New Study Pinpoints Unique Genetic Susceptibility for Viral Encephalitis

By Eric Sauter

Working in close collaboration with a group of French researchers, scientists from The Scripps Research Institute have helped uncover a unique genetic immunodeficiency that leaves patients vulnerable to herpes simplex encephalitis, a rare yet devastating infection of the brain that affects a small minority of people infected with a common virus.

The study is being published September 14 in Science X-Press, an advanced, online edition of the journal Science.

In the study, the researchers suggest that herpes simplex encephalitis may reflect a single gene immunodeficiency that confers susceptibility to herpes simplex virus, an idea that contrasts with the prevailing scientific theory of how genes work to make people vulnerable to infections. These new findings, the study added, may apply to other infectious diseases as well.

In the study, scientists focused on blood cells from two French children with a deficiency for UNC-93B, an endoplasmic reticulum protein involved in the recognition of pathogens. When infected with herpes simplex virus-1, the UNC-93B-deficient cells were unable to produce natural interferons alpha, beta, and gamma (IFNs -a/b and -g). Interferons are produced by the immune system to fight infections and tumors.

This deficiency resulted in high rates of herpes simplex virus-1 proliferation and cell death. Assuming these findings extend to neurons, they provide a plausible mechanism for herpes simplex encephalitis.

"We and our colleagues have identified recessive UNC-93B deficiency as a genetic etiology of herpes simplex encephalitis in otherwise healthy patients," said Professor Bruce Beutler, one of three Scripps Research scientists who contributed to the study. "The discovery of this genetic cause for herpes simplex encephalitis not only broadens our understanding of these types of immunodeficiencies, but also has important therapeutic implications—some of these patients could benefit from recombinant interferon alpha (IFN-a) treatment, just as patients with low levels of naturally occurring interferon gamma (IFN-g) benefit from a similar life-saving approach."

Herpes simplex virus-1 is a common virus that infects about 80 percent of young adults worldwide. Herpes simplex encephalitis, a viral infection of the brain that affects otherwise healthy patients, affects an extremely small percentage of those infected with herpes simplex virus-1: the number of annual cases is two per million people, according to the University of Maryland Medical Center.

Nonetheless, herpes simplex encephalitis, which was first described in 1941, is the most common type of sporadic viral encephalitis in developed countries, accounting for about 10 to 20 percent of all viral encephalitis cases, according to the University of Maryland Medical Center. Before the advent of anti-viral drugs vidarabine in 1973 and acyclovir in 1981, mortality rates reached up to 70 percent. While the introduction of anti-viral treatment has been a boon to patients, brain damage still poses a substantial risk.

"In contrast to most current thinking, we suspected that herpes simplex encephalitis susceptibility could be inherited as a monogenic trait resulting in the specific impairment of immunity to herpes simplex virus-1," Beutler said. "Here we have defined a genetic lesion that is permissive for an infection:  a trait that most would regard as quintessentially environmental in cause.  It is likely that other mutations will also be found to permit herpes simplex virus encephalitis, and likely that other infectious diseases will ultimately be traced to mutations that affect UNC-93B."

In addition to Beutler, authors of the study, titled "Herpes Simplex Virus Encephalitis in Human UNC-93B Deficiency," include: Laurent Abel, Armanda Casrouge, Céline Eidenschenk, Anne Puel, Nathalie Nicolas, Lazaro Lorenzo, Sabine Plancoulaine, Alexandre Alcais and Nora Mahfoufi of the Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descarte-INSERM, Paris; Shen-Ying Zhang, Emmanuelle Jouanguy and Kun Yang of the Laboratoire de Génétique Humaine des Maladies Infectieuses and the French-Chinese Laboratory of Genomics and Life Sciences, Rui-jin Hospital, Shanghai, People's Republic of China; Capucine Picard of the Laboratoire de Génétique Humaine des Maladies Infectieuses and the Centre d'Etude des Déficits Immunitaires, Hôpital Necker, Paris; Brigitte Sénéchal and Frédéric Geissmann of the Laboratoire d'Etude des Cellules Mononucléées, Hôpital Necker, Paris; Koichi Tabeta, Xin Du and Kasper Hoebe of the Scripps Research Insitute; Richard L. Miller of the 3M Center, St. Paul, MN; Bénédicte Héron, Cyril Mignotand Thierry Billette de Villemeur of the Service de Neurologie Pédiatrique, Hôpital Trousseau, Paris ; Pierre Lebon and Flore Rozenberg of Service de Virologie, Hôpital Saint-Vincent de Paul, Paris; Olivier Dulac of the Service de Neurologie Pédiatrique, Hôpital Necker, Paris ; Marc Tardieu of the Service de Neurologie Pédiatrique et INSERM, Hôpital de Bicêtre, Kremlin-Bicêtre, France; and Jean-Laurent Casanova of the Laboratoire de Génétique Humaine des Maladies Infectieuses, the French-Chinese Laboratory of Genomics and the Life SciencesUnité d'Immunologie et d'Hématologie Pédiatriques, Hôpital Necker, Paris.  Céline Eidenschenk has recently joined the Beutler laboratory at Scripps Research in La Jolla.

This study was supported by the Fondation pour la Recherche Médicale, the Schlumberger Foundation, the BNP-Paribas Foundation, the GIS Maladies Rares, the Action Concertée Incitative de Microbiologie, the Agence Nationale pour la Recherche, and the March of Dimes.

Send comments to: mikaono[at]scripps.edu

“The discovery of this genetic cause for herpes simplex encephalitis not only broadens our understanding of these types of immunodeficiencies, but also has important therapeutic implications."

—Bruce Beutler