Research in this laboratory revolves around the study of viral pathogenesis, the development of therapeutics for orthopoxvirus infections, and the diagnosis of microbial infections. Pathogenesis is an interplay of the genetic expression of the infecting agent and the host's responses to infection, with the dynamics dictating the severity and the outcome of the disease process. Our goal is to define the genetic basis for poxvirus virulence in the mouse (ectromelia virus) and humans (molluscum contagiosum virus; MCV), as well as the multifactorial host response to infection, which precedes recovery from disease. MCV has a world-wide distribution causing persistent, benign, skin tumors in children, sexually active adults and is an opportunistic infection of acquired immunodeficiency syndrome (AIDS) patients. The study of poxvirus pathogenesis has gained added importance with the proposed use of recombinant vaccinia viruses as vaccines for humans, domesticated animals and wild-life, and as therapeutics for the treatment of solid tumors.
We are currently involved in efficacy testing of anti-virals and vaccines against orthopoxviruses in small animal models. Although four orthopoxviruses have been shown to cause disease in humans, only vaccinia (VACV), cowpox (CPXV) and monkeypox virus (MPXV) still cause human infections. With the global eradication of the disease smallpox in 1979, the causative agent variola virus (VAR) no longer circulates in human populations; however, there is concern that VAR could be reintroduced through bioterrorism and/or biowarfare. The reintroduction of aerosolized VAR (or perhaps monkeypox virus) into human populations would result in high levels of mortality since an efficacious anti-viral therapy is not available for the treatment of exposed individuals. Also the routine immunization of the U.S. civil population with VAC had all but ceased in the early 1970's, resulting in the population under the age of 30 lacking cross-protective immunity to VAR. Furthermore, the strength of vaccine immunity in older Americans has decreased with the passage of time leaving these individuals with less than optimal protection against smallpox. And finally, a growing segment of the American population is immunocompromised as a result of infection with human immunodeficiency virus (HIV), and the use of immunosupressive drugs for treatment of cancer and prevention of the rejection of organ transplantations.
Cytokines are pivotal to a balanced innate or cell-mediated immune response, can be indicative of disease progression and/or resolution, and are being evaluated as therapeutics. There is a need to purify and/or to measure key cytokines rapidly with accuracy, precision and sensitivity. The current technology, which is based on antibodies, has a number of drawbacks. An alternative approach explored in our laboratory, is the use of pathogen-encoded cytokine-binding proteins. It is anticipated that pathogens have evolved binding proteins, antagonists and/or specific neutralizing phenotypes directed against key signaling and effector molecules involved in the multi-faceted host defense system. Thus by screening the genomes of a wide-range of microbial agents we would expect to find coding sequences for binding proteins for the most important cytokines. Consistent with this view is the identification of poxvirus genes encoding binding activities for TNF, type I and type II interferons (IFN), IL-1ß, IL-18 and ß-chemokines. As proof-of-concept, we have developed a sensitive assay for measuring both mouse and human IFN-? using the IFN-? binding protein encoded by the orthopoxvirus ectromelia.. A longer term goal is to develop an instrument based on this technology to measure rapidly cytokines indicative of disease. It is envisaged that such an instrument will be of great value in the stratification of patients for treatment, and the development of treatments, for sepsis.
The long-term goal of this research is to apply our knowledge concerning the host's responses to infection and the ectromelia virus and MCV hrm genes to construct improved poxvirus vectors for gene therapy and vaccine applications as well as the design of anti-viral therapies. Currently we are evaluating poxvirus vectors for cancer therapy and as a recombinant vaccine against HIV.