develop small molecule inhibitors to combat paramyxoviral infections. IMPORTANCE: Henipaviruses cause deadly infections in humans, with a mortality rate of about 40%. Hendra virus outbreaks in Australia, all involving horses and some involving transmission to humans, have been a continuing problem. Nipah virus caused a large outbreak in Malaysia in 1998, killing 109 people, and smaller outbreaks have since occurred in Bangladesh and India. In this study, we have defined, for the first time, host factors that interact with henipavirus M proteins and contribute to viral particle assembly. We have also defined a new host protein-viral protein binding interface that can potentially be targeted for the inhibition of paramyxovirus infections.

Lack of Alignment Between WHO Joint External Evaluation and State Party Self-Assessment Scores Undermines Utility as Evaluation Tools for the Department of Defense.

The International Health Regulations 2005 (IHR) set standards for countries to detect and respond to public health threats such as COVID-19. The US Department of Defense engages with partner nations to build IHR-related health security capacities. In this article, we compare 2 elements of the IHR Monitoring and Evaluation Framework to determine if they align in a useful way. The version of the State Party Self-Assessment Annual Reporting (SPAR) tool used for this study is a self-assessment of 13 capacities, while the Joint External Evaluation (JEE) requires collaboration with international subject matter experts to evaluate 19 capacities. The SPAR indicators are scored separately from 0% to 100%, whereas the JEE uses a rank-ordered scale from 1 to 5 for variable numbers of indicators in each capacity. Using 2018-2019 data from the World Health Organization, we quantitatively and qualitatively evaluated the alignment of the SPAR and JEE scoring systems, using paired t tests for related capacities and 3 approaches to matching the scales. Whether using a simple, evenly divided scale for the SPAR or downscaling the SPAR scores to match with lower JEE scores, the paired t tests indicate that the JEE and SPAR scoring systems are not aligned. Many of the capacities in the JEE and SPAR are defined differently, pointing to one of the reasons for the discordance. We discuss implications for revision of the JEE and SPAR assessment tools along with ways in which the scores might be used for planning global health engagement capacity-building activities.

Military Participation in Health Security: Analysis of Joint External Evaluation Reports and National Action Plans for Health Security.

Militaries around the world play an important but at times poorly defined and underappreciated role in global health security. They are often called upon to support civilian authorities in humanitarian crises and to provide routine healthcare for civilians. Military personnel are a unique population in a health security context, as they are highly mobile and often deploy to austere settings domestically and internationally, which may increase exposure to endemic and emerging infectious diseases. Despite the role of militaries, few studies have systematically evaluated their involvement in global health security activities including the Global Health Security Agenda. We analyzed Joint External Evaluation (JEE) mission reports (n = 94) and National Action Plan for Health Security plans (n = 12), published as of July 2020, to determine the extent to which military organizations were involved in the evaluation process, military involvement in health security activities were described, and specific recommendations were provided for the country's military. For JEE reports, descriptions of military involvement were highest in 3 of the 4 core areas: Respond (76%), Prevent (39%), and Detect (32%). Similarly, National Action Plan for Health Security plans mentioned military involvement in the same 3 core areas: Respond (58%), Prevent (33%), and Detect (33%). Only 28% of JEE reports provided recommendations for the military in any of the core areas. Our results indicate that military roles and contributions are incorporated into some aspects of country-level health security activities, but that more extensive involvement may be warranted to improve national capabilities to prevent, detect, and respond to infectious disease threats.

Reassessing Biological Threats: Implications for Cooperative Mitigation Strategies.

Multiple factors ranging from globalization to ecosystem disruption are presenting the global community with evolving biological threats to local, national, and global security that reach beyond the realm of traditional bioweapon threats. As a result, mitigation strategies have adapted necessarily to the increased diversity of biological threats. In general, response and preparedness strategies have largely shifted from being primarily reactive to traditional biological weapons to more proactive in nature. In this review, we briefly explore biological threats through a wider aperture, to embrace a greater appreciation of viral pathogens, antimicrobial resistance, and agricultural pathogens, and their potential to cause civil, economic, and political devastation. In addition, we discuss current mitigation strategies codified by the Global Health Security Agenda and the One Health paradigm as well as some of the available tools to assist with their sustainable implementation.