TWiV 869 delves into two pivotal areas of virology: an historical examination of poliomyelitis and groundbreaking research connecting Epstein-Barr virus (EBV) to multiple sclerosis (MS). The first segment reviews Dorothy Horstmann's 1954 paper on polio viremia, illustrating early scientific method and the evolving understanding of polio pathogenesis. The main focus then shifts to two recent studies in Science and Nature. The Science paper presents epidemiological evidence from a large military cohort, demonstrating a 32-fold increased risk of MS after EBV infection, positioning EBV as a primary causal factor. The Nature paper uncovers a molecular mechanism, showing that clonally expanded B cells in MS patients produce antibodies that cross-react with both an EBV nuclear antigen (EBNA1) and a central nervous system protein, GlialCAM, with phosphorylation of GlialCAM enhancing this cross-reactivity. The discussion explores implications for MS prevention through an EBV vaccine and potential therapeutic interventions targeting this molecular mimicry.
Exploring the Links Between Viruses and Disease
0:00 Introduction & Announcements: The hosts of "This Week in Virology" (TWiV) introduce the episode, setting the stage for discussions on virus-related research and news.
2:08 ABRCMS ePoster Spring Symposium for Emerging Scientists: An announcement for a new online meeting hosted by the Annual Biomedical Research Conference for Minority Students (ABRCMS), designed for high school to first-year undergraduate students to present formalized research. Abstract submissions are due March 15th, and opportunities for graduate students and postdocs to serve as abstract reviewers are available.
3:11 ASV Annual Meeting Registration (ASV): Registration is open for the American Society for Virology (ASV) 2022 annual meeting (November 9-12 in Anaheim, CA). Abstracts are due March 1st, and travel grant applications for students, postdocs, and undergraduate virology teachers are due March 3rd. ASV Cares grants for dependent care are also available.
3:46 Microbiology & Immunology at LSU Health: The Department of Microbiology and Immunology at Louisiana State University Health in Shreveport encourages applications for its MS and PhD programs for Fall 2022. The deadline has been extended to March 1st for their program focusing on DNA and RNA viruses, innate immunology, and intracellular bacteria.
5:11 Viremia in human poliomyelitis (J Exp Med): A deep dive into Dorothy Horstmann's 1954 Journal of Experimental Medicine paper, which first described viremia (virus in the blood) in human poliomyelitis.
Key Details: Early attempts (since 1909) to find polio virus in blood were largely negative. Horstmann's lab, using rhesus monkeys and monkey testicular/kidney cell cultures (roller tubes), successfully isolated virus from the blood of six out of 33 individuals, particularly during the early minor illness phase.
Takeaway: This paper shifted understanding from polio being solely neurotropic to involving an early viremic phase, essential for the virus to access the central nervous system, and highlighted the importance of early sample collection.
33:12 Two Papers Connecting MS and EBV: The episode shifts focus to two recent, highly impactful papers linking Epstein-Barr virus (EBV) to Multiple Sclerosis (MS).
33:24 EBV Overview: EBV is a herpesvirus that causes infectious mononucleosis, nasopharyngeal carcinoma, and Burkitt's lymphoma. It infects lymphoid tissue, specifically B cells, and establishes lifelong latency. Most of the global population is infected asymptomatically.
39:34 EBV associated with MS (Science): Discussion of a Science paper (Cortese et al.) providing epidemiological evidence for EBV as a major cause of MS.
Key Details: A 20-year longitudinal study of over 10 million U.S. military personnel, using 62 million archived serum samples. They identified 801 MS cases and 1566 matched controls. Only one MS case was found in an EBV-negative individual.
Key Finding: Individuals who seroconverted for EBV had a 32-fold higher risk of developing MS. Seroconversion for Cytomegalovirus (CMV), used as a control, showed no such link. Neurofilament light chain, a biomarker for neuroaxonal degradation, also increased after EBV infection but before MS onset.
Takeaway: This study strongly suggests EBV infection is a prerequisite for MS, opening possibilities for MS prevention via an EBV vaccine.
56:38 MS antibodies Bind EBV EBNA1 and GlialCAM (Nature): Discussion of a Nature paper (Lanz et al.) investigating the molecular mechanism linking EBV to MS.
Key Details: Researchers sorted single B cells from the cerebrospinal fluid (CSF) of MS patients and found highly clonal B cell populations, suggesting antigen-specific proliferation within the CSF. They cloned antibodies from these B cells.
Key Finding: A significant portion of these antibodies (from 6 out of 9 patients) bound to EBV nuclear antigen 1 (EBNA1), a viral transcription factor. Crucially, these same antibodies also cross-reacted with GlialCAM, a human glial cell adhesion molecule found in MS plaques.
Mechanism: The cross-reactivity is enhanced by phosphorylation of GlialCAM, suggesting a pathogen-induced autoimmunity where an EBNA1 antibody recognizes phosphorylated GlialCAM. The germline (unmutated) form of the antibody also binds EBNA1, but somatic hypermutation (possibly in the CSF) refines its affinity, especially for GlialCAM.
Mouse Model: Immunizing mice with the EBNA1 peptide exacerbated experimental autoimmune encephalomyelitis, inducing antibodies to both EBNA1 and GlialCAM, CNS immune cell infiltration, and demyelination.
Takeaway: This paper provides a molecular mimicry mechanism for how EBV infection can trigger MS, where antibodies initially targeting EBV cross-react with a critical CNS protein, particularly after phosphorylation, leading to demyelination.
1:28:02 Discussion on Intervention: The hosts discuss the challenges of an EBV vaccine (requiring sterilizing immunity) and the potential for early diagnosis or therapies that target the cross-reactive antibodies or the phosphorylation process.
1:33:58 Rapid intensification of the emerging southwestern North American megadrought in 2020β2021: Dickson's pick, an article describing a 1200-year history of drought in North America, showing that the current megadrought in the Southwest is the most severe, exacerbating natural climate cycles with anthropogenic effects, impacting food, power, and communities.
1:41:02 Which Immune Cell Are You: Brienne's pick, an online quiz to determine which immune cell aligns with your personality, with Brienne revealing she is a "Natural Killer cell."
1:42:29 Nikola Tesla 3D Anamorphosis: Rich's pick, a video showcasing a 3D anamorphosis artwork of Nikola Tesla by Patrick Proskow at the Illusion Art Museum in Prague, where a collection of electronic components forms a recognizable portrait from a specific viewpoint.
1:44:33 Pauls Uncle Doesnt Want to Get Vaccinated: Vincent's pick, a free children's book (PDF) in Spanish and English by the team in Mexico, aiming to educate children about vaccines and vaccine hesitancy, similar to their previous books on measles and mosquitoes.
1:45:38 The 1969 Apollo Guidance Computer: Bob's listener pick, a YouTube video offering a detailed look at the Apollo Guidance Computer from 1969, praised for its depth.
1:46:04 Decoding the Gurus with Dan Wilson: Ian's listener pick, a podcast discussing misinformation, specifically referencing an episode featuring microbiologist Dr. Dan Wilson who debunks anti-vaxx claims, with the hosts expressing appreciation for TWiV.
1:47:21 FrenchGuyCooking: Beth's listener pick, a YouTube channel featuring cooking shows, noted for its unique mix of tools and variety of cuisine.
1:48:13 How to Contribute: An encouragement for listeners to support Microbe.tv's educational efforts, as their podcasts run without ads and rely on listener contributions.
Summaries of Linked Articles:
ABRCMS ePoster Spring Symposium for Emerging Scientists (Link to abrcms.org/index.php/symposium-home): This link leads to the official page for a new online symposium for emerging scientists, including high school, community college, and first-year undergraduate students, to present research posters. It also offers opportunities for graduate students and postdocs to volunteer as abstract reviewers and judges.
ASV Annual Meeting Registration (ASV) (Link to asv.org/asv2022/registration/): This link provides information on registering for the American Society for Virology's (ASV) annual meeting in Anaheim, California (November 9-12). It details abstract submission deadlines, travel grant applications for students, postdocs, and teachers, and available ASV Cares grants for dependent care.
Microbiology & Immunology at LSU Health (Link to www.lsuhs.edu/our-schools/school-of-graduate-studies/phd-programs/admissions): This link directs to the admissions page for the Department of Microbiology and Immunology at Louisiana State University Health in Shreveport. It encourages applications for their MS and PhD programs, highlighting their faculty's research in various viruses, innate immunology, and intracellular bacteria, and noting an extended application deadline.
Viremia in human poliomyelitis (J Exp Med) (Link to pubmed.ncbi.nlm.nih.gov/13152281/): This link is to the PubMed entry for the 1954 Journal of Experimental Medicine paper by Horstmann, McCollum, and Mascola. The paper details the discovery of poliovirus in the blood of human patients during the early, minor illness phase of infection, a finding that challenged previous understandings of polio's pathogenesis and highlighted the importance of viremia for central nervous system invasion.
EBV associated with MS (Science) (Link to www.science.org/doi/10.1126/science.abj8222): This link is to the Science journal article by B. C. Cortese et al. It presents epidemiological evidence from a large, longitudinal study of U.S. military personnel, demonstrating a significantly increased risk (32-fold hazard ratio) of developing multiple sclerosis after infection with Epstein-Barr virus, with virtually all MS cases in the cohort preceded by EBV infection.
MS antibodies Bind EBV EBNA1 and GlialCAM (Nature) (Link to www.nature.com/articles/s41586-022-04432-7): This link is to the Nature journal article by T. V. Lanz et al. It describes the molecular mechanism underlying the link between EBV and MS. The study identifies clonally expanded B cells in MS patients' cerebrospinal fluid that produce antibodies cross-reactive with both the EBV nuclear antigen 1 (EBNA1) and the human central nervous system protein GlialCAM. This cross-reactivity is found to be significantly enhanced by the phosphorylation of GlialCAM.
Letters read on TWiV 869 (Link to www.microbe.tv/twiv/twiv-869-letters/): This link directs to a separate blog post or page on Microbe.tv that contains letters and comments from listeners related to TWiV 869, which were read and discussed during the podcast. This is not an external scientific article but supplementary content for the podcast episode.