How is human activity influencing viral circulation?
Human activity is impacting both regional and global ecology on a scale previously unseen. As human populations have grown and the boundaries between human and wild spaces are impacted, both by resource exploitation and physical interaction, ecological processes are likely to be effected, including disease transmission and evolution. Infectious disease dynamics are clearly impacted by human activity and influenza is a good example. Cross species transmission and incursion into human populations threatens emerging epidemics. We are investigating the impacts of human activity on influenza ecology and evolution by studying the impact of fisheries activity on viral distribution and prevalence in both gulls and shorebird species in Alaska. This work will lead to new understanding and model parameters that help us determine what factors are important in the evolution of new, potentially pandemic strains of virus and to understand how we may intervene to delete such viruses in their infancy.
Are shorebirds sharing virus with co-migrating species? Does virus peak at any time and is it consistently present in this western flock?
One of the best described and most infamous locations for investigating avian influenza is Delaware Bay, New Jersey. A detailed relationship between Horseshoe crab spawning and shorebird migration appears to amplify virus transmission in a unique manner important to the persistence and prevalence of virus. Outside of Delaware Bay, investigations are sparse but suggest the Delaware Bay ecology is unique. We have undertaken surveillance studies of shorebirds in another major aquatic ecosystem, the Copper River Delta, to determine how the viral ecology in this shorebird migration compares to the infamous Delaware Bay. Our findings, along with those of our other Alaska studies will help to understand the unique and common parameters important to shorebird carried influenza virus transmission across diverse but important ecosystems.
What virus are grey seals responding to and shedding? Do they represent different pools? Are all seals/seal populations/pinnipeds created equal in influenza susceptibility?
Over the past 30-40 years, numerous instances have been documented of influenza disease outbreak in pinnipeds, primarily harbor seals, and primarily in the Northwest Atlantic Ocean ecosystem. Recent studies by our group have demonstrated the presence and likely endemic circulation of influenza viral strains in Atlantic Grey Seals who are exposed to virus with apparently few clinical signs. Studies of other RNA virus indicates that Harbor Seals may be more sensitive to emerging infection than cohabitating Grey seals. Our investigations are seeking to understand the ecology of influenza in pinniped species and to explore the importance of differences in immune response between Harbor and Grey seal species.
Viral Diagnostics (MIT Underworlds Team)
Is influenza detectable in public sewage streams? If so, can we detect rising prevalence before other types of data? Are other viral pathogens detectable? What is the best method to detect virus? Can we improve on the method?
Human data on publicly significant viral infection is garnered primarily from hospital admissions and visits that are inconsistently reported and may take weeks to filter through to epidemiological investigations. Surveillance for Influenza and other disease agents, undertaken in a more timely, consistent, and comprehensive manner could have major impact on public health response. We are investigating the logistical and technical challenges of using waste streams as a reliable and informative source of information on pathogen epidemiology.
Do influenza viruses undergo characteristic adaptations to replication in the cells of new species? How do they differ?
Movement of influenza virus between species has proven crucial to emergence of dangerous viral strains in humans. However, we know that mutational and reticulare processes are key to the interspecies events that make this possible. We are exploring the constraints and possibilities of viral adaptation in host species, particularly mammalian hosts to understand more fully the ability of different viral strains and potential wild hosts to play critical roles in emerging disease in humans.
How does microbial community and environmental factors (physical, chemical) impact persistence of influenza virus (or other virus)?
In avian species in particular, environmental factors play a critical role in the survival and transmission of virus to new hosts. Virus shed into the environment must persist as infective particles to enable transmission into new hosts. Despite this, our understanding of environmental persistence does not go far beyond basic chemical parameters. We are investigating the complexities of environmental transmission including factors associated with bacterial communities, likely a strong component for survival both outside and inside the influenza host.
Can we effectively model (by machine learning) influenza phenotype by sequence and limited phenotypic assay? Is this a model for other virus/pathogen? Can we make phenotypically predictive changes in viral proteins?
Mutations in the influenza viral genome that have been experimentally tested to enhance viral adaptation to mammalian cells are used to identify naturally occurring strains of increased risk to public health. Our preliminary data suggest that this mutational data alone are, at best, insufficient for concluding that a virus is of high risk. Additionally, viral genetic background is often an untested confounder preventing balanced comparison of viral phenotypes between experiments designed to characterize new viruses of interest. This has resulted in an inability to accurately assess and compare the potential of newfound viruses for human pathogenesis. Combined with the volume of viral genomic sequence diversity being generated by viral surveillance efforts, this problem requires a new, rational, comprehensive approach to achieve the goals of predictive and preventative pathogen surveillance. We have begun development of a new platform to assess viral risk. In this work we are systematically characterizing the functional differences attributable to natural polymorphic diversity of influenza virus polymerase genes. The resulting high quality dataset, covering all known polymorphic diversity in contemporary viruses is then being used to train machine learning models to predict the phenotype of novel virus from their nucleic acid sequence. This project will deliver a high quality dataset for the influenza research community, including a web-based front-end to the predictive model of influenza phenotypes from genotype, which will find downstream use in drug development, influenza surveillance, and other translational applications. We are in the initial steps of a long range plan to expand a platform for influenza risk assessment based on viral genomic sequence alone. Our study will also serve as a template study design for merging data science with experimental techniques to advance broadly applicable pathogen characterization efforts.
Are there features of proteoglycan “receptors” that define binding of flu virus? Can they be exploited therapeutically?
A focal point of the G/P work is on understanding the critical features of proteoglycan receptors and viral ligands that define host/pathogen interactions. Through a combination of computational and experimental means, we are attempting to define the shared features of influenza virus that impact viral docking to host cells and that distinguish the predilection of viral subtypes for host species
How does the composition of host membranes impact viral life cycles? How is this controlled by the host/virus?
Influenza virus enters and exits a host cell via interactions with cell membrane components, both viral and host derived. Experimental evidence suggests that, like many cellular pathogens, the assembly and budding of viral progeny is not random with respect to the known organizational characteristics of host cell membranes. For instance, viral assembly is likely occurring at regions of lipid rafts in the host cell. We are working to understand the differences in host cell membrane components between influenza hosts and how those differences impact and might be exploited to alter the efficiency of viral replication.
Can we demonstrate high-throughput utility of gibson cloning method and demonstrate impact of predicted changes to the H3N8 virus?
Experimental work with influenza viruses relies on the creation and recreation of viral strains that can be tested and studied in the laboratory. Up to the present, viral synthesis is accomplished via restriction target driven reassembly of the viral segments of interest that can be used in a reverse genetics system to regenerate virus of interest. We are demonstrating how now common techniques in molecular manipulation of viral plasmids can be employed for the high-efficiency and rapid regeneration of influenza virus of interest. These tools can then be easily used by anyone in the field to create experimental reagents.
Toxicology and Infection
Do environmental contaminants or natural products impact immunity/resistance to influenza infection? If so, does this influence the frequency of spillover events?
Several studies have demonstrated, in both animal models and in natural occurrences the bioaccumulation and immune effector impacts of contaminant molecules. Likewise, it is well established that viral (and more generally microbial) infection also can result in both immune stimulation but also immune modulating impacts. With increasing evidence of environmental contamination due to an ever increasing array of natural and man-made compounds, the interaction of contaminants and infectious agents is likely to be impacting disease ecology and evolution in the natural environment. Yet, to date, surprisingly little scientific work is being done to examine these interactions. Our work is building on a small body of prior work to understand how contaminant exposure may impact the susceptibility of animals and humans to influenza infection and what the interaction may mean for disease transmission, persistence and evolution.