We are fascinated by viral evolution, dissemination, and host response
Viruses encounter several environments and niches as they travel within and between hosts. For example, enteric viruses are exposed to the external environment, digestive enzymes, and intestinal microbes before they initiate replication in the gut. Some enteric viruses can disseminate to the central nervous system through blood or neural routes. How do these different environments influence viral replication, evolution, pathogenesis, and transmission? What barriers limit viral dissemination? Our lab uses tractable model viruses to learn about niche-specific factors that influence viral infection and evolution.
Our Strategy
We leverage the power of genetics and viral model systems to explore complex interactions, such as the impact of the intestinal environment or the effect of circadian rhythms on viral infection. We use a variety of tractable viruses including coxsackievirus, rhinovirus, reovirus, and murine norovirus.
Virus-microbiota interactions
Enteric viruses encounter a vast microbial community in the mammalian digestive tract prior to initiating infection. We found that gut microbes are required for replication and pathogenesis of two unrelated mammalian enteric viruses, poliovirus and reovirus. Similarly, other groups have demonstrated that a mouse retrovirus and norovirus also rely on intestinal microbiota for replication. A common theme has emerged: Enteric viruses bind bacterial surface polysaccharides. We found that exposure to bacteria or bacterial surface polysaccharides enhanced viral stability and cell attachment, providing one mechanism by which intestinal microbiota promote enteric virus infection. Virion stabilization by bacteria may be important for transmission, since a mutant poliovirus with reduced binding to bacteria had a fecal-oral transmission defect due to virion instability in feces. Additionally, we visualized virion-bacteria interactions using electron microscopy and found that each bacterium binds several poliovirus or reovirus virions and we demonstrated that bacteria can deliver multiple virions to host cells to initiate infection. In fact, virion-bound bacteria are likely transmitted between hosts, which may redefine the viral “infectious unit”. We are currently exploring the breadth of microbiota effects on viruses as well as molecular mechanisms by which microbiota promote enteric virus infection.
Viral evolution and population dynamics
RNA viruses exist as populations of genetically diverse viruses with varying levels of fitness. Viral genetic diversity is generated through error-prone RNA replication. Mutations can have several consequences: most are deleterious, some are neutral, and a few may be beneficial.
We have a variety of projects related to viral evolution, including how unique environments shape viral populations and drive emergence of unique variants, how co-infection influences viral evolution and fitness, and how the complex intestinal environment affects enteric virus evolution and transmission. We also examine host barriers that limit dissemination of viral populations.
Experimental evolution
Over the past 20 years, we have used “gain of function” forward genetic screens with BSL2 viruses to identify unique factors that influence viral fitness. By serially passaging viral populations in the presence of selective pressures (drug, mice, heat, speed), unique mutants emerge and can illuminate new aspects of virology ranging from tropism determinants to replication inefficiencies.
Host response to infection
We have been examining the impact of circadian rhythms on enteric virus infection. Circadian rhythms are 24 hour oscillations in a variety of processes that are entrained by environmental cues including light. Molecularly, this “clock” is driven by key transcription factors and feedback loops that generate rhythmic expression of thousands of mammalian genes in a variety of tissues. Past work has revealed the impact of circadian rhythms on metabolism and immunity. However, the impact of circadian rhythms on infection, particularly enteric virus infection, is understudied. Preliminary experiments using coxsackievirus B3 revealed a profound circadian effect on infection. Our ongoing work is examining the mechanisms and consequences of host rhythmic gene expression on enteric virus infection.
