Laboratory Research at Yale on Human Viral Pathogens
Arthropod-borne (arbo-) viruses are transmitted between vertebrate hosts by mosquitoes, ticks, and other invertebrates; these include flaviviruses, alphaviruses, and bunyaviruses. Dr. Brett Lindenbach studies the replication and pathogenesis of several flaviviruses, including yellow fever, dengue, Powassan, and Zika viruses. Dr. Nathan Grubaugh uses advanced genomics techniques to examine the emergence and spread of mosquito-borne viruses like Zika, chikungunya, dengue, and West Nile. Dr. Akiko Iwasaki has developed unique mouse models to study the sexual transmission and pathogenesis of Zika virus. Dr. Peter Cresswell is examining the molecular mechanisms by which Viperin — a cellular antiviral gene discovered in his lab — inhibits the replication of many viruses, including flaviviruses. Dr. Priti Kumar is developing RNA-based strategies to inhibit the pathogenesis of dengue and West Nile virus (flaviviruses). Dr. Erol Fikrig is interested in arthropod vector transmission of several arboviruses, including West Nile virus, Zika virus, Powassan virus, and chikungunya virus (an alphavirus) and how transmission impacts pathogenesis. Dr. Paul Turner studies the evolutionary robustness of dengue virus and chikungunya virus, as well as viral adaptation to arthropod and vertebrate hosts.
Many unrelated RNA and DNA viruses target the liver, a large, highly vascularized organ that regulates metabolism and blood composition, causing hepatitis. Dr. Lindenbach uses reverse genetic and virus culture systems to study the RNA replication and virus particle assembly of hepatitis C virus (HCV; a positive-strand RNA virus). Drs. Anna Pyle and Lindenbach collaborate to understand the structure of the HCV RNA genome and the role of the HCV RNA helicase and other viral nonstructural proteins in RNA replication. Dr. Michael Kozal is interested in HCV diversity and the evolution of drug resistance. Drs. Robert Heimer and Elijah Paintsil are using cell culture models of HCV particle inactivation to develop public health recommendations on how to minimize HCV exposure in high-risk populations. Dr. Yung-chi (Tommy) Cheng is developing new drugs with antiviral activities against HCV and hepatitis B virus (a reverse-transcribing DNA virus).
Nearly every human is infected with one or more herpesviruses, a large family of DNA viruses that can cause acute infections as well as smoldering latent infections that can contribute to cancer. Drs. George Miller and Ayman El-Guindy are studying transcriptional regulation by Epstein-Barr virus and Kaposi's sarcoma herpesvirus and the basis for the switch between latent and lytic infection by these viruses. Dr. Joan Steitz is studying the role of small viral RNAs and cell activation in herpes virus replication and transformation. Dr. Tommy Cheng is testing the activity of small molecule inhibitors of herpes virus replication. Dr. Akiko Iwasaki is characterizing mucosal immunity to herpes virus infection. Dr. Anthony Van den Pol is studying the mechanisms of infection and treatment for CMV infections of the central nervous system. Dr. Christian Schlieker uses herpesviruses as tools to study the dynamics and stress pathways of the cell nucleus.
Norwalk virus is the leading cause of gastroenteritis in humans, yet it has been difficult to study due to a lack of efficient cell culture systems and genetic tools. Dr. Craig Wilen uses murine norovirus as a model system to dissect the tropism, replication, and immune response to noroviruses, then applies these discoveries to better understand human noroviruses.
Papillomaviruses are small DNA viruses that are experts in manipulating the cell cycle of their vertebrate hosts; some can directly cause cancer. Dr. Dan DiMaio is exploring the role of cellular proteins in human papillomavirus (HPV) entry and intracellular trafficking to the nucleus. He is also using the bovine papillomavirus E5 protein as a platform to develop artificial transmembrane proteins with a variety of biological activities, including antiviral activity. Dr. Akiko Iwasaki is developing new vaccination strategies to prevent and treat papillomavirus infections; these latter studies are carried out in collaboration with colleagues in Immunobiology, Pathology, Comparative Medicine, Microbial Pathogenesis, and Biomedical Engineering.
Parvoviruses are small, unusual viruses with single-stranded DNA genomes. Dr. Peter Tattersall is exploring the mechanisms of parvovirus DNA replication and packaging and the use of parvoviruses as vaccines and oncolytic agents. Dr. Tattersall also studies the epidemiology and biology of bocavirus, a recently-discovered parvovirus that causes human disease.
Dr. DiMaio is using functional genomics, cell biology, and biochemistry to study the process by which JC virus and BK virus enter cells. These common human viruses can cause serious disease in immunosuppressed individuals, including AIDS patients.
The human respiratory tract, a highly-vascularized portal into the body, is targeted by numerous viruses. Dr. Ellen Foxman studies innate immunity and pathogenesis of rhinovirus (a picornavirus) and other respiratory pathogens. Dr. Charles Dela Cruz studies the impact of chronic lung disease on innate immunity to influenza virus (an orthomyxovirus) and respiratory syncytial virus (a paramyxovirus). Dr. Richard Martinello is studying the transmission of respiratory viruses and the prevention of respiratory virus infections.
A strong group of HIV-1 researchers work on various aspects of HIV-1 biology, pathogenesis, retroviral restriction, antiretroviral therapies and cure research. Drs. Walther Mothes, Yong Xiong, and Jun Liu study the structural biology of HIV particles, accessory proteins and restriction factors. Dr. Walther Mothes studies HIV-1 entry, pathogenesis and transmission. Drs. Ya-Chi Ho and Kathryn Miller-Jensen study HIV-1 latency by using single cell technologies. Drs. Michael Kozal, Karen Anderson and Elijah Paintsil develop and improve antiretroviral therapies and study drug resistance. Dr. Sutton is studying HIV+ elite controllers and develops vectors to express broadly neutralizing antibodies. Drs. Ya-Chi Ho, Priti Kumar and Richard Sutton work towards a cure of HIV-1 that includes eradication strategies of latently infected cells and the restoration of immune control. Dr. Cheng is testing the activity of small molecule inhibitors of HIV replication, and Dr. David Spiegel is developing small molecule immunotherapies that target HIV-1 for eradication. Dr. Amy Justice studies clinical outcomes in aging HIV-1 infected patients on long-term antiretroviral therapies. Dr. Sten Vermund studies HIV-1 associated virally induced cancers and is a leader in global HIV-1 prevention and treatment programs.
Dr. John Rose is studying rhabdovirus replication and is developing VSV as a novel vaccine agent against multiple viral pathogens including HIV, papillomavirus, and influenza. Drs. Van den Pol and Tattersall are exploring the use of VSV and other viruses as oncolytic agents. Dr. Turner uses VSV as a model RNA virus to study the molecular basis of evolution.
Transmissible Spongiform Encephalopathies
Dr. Laura Manuelidis has a long-standing interest in late onset neurodegenerative diseases and their potential causation by viruses or virus-like agents. In this context, her lab established small animal models of human neurodegenerative diseases (Creutzfeld-Jacob Disease, kuru, and bovine spongiform encephalopathy) associated with prion-like agents. More recently, Dr. Manuelidis discovered ancient bacterial viruses in the cytoplasm of mammalian brain cells and is interrogating their potential participation in TSE infection and neurodegeneration.