It's been 60 years since Epstein-Barr virus (EBV) was discovered. Still, still scientists are continuing to learn fascinating facts about this EBV. A new paper in @Nature by Sylvain Latour and colleagues from INSERM, Paris, report a remarkable human genetics discovery that reveals an important biology of EBV infection--the role of IL27 and its receptor in EBV infection. Martin et al. Nature nature.com/articles/s41586-0… The authors found that individuals who were born with complete deficiency of a cytokine receptor, IL27RA, are highly susceptible to severe EBV infection. But the remarkable part of the discovery is that, despite severe EBV infection, none of these individuals developed cancer; they are protected from EBV-induced cancer risk. If there is one virus that oncologists might know better than virologists, it's EBV. Discovered in 1964 based on microscopy examinations of tumor cells from cancer tissue biopsied from African children, EBV was the first ever known oncogenic virus (thelancet.com/journals/lance…). If you are curious, listen to this 6 mins video where famous scientist/author Dorothy Crawford tells the story of EBV discovery (youtube.com/watch?v=_-Jx4KqC…). EBV infection is extremely common. More than 95% of the population gets it at some point in their life. Once the virus enters the body, it permanently lives dormant in your B cells until you die. In some individuals, such as those immunocompromised, reactivation of this latent infection results in uncontrolled proliferation of B cells causing lymphoma. Not just lymphoma, EBV also cause stomach cancer and nasopharyngeal cancer. Most of the knowledge on the immune pathways hijacked by EBV came to light through humans born with rare genetic mutations causing different types of immunodeficiency. All such known monogenic conditions leading to severe EBV infection almost always have led to cancer. This is the first time scientists are encountering a genetic defect which increases the risk of severe EBV infection but protects against cancer. The finding has perhaps revealed the Achilles' heel of EBV infection, which could be exploited to prevent cancer development in immunocompromised individuals with EBV infection. The other fascinating part of the finding is one of the loss of functions has drifted to higher frequency (0.7%) in Finnish population. So, there are more than 200 individuals in Finland who are knockouts for IL27RA. In the Finngen biobank, the authors found 15 homozygotes, of which two were hospitalized for EBV infection (>50-fold enrichment). The Finnish variant is probably incompletely penetrance because the variant do not completely inactivates IL27R; it leaves behind some residual activity. Just a couple of years ago, Bjornevik et al. demonstrated the strong association of EBV with multiple sclerosis (science.org/doi/10.1126/scie…). Shortly after this report, Lanz et al showed that the reason for 32-fold increased risk of MS after EBV infection is because of the resemblance of a antigen protein in EBV with a glial cell protein in the CNS, resulting in collateral damage in the immune defense against EBV (nature.com/articles/s41586-0…). Currently, mRNA vaccines are being trialed based on this finding. With the recent discovery of IL27 and its receptor IL27RA in EBV, I wonder if these genes have links to MS risk. If so, targeting these genes might also help with treating MS. We will know soon. Amazing discovery. Yet another incredible demonstration of the power of 'natural experiments' aka human genetics in understanding the fundamental biology. Martin et al. Nature nature.com/articles/s41586-0…