Viral Manipulation of Cellular Systems
One of the major goals of virology is to determine how each viral protein contributes to viral infection and pathology. In many cases disease results from the destruction of tissue by infection itself, or from the consequences of immune action in response to the infection. In other cases, pathology is the unintended consequence of an infection gone wrong. Such is the case in many virus-associated cancers. Currently we are focused on learning the mechanisms by which polyomaviruses manipulate cellular pathways, and how these actions contribute to viral disease.
BKV and JCV are human polyomavirus that infect and persist in most humans. In most individuals these infections are harmless. However, both viruses can cause severe, even fatal, diseases in immunocompromised individuals. BKV is an important pathogen of kidney transplant patients, where the virus can undergo a rampant infection that destroys their kidneys. JCV is the causative agent of progressive multifocal leukoencephalopathy or PML, a progressive brain disease that leads to dementia and death. Little is known of the factors that suppress the replication of BKV and JCV in most individuals, nor of the specific mechanisms by which these viruses escape suppression during productive infection. We are exploring these mechanisms by comparing infections of primary human cell types that allow robust viral replication with those in which viral infection is restricted.
Large Scale Metagenomic Monitoring of Ecosystems
Viruses are everywhere. Every organism on Earth harbors viruses as components of their microbiome, or as transiently acquired infections. The diversity of known viruses is staggering in terms of structure, genome architecture, and strategies of replication and spread. New types of viruses are constantly emerging either due to host jumping, or to mutation and/or recombination of viruses within hosts. Yet little is known of the distribution of viruses in their natural environments, nor of the movement of viruses within and across species in the wild. We are developing molecular and computational tools for exploring viral diversity, surveilling viruses in nature, and understanding the factors that favor or restrict viral spread. We have developed powerful computational tools for detecting viruses in NGS sequence databases. Currently we are developing strategies to apply these methods to relatively large scale ecosystems.
We are examining four types of samples to identify viruses present in a given ecosystem, and to garner information about their distribution. These include feces, untreated wastewater, mosquitoes, and pollen. Feces in some form are deposited by nearly all life forms. In many cases feces are straightforward to collect and to identify the species of the depositor. The feces of most humans are collected in the form of sewage. We are identifying viruses present in individual fecal samples as well as in untreated wastewater in order to map the distribution of viruses within a defined geographic region, and to associate viruses with specific hosts. We are also using mosquitoes, and other biting insects, as tools for collecting blood from vertebrate species. This involves a longstanding collaboration with Microsoft as part of their Project Premonition. Microsoft has developed robotic insect traps that allow for large scale collection and barcoding of individual mosquitoes. NGS sequencing of individual mosquitoes and subsequent computational analysis allows the identification of the mosquito species and the species of any bloodmeal, as well as the detection of bacteria, viruses, and other microbes. Finally, we are collaborating with the laboratory of Dr. Tia-Lynn Ashman to define and understand the pollen virome.
