This This Week in Virology episode, recorded at Virginia Tech's CEZAP (Center for Emerging Zoonotic and Arthropod-borne Pathogens) Symposium, features interviews with virologists XJ Meng and Kylene Kehn-Hall.
The first segment with XJ Meng focuses on Hepatitis E Virus (HEV), a globally significant pathogen responsible for 20 million annual infections. The discussion covers its zoonotic nature, with reservoirs in pigs, deer, and rats, highlighting the foodborne transmission risk from undercooked meat. A key point is the discovery of a naturally occurring recombinant HEV containing a human ribosomal protein insert, which confers a nuclear trafficking capability and expands its host range. The interview also touches on clinical aspects, including severe disease in pregnant women, chronic infections in the immunocompromised, and extrahepatic neurological manifestations, while noting the lack of an FDA-approved diagnostic or a widely available vaccine in the US.
The second interview with Kylene Kehn-Hall details her research on Rift Valley Fever Virus (RVFV), a mosquito-borne pathogen. The main focus is its nonstructural protein NSs, a primary virulence factor she dubs the "viral Houdini." NSs is a multifaceted antagonist of the host's innate immunity, forming large filaments in the nucleus to suppress the interferon response, block general transcription and mRNA export, and trigger DNA damage signaling without actual DNA damage. A central finding discussed is that NSs inhibits autophagy by using a specific LIR motif to bind and sequester LC3 family proteins in the nucleus, a mechanism confirmed through structural and mutational analyses. Both interviews conclude with a commentary on the challenging state of science funding and the critical need for effective science communication.
A Tale of Two Viruses: Hepatitis E and Rift Valley Fever
0:37 CEZAP Explained: XJ Meng introduces the Center for Emerging Zoonotic and Arthropod-borne Pathogens (CEZAP) at Virginia Tech, an interdisciplinary center with 140 faculty designed to foster collaborative research on infectious diseases.
5:34 Hepatitis E Virus (HEV) Overview: HEV is a small, non-enveloped RNA virus causing an estimated 20 million infections and 44,000 deaths globally each year. Transmission is primarily via contaminated food and water.
8:19 A Natural Gain-of-Function: A naturally occurring recombinant HEV was identified containing an inserted human ribosomal protein (S17). This unique insertion gives the virus a nuclear stage and an expanded host range.
9:21 A Zoonotic Threat: Once believed to be a human-only virus, HEV is now known to have a broad host range including pigs, wild boar, deer, and rats. This poses a significant food safety risk, particularly from undercooked pork products, as a high percentage of pigs at slaughter can be viremic.
15:27 More Than a Liver Virus: HEV infection is not confined to the liver; it is linked to a number of neurological complications and has been shown to cross the blood-brain barrier.
16:47 Chronic Infection Risk: While typically causing acute illness, HEV can establish chronic infections in immunocompromised individuals, such as organ transplant recipients. In this population, up to 80% of those infected develop chronic disease.
19:01 Diagnostic and Vaccine Gaps: There is no FDA-approved diagnostic test for HEV in the US, and the blood supply is not routinely screened. A vaccine exists but is only licensed for use in China.
48:41 Rift Valley Fever Virus (RVFV): Kylene Kehn-Hall discusses her research on RVFV, a BSL-3 select agent. It is a mosquito-borne virus that causes severe disease in livestock and a spectrum of illness in humans, from mild fever to fatal hemorrhagic fever and encephalitis. It can be maintained in the mosquito population through transovarial transmission.
55:59 The "Viral Houdini" - NSs Protein: Her work centers on the RVFV nonstructural protein NSs, a key virulence factor and potent interferon antagonist. The protein forms large, amyloid-like filaments in the host cell nucleus to systematically dismantle antiviral defenses.
59:50 Autophagy Inhibition: A key mechanism of NSs is the inhibition of autophagy. The protein contains a specific LIR motif that allows it to bind directly to LC3 family proteins, sequestering them in the nucleus and preventing the formation of autophagosomes. Disrupting this interaction with a single amino acid change attenuates the virus.
1:07:52 DNA Damage Mimicry: NSs also triggers DNA damage signaling pathways (ATM and p53) without causing detectable DNA damage. It is hypothesized that the cell's machinery mistakes the large NSs nuclear filaments for a form of cellular damage.
1:14:13 The Science Communication Imperative: Both interviews conclude with a discussion on the precarious state of science funding and public trust in the US, emphasizing the need for scientists to actively engage in clear and effective public communication.