Pathology – Dr. Fu’s Lab
Our research focuses on the investigation of the mechanisms by which rabies virus causes neurological diseases and by which rabies virus is attenuated.
We work with rabies and rabies virus. Rabies is a viral disease that affects the central nervous system of mammals, and death usually occurs within days of the onset of symptoms. Rabies is one of the ancient diseases and its history can be traced back to 5000 year ago. Rabies still presents a public health threat today despite extensive research and development in the past one hundred years. Around the globe, more than 70,000 people succumb to rabies every year and millions seek post-exposure treatment due to bites by rabid and suspected rabid animals. Our research focuses on the investigation of the mechanisms by which rabies virus causes neurological diseases and by which rabies virus is attenuated. Since rabies is an infectious disease and a zoonosis, our research efforts have important implications in infectious diseases, neuroscience, and public health.
We are also engaged in the development of immune therapy for clinical rabies. One of the hallmarks for rabies is that almost all the rabies will die once clinical signs develop. Our research as well as research from other laboratories have indicated that rabies patients (animals) do not develop virus neutralizing antibodies (VNA) at the time of death. Furthermore, VNA developed in the periphery may not be able to cross the Blood-brain Barrier (BBB) to neutralize the virus in the central nervous system (CNS). Indeed, VNA was found in the cerebral spinal fluid (CSF) in a few cases who survived the diseases. We have been interested in investigate if delivery of VNA into the CNS can aid virus clearance from the CNS and protect animals from dying of rabies.
Rabies is one of the most important zoonotic infections and still causes more than 70,000 human deaths each year. Most of the human rabies cases occur in Asia and Africa where dog rabies is prevalent. In the United States, dog rabies has been eliminated through massive vaccination during the past 7 decades. However, bat (particularly the silver-haired bats) rabies has emerged to be responsible for most of the human rabies cases in the past 30 years. Once clinical signs develop, rabies is almost always fatal. Despite the lethality of rabies, only mild inflammation and little neuronal destruction were observed in the CNS of rabies patients. On the other hand, laboratory-attenuated RV induces extensive inflammation and neuronal degeneration in experimentally infected animals. To understand the mechanism of virus attenuation, we have investigated the induction of innate immunity by virulent and attenuated rabies viruses. It has been found that laboratory-attenuated RV activates innate immunity and induces extensive inflammation, apoptosis, and neuronal degeneration in the CNS; however, wt RV caused little to no inflammation or neuronal damage. The induction of innate immunity has been confirmed when other laboratory-attenuated viruses were used to infect mice or neuronal cells. Induced innate immune response genes include inflammatory chemokines (including RANTES, MIP-1a, IP-10) and cytokines (IL-6, IL-1b, and TNF-a), IFN and IFN-related genes (IFN-a/b, STAT1), as well as Toll-like receptors (TLR). These observations led us to hypothesize that wild-type rabies viruses evades the innate and adaptive immunity by inhibiting the induction of chemokines and cytokines, the activation of dendritic cells, and the development of adaptive immune (VNA) responses.
The expression of chemokines by the attenuated rabies viruses correlates with the infiltration of inflammatory cells into the CNS and the enhancement of the BBB permeability. Enhancement of BBB permeability has been proposed to play an important role in allowing immune effectors to cross the BBB and enter the CNS. We have found that the induction of chemokine/cytokine expression correlates with the enhancement of BBB permeability, suggesting that chemokine/cytokine expression may be responsible to the changes in BBB permeability.
Another important project derived from above studies is to develop live-avirulent rabies virus vaccines by cloning and expressing chemokines in rabies virus genome. Up-to-date, many chemokines and cytokines have each been incorporated into the rabies virus genome. It was found that recombinant rabies virus expressing these chemokines and cytokines was further attenuated and does not induce any disease in mice after intracerebral infection. Furthermore these recombinant rabies viruses induce higher levels of VNA and provides better protection than the parental virus. These data indicate that recombinant rabies virus expressing innate immune molecules has the potential to be developed as live-avirulent rabies virus vaccines.
Currently, Dr. Fu is focused in developing therapeutics for clinical rabies because there is no successful treatment protocol available. One of the major findings in human rabies survivors is the detection of VNA in the CSF at the time of clinical onset. Similarly, VNA have also been found in the CSF of recovered dogs and ferrets after experimental infections. Thus, VNA in the CNS plays a vital role in rabies virus clearance from CNS. Thus, Dr. Fu is involved in developing VNA-based immune therapy for clinical rabies.
Our research has been funded by the National Institutes of Health and pharmaceuticals companies.
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