I completed my undergraduate studies at Washington University in St. Louis with a major in Biology. During my time there I worked in the lab of Dr. Craig Pikaard investigating chromatin silencing and gene expression. I then received my PhD from The Johns Hopkins University where I was mentored by Dr. Brendan Cormack in the Department of Molecular Biology and Genetics. There I studied the yeast cell wall and how cell wall proteins affect pathogenesis of Candida glabrata. My post-doctoral training was at The University of North Carolina at Chapel Hill in the laboratory of Dr. Ralph Baric where I studied the Innate Immune Response to the SARS Coronavirus. After my post-doctoral fellowship I joined the faculty in The Department of Microbiology and Immunology at The University of Maryland School of Medicine where I began my own lab in July of 2009. My lab mainly focuses on the Pathogenesis and Host Response of the SARS Coronavirus.
The emergence of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2003 put a spotlight on emerging infectious diseases worldwide. While these new pathogens attempt to infect us, our bodies have many basic defenses to thwart their attacks. My lab investigates the interaction between the SARS-CoV and the host during infection. In the case of SARS-CoV and other highly pathogenic respiratory viruses, while the virus causes much damage to the lungs during infection, it is the body's response to the infections that lead to the most damage. My lab studies the interaction of SARS-CoV with the innate immune system, the host's response to viral infection and the pathways that after infection cause lung damage leading to acute lung injury (ALI), pulmonary fibrosis and Acute Respiratory Distress Syndrome (ARDS).
SARS-CoV and the Innate Immune Response
Many highly pathogenic viruses interact directly with the innate immune response during infection. The innate immune system is the first line of defense against invading pathogens. Unlike the Adaptive Immune response that uses antibodies specific to the target, the innate immune response offers broad-spectrum protection against viruses and bacteria. Once the body senses the invading virus a signaling pathway is activated leading to the expression of hundreds of proteins to quench the replicating pathogen. We found that SARS-CoV blocks the induction of this anti-viral pathway, specifically the Interferon activation (RIG-I, IRF3, NFkB) and Interferon signaling pathway (STAT1). We have identified several proteins in SARS-CoV that inhibit either the activation, signaling, or nuclear transport of host proteins responsible for inducing the innate immune response. We are currently identifying the mechanism of action of these proteins and their roles in pathogenesis.
SARS-CoV and the Induction of Acute Lung Disease
The interaction of SARS-CoV and the host is highly regulated. The Spike protein on the surface of the SARS-CoV binds to ACE2 on the surface of airway epithelial cells. Once bound, the virus is endocytoced into endosomes and released into the cytoplasm where it starts its replication. As virus replicates and begins to traffic out of the cells into the surrounding milieu, the infected cells start to die. During this whole process the immune system begins to respond to the viral infection by recruiting inflammatory cells such as neutrophils, eosinophils, macrophages and dendritic cells to the site of infection. The SARS-CoV causes damage not only to the cells it infects but by manipulating the immune response so that the infiltrating cells also cause excessive damage to the tissue around the infection. This leads to the induction of a wound healing response and the recruitment of fibroblasts to repair the damaged tissue leading to more recruitment of inflammatory cells.
The pathways controlling the healing process, mainly controlled by the Epithelial Growth Factor Receptor (EGFR), are critical to survival from SARS. If the infection can be controlled and these pathways function correctly then the person survives, however if they become uncontrolled and the response leads to increased damage then the person may die. This damage does not always lead to immediate death. The repair process leaves severe scarring behind in humans and in mouse models of SARS-CoV which can cause death up to 2 years later in infected people. We are utilizing the mouse model of severe SARS-CoV infection to understand the role that the host response plays in the lethality of SARS-CoV.
Bats and emerging human viruses
Bats are among the most ancient and diverse mammals and have been implicated as the key reservoir species for several emerging and reemerging human viruses, like Ebola, Marburg, Severe Acute Respiratory Syndrome (SARS-CoV), Rabies (RABV), Hendra, and Nipah viruses. However, bats also harbor viral diseases more commonly associated with rodent reservoirs. In fact, Arenavirus, Bunyavirus, Flavivirus and Alphavirus are commonly harvested from bats globally, suggesting that bats may function as spillover reservoirs, augmenting the geographic dissemination of many common vector borne viruses that are typically maintained in reservoir pools like rodents and birds. These observations strongly argue that bats play a critical role in harboring and disseminating zoonotic-human viruses across the species barrier.
Using a multidisciplinary approach that includes bat ecologists, computational biologists, state of the art deep sequencing methodologies, and synthetic molecular genetics; our long-term goal is to detect, identify, and characterize the viromes of different bat species, and determine the viral and host factors that that facilitate cross-species transmission of these viruses to human and animal populations. We are going to identify and characterize the RNA virome of at least seven eastern North American bat species, evaluate the role of bats as reservoir hosts for common emerging viruses, develop a panel of select bat orthologous receptors and synthetic viral genomes that will facilitate research in the area of recovery, cultivation and trans-mammalian transmission.
Novel emerging Beta Coronavirus
A novel Coronavirus has recently emerged in the Middle East causing 17 known infections and 11 deaths. This new Coronavirus, named hCoV-EMC for Erasmus Medical College where the initial isolate was sequenced, is a beta Coronavirus that is phylogenetically similar to two bat Coronaviruses, BtCoV-HKU4 and BtCoV-HKU5. BtCoV-HKU4 and BtCoV-HKU5 were sequenced from bats in China however no viral isolates have been recovered from animals. These 3 viruses are also phylogenetically related to the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) which also emerged from a bat reservoir in China causing severe respiratory illness and death in ~10% of the ~8000 infected individuals. Patients infected with hCoV-EMC present with severe respiratory illness, renal failure and, in greater than 50% of cases, this resulted in death. We are currently studying the ways that hCoV-EMC, BtCoV-HKU4 and BtCoV-HKU5 viral proteins interact with the innate immune response, the host response to infection and the identification of novel therapeutics for treatment of hCoV-EMC infection.
Grants and Contracts:
NIH NIAID RO1
RMRCE Grant NIH/NIAID
SERCE Grant NIH/NIAID
K22 NIH/NIAID Research Scholar Development Award