RESEARCH OVERVIEW

High-throughput genomic and proteomic technologies have opened exciting new avenues for exploring virus-host interactions, providing a global view of the cellular gene expression and protein abundance changes that occur in response to virus infection. We make extensive use of these technologies to better understand the similarities and differences in the host response to a variety of highly pathogenic viruses and to explore the diverse means employed by viruses to evade cellular defense mechanisms.

Influenza virus

Every winter, influenza virus infects from 10 to 20% of the U.S. population and claims the lives of approximately 36,000 people. The greater threat from this virus, however, comes from its ability to occasionally generate particularly virulent strains that are capable of causing worldwide pandemics. The best known of these, the 1918 "Spanish flu" resulted in approximately 500,000 deaths in the U.S. and over 50 million worldwide. Despite advances in medical care and technology, another pandemic is thought to be inevitable, and it is estimated that as many as 200,000 deaths could occur in the next U.S. pandemic.

A primary objective of our work with influenza virus is to determine the viral and cellular factors responsible for the increased virulence of pandemic strains, particularly the 1918 virus. Toward this end, we are working with groups at the Mount Sinai School of Medicine, the Centers for Disease Control and Prevention, and the University of Wisconsin to study the fully reconstructed 1918 virus, as well as engineered viruses that contain one or more of the 1918 virus genes. Experimental systems for our influenza studies include cultured cell lines, primary differentiated human tracheobronchial epithelial cells, and mouse and macaque models of infection.

Hepatitis C virus

Most people infected with hepatitis C virus (HCV) develop a life-long infection. Although some will show little or no ill effects from the virus, the majority will develop chronic liver disease, which over a period as long as 20 to 30 years may result in cirrhosis and ultimately in liver failure. HCV-associated liver disease is now the leading cause for liver transplantation.

Our studies on HCV are aimed at providing a better understanding the molecular events underlying HCV-associated liver disease. We use a variety of experimental systems for our analyses, including a primary human hepatocyte culture system, the HCV-2a infection system, and the SCID-beige/Alb-uPA chimeric mouse model. We also work with clinicians from the University of Washington Liver Transplantation Program to perform genomic and proteomic analyses on serial liver biopsies from patients with recurrent hepatitis C after liver transplantation.

SARS coronavirus

Severe acute respiratory syndrome (SARS) first emerged in Hong Kong in November 2002 and quickly spread to 27 countries, resulting in over 8,000 cases and 774 deaths. Since the emergence of SARS and the subsequent identification of SARS coronavirus (SARS-CoV) as the etiologic agent, the virus has largely disappeared. There remains, however, a distinct possibility for another SARS outbreak. Our work on SARS-CoV centers on using a macaque infection model to evaluate the pathogenesis of SARS-CoV and the development of lung disease. In addition, we work with in vitro infection systems, including cultured primary bronchial and small airway epithelial cells and primary type-2 pneumocytes. Our goal is to use these experimental systems, together with high-throughput genomic technologies, to increase our knowledge of SARS-CoV pulmonary pathogenesis and to identify sets of genes whose expression patterns in response to infection may form the basis for diagnostic or prognostic assays, or which may suggest novel targets for antiviral therapies.

HIV-1 and SIV

Lentiviral infections lead to a broad range of outcomes in various primate species. For example, the same SIV strain that grows innocuously in African green monkeys will cause disease when introduced into pigtailed macaques. To better understand these diverse outcomes, we are collaborating with investigators at the University of California, San Francisco to use gene expression profiling to examine acute SIV infection in pigtailed macaques and African green monkeys. Our objective is to obtain information about which pathways of innate and adaptive immune activation are associated with pathogenic or nonpathogenic outcomes.

We are also using microarrays to analyze blood samples obtained from macaques in AIDS vaccine studies. Blood samples are taken prior to immunization, at multiple points during the immunization phase, and at multiple points following viral challenge. Expression profiles are then analyzed for features that correlate with innate or acquired immunity or with attenuation of disease. Our long-term goal is to identify gene expression signatures that define successful vaccination and differentiate vaccine candidates in a qualitative fashion.

Herpes simplex virus

In addition to causing cold sores, genital sores, and viral encephalitis, herpes simplex virus (HSV) is a leading cause of nontraumatic blindness, with more than 200,000 cases per year in the U.S. The life cycle of HSV is characterized by a lytic phase of infection at peripheral sites such as the cornea and skin, and a latent phase of infection in neurons, during which viral gene expression is extremely limited. Latency represents a lifelong source of virus, which can reactivate periodically causing severe ocular and other mucocutaneous damage. In collaboration with investigators at Washington University, we are using mouse infection models and DNA microarrays to study how HSV alters cellular gene expression, with particular attention to the mechanism by which the virus evades the innate immune response.


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ANNOUNCEMENTS Publication Highlight Chan et al., 2007. Quantitative analysis of HIV-1 infected CD4+ cell proteome: dysregulated cell cycle progression and nuclear transport coincide with robust virus production. J. Virol. 81-7571-7583. Read more...	RESEARCH OVERVIEW PEOPLE EMPLOYMENT PHOTOS LINKS RESEARCH OVERVIEW High-throughput genomic and proteomic technologies have opened exciting new avenues for exploring virus-host interactions, providing a global view of the cellular gene expression and protein abundance changes that occur in response to virus infection. We make extensive use of these technologies to better understand the similarities and differences in the host response to a variety of highly pathogenic viruses and to explore the diverse means employed by viruses to evade cellular defense mechanisms. Influenza virus Every winter, influenza virus infects from 10 to 20% of the U.S. population and claims the lives of approximately 36,000 people. The greater threat from this virus, however, comes from its ability to occasionally generate particularly virulent strains that are capable of causing worldwide pandemics. The best known of these, the 1918 "Spanish flu" resulted in approximately 500,000 deaths in the U.S. and over 50 million worldwide. Despite advances in medical care and technology, another pandemic is thought to be inevitable, and it is estimated that as many as 200,000 deaths could occur in the next U.S. pandemic. A primary objective of our work with influenza virus is to determine the viral and cellular factors responsible for the increased virulence of pandemic strains, particularly the 1918 virus. Toward this end, we are working with groups at the Mount Sinai School of Medicine, the Centers for Disease Control and Prevention, and the University of Wisconsin to study the fully reconstructed 1918 virus, as well as engineered viruses that contain one or more of the 1918 virus genes. Experimental systems for our influenza studies include cultured cell lines, primary differentiated human tracheobronchial epithelial cells, and mouse and macaque models of infection. Hepatitis C virus Most people infected with hepatitis C virus (HCV) develop a life-long infection. Although some will show little or no ill effects from the virus, the majority will develop chronic liver disease, which over a period as long as 20 to 30 years may result in cirrhosis and ultimately in liver failure. HCV-associated liver disease is now the leading cause for liver transplantation. Our studies on HCV are aimed at providing a better understanding the molecular events underlying HCV-associated liver disease. We use a variety of experimental systems for our analyses, including a primary human hepatocyte culture system, the HCV-2a infection system, and the SCID-beige/Alb-uPA chimeric mouse model. We also work with clinicians from the University of Washington Liver Transplantation Program to perform genomic and proteomic analyses on serial liver biopsies from patients with recurrent hepatitis C after liver transplantation. SARS coronavirus Severe acute respiratory syndrome (SARS) first emerged in Hong Kong in November 2002 and quickly spread to 27 countries, resulting in over 8,000 cases and 774 deaths. Since the emergence of SARS and the subsequent identification of SARS coronavirus (SARS-CoV) as the etiologic agent, the virus has largely disappeared. There remains, however, a distinct possibility for another SARS outbreak. Our work on SARS-CoV centers on using a macaque infection model to evaluate the pathogenesis of SARS-CoV and the development of lung disease. In addition, we work with in vitro infection systems, including cultured primary bronchial and small airway epithelial cells and primary type-2 pneumocytes. Our goal is to use these experimental systems, together with high-throughput genomic technologies, to increase our knowledge of SARS-CoV pulmonary pathogenesis and to identify sets of genes whose expression patterns in response to infection may form the basis for diagnostic or prognostic assays, or which may suggest novel targets for antiviral therapies. HIV-1 and SIV Lentiviral infections lead to a broad range of outcomes in various primate species. For example, the same SIV strain that grows innocuously in African green monkeys will cause disease when introduced into pigtailed macaques. To better understand these diverse outcomes, we are collaborating with investigators at the University of California, San Francisco to use gene expression profiling to examine acute SIV infection in pigtailed macaques and African green monkeys. Our objective is to obtain information about which pathways of innate and adaptive immune activation are associated with pathogenic or nonpathogenic outcomes. We are also using microarrays to analyze blood samples obtained from macaques in AIDS vaccine studies. Blood samples are taken prior to immunization, at multiple points during the immunization phase, and at multiple points following viral challenge. Expression profiles are then analyzed for features that correlate with innate or acquired immunity or with attenuation of disease. Our long-term goal is to identify gene expression signatures that define successful vaccination and differentiate vaccine candidates in a qualitative fashion. Herpes simplex virus In addition to causing cold sores, genital sores, and viral encephalitis, herpes simplex virus (HSV) is a leading cause of nontraumatic blindness, with more than 200,000 cases per year in the U.S. The life cycle of HSV is characterized by a lytic phase of infection at peripheral sites such as the cornea and skin, and a latent phase of infection in neurons, during which viral gene expression is extremely limited. Latency represents a lifelong source of virus, which can reactivate periodically causing severe ocular and other mucocutaneous damage. In collaboration with investigators at Washington University, we are using mouse infection models and DNA microarrays to study how HSV alters cellular gene expression, with particular attention to the mechanism by which the virus evades the innate immune response.
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