Life threatening viral encephalitis, caused by viral infections of the central nervous system, are a major cause of human disease and mortality, but the mechanisms by which it develops remain poorly understood. In the Laboratory of Human Genetics of Infectious Diseases (headed by Jean-Laurent Casanova), Zhang leads a team studying single-gene inborn errors of immunity that predispose individuals to viral encephalitis.
The major added value of human studies is that they enable scientists to define the function of host defense genes under the natural conditions of an infection. Zhang and her colleagues have found that childhood encephalitis caused by a variety of viruses can result from single-gene inborn errors of immunity in the central nervous system. For example, forebrain encephalitis caused by herpes simplex viruses 1 (HSV-1) can result from inborn errors of antiviral mechanisms, including those involving Toll-like receptor 3 (TLR3) and interferon (IFN)-α/β. They also discovered defective IFN immunity due to DOCK2 and POLIII deficiencies in some children with encephalitis caused by varicella zoster virus. More strikingly, brainstem encephalitis caused by HSV-1, influenza virus, or norovirus can result from inborn errors in a form of RNA processing called RNA lariat metabolism, due to mutations in DBR1. These findings provided proof-of-principle that childhood viral encephalitis in general may result from inborn errors of tissue-specific, cell-autonomous immunity.
Zhang’s current research investigates the molecular and cellular basis of antiviral immunity in the central nervous system with great breadth and depth. She hopes to achieve a fundamentally revolutionized understanding of human antiviral immunity in the central nervous system, to provide guidance for the development of new viral encephalitis treatment strategies.