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Our group seeks to understand how viruses cause disease in humans. A better understanding of these mechanisms can lead to the development of vaccines to prevent new infections and anti-viral drugs to treat current infections. The lack of animal models that can be infected with human viruses and exhibit similar disease has seriously hampered these areas of research. In order to study viral infections of human cells in vivo, we use “humanized mice.” A humanized mouse is one in which human cells have been transplanted. We transplant mice with human hematopoietic stem cells; this leads to production of a variety of human blood cell types and development of a human immune system in the mouse. Antibody and cellular immune responses of human origin can then be generated in the mouse.
We are interested in studying viral pathogens that infect human blood cells in our humanized mice. Examples include Human Immunodeficiency Virus (HIV), Human herpesvirus 6 (HHV-6), Kaposi’s Sarcoma Herpesvirus (KSHV), and Human T-Lymphotropic virus (HTLV). About 34 million people worldwide are HIV+, and millions die each year from complications due to AIDS. No vaccines exist, and although effective antiviral drugs are available, they have undesirable side effects and the virus can mutate to escape. One side effect of AIDS is HIV-associated lymphoma (cancer of white blood cells) which commonly arise in patients co-infected with gammaherpesviruses like KSHV. No vaccine is available for KSHV, and we have little understanding of how immunosuppression leads to development of cancer. HHV-6 is a common human pathogen which may cause autoimmune disease in humans, but it has not been well studied to date. We have recently published on a new humanized mouse model of HHV6 type A infection and disease. HTLV causes Adult T cell Leukemia/Lymphoma (ATLL) in humans many years after initial infection, but mechanisms of oncogenesis are poorly understood.
Left to Right: (1) Figure 1. Lymphoid organs are populated with human T cells in humanized mice (red spots) (2) Figure 2. Humanized mice can be infected with human pathogens such as HIV (HIV RNA detected in purple spots)
The lack of good animal models to study how these viruses cause disease has prevented research and development of vaccines and antiviral therapies. Our humanized mice support infection with each of these viral pathogens. Further, human immune responses can be detected against the pathogens, making this a promising model to study vaccines. Work in our lab involves infecting humanized mice with various viral pathogens, and then studying how disease is caused. Immunization strategies are being investigated to develop potential vaccines for humans. Additionally, antiviral drugs can be tested for efficacy and toxicity. Those who work in the lab gain valuable experience in the areas of: laboratory mouse handling/manipulation, mouse injections, mouse dissections, drawing blood, production of virus stocks, virus titering, tissue culture, handling infectious substances, RNA in situ hybridization, immunostaining, flow cytometry (FACS), DNA and RNA extraction, PCR, RT-PCR, and Quantitative PCR, ELISA, and analysis of human immune responses (antibody and cellular).
Left to Right: (1) Figure 1. Humanized mouse antibodies against Dengue virus are able to neutralize infection of cultured cells (green dots depict infected cells) Figure 2. Overview of procedure to engraft mice with human immune stem cells (2)
We are also performing research on Staphylococcus aureus. S. aureus (SA) is a common human pathogen that causes many different types of diseases in humans, ranging from pneumonia to skin lesions to bone infections. There are no vaccines available to prevent SA infections, and while some antibiotics are effective SA has gained resistance to many common antibiotics. Methicillin-resistant S. aureus (MRSA) strains are becoming more and more common, and these strains tend to be resistant to most available antibiotics. We are performing studies to better understand how humans get exposed to SA and MRSA, including through contaminated meat products available at local grocery stores. We have frequently detected SA and MRSA in raw meat samples, and we have characterized the levels of antibiotic resistance in these strains. New treatments and approaches are needed to both treat existing SA infections, and to prevent new infections, which are common on hospital settings. We have discovered bacteriophage which can kills MRSA, and we have shown that we can decontaminate surfaces containing MRSA effectively by adding phage. We are also doing research on SA biofilms. Biofilms are a sort of microbial community, with thick walls built around for protection. Bacteria like to form biofilms because anti-bacterial drugs and immune cells can be excluded from these environments, thus allowing the bacteria to survive. SA and MRSA form multiple types of biofilms, ranging from polysaccharide-based to protein and DNA-based. The regulation of how these are formed is poorly understood, but MRSA biofilms tend to be protein/DNA-based and methicillin-susceptible strains tend to be polysaccharide-based. We are seeking to understand how these decisions are made, which genes are involved, and why it is that some strains can shift their biofilm type (likely a complex process) by introduction of a single gene (with no clear relation to biofilm formation).