Assesment of influenza:host interactions

Influenza A virus is a major human pathogen and a global health threat, thus the development of novel intervention strategies and therapeutics remains paramount. The single-stranded negative-sense influenza virus genome consists of 8 segments, each flanked by short conserved elements at their termini, which form the viral promoter that is recognized by the viral RNA-dependent RNA polymerase (vPOL). vPOL is essential for influenza biogenesis because of its central role in transcription and replication of the viral genome. Mutations in vPOL and factors that affect vPOL activity can cause adaptation of animal viruses to the human host. Using novel reporter viruses, proteomics, and next-generation sequencing techniques we are characterizing, in a physiological setting of infection, virus:host interactions, the basis of viral transcription, and the interplay between cellular and viral transcription at genomic scale. For each of these processes we are assessing their role in influenza virulence and pathogenesis.

 

Influenza genotyping and surveillance

Despite the availability of vaccines, the influenza A virus continues to pose a significant burden on human health and causes approximately half a million deaths worldwide every year. Influenza pandemics in particular can cause high levels of mortality, as exemplified by the 1918 Spanish Flu and more recent outbreaks of H5N1. Human pandemic viruses typically originate from animal populations such as wild birds and pigs and are able to spread rapidly, as any existing immunity to human influenza strains is ineffective against the new strain. Very little is known about the distribution and dynamics of influenza viruses in animal populations, and yet this information is crucial to understand the origin of pandemics. As a member of the Center for Research on Influenza Pathogenesis (CRIP) and part of the CEIRS network, we are performing surveillance of influenza viruses circulating in animals to help identify strains that are at risk for causing human pandemics.

 

 

Genomic analysis of hospital acquired infections

Hospital-acquired infections (HAIs) such as MRSA and C. difficile pose a ubiquitous, insidious, and potentially fatal threat to patients across the country. The Centers for Disease Control estimate HAIs account for roughly 1.7 million serious infections every year in the United States and cause or contribute to 99,000 deaths annually with a greater burden in immunocompromised hosts. As part of a multidiciplinary team at Mount Sinai we are using whole-genome sequencing a means to understand the molecular basis of evolution and transmission of infectious diseases, host-pathogen interactions, and to identify novel pathogens. We anticipate that a better understanding of the role of genetic diversity in bacterial infections will result in improved patient care and outcomes.

 

 

Profiling of craniofacial development

Craniofacial sutures are the fibrous joints between bones, allowing growth of the skull from prenatal to postnatal development until adult size is achieved. Proper suture development is crucial because abnormal suture fusion can require major surgical intervention to restore head and facial appearance and to prevent secondary damage to the brain, eyes, hearing, breathing, and mastication. Craniosynostosis, the premature fusion of skull sutures, is a common birth defect, occurring in 1/2500 live births. A more comprehensive understanding of suture biology and pathology can be aided by knowledge of gene expression profiles of sutures. Therefore, as part of the FaceBase project we are preparing gene expression atlases of specific populations of cells from the different subregions of each suture. These atlases will enable rapid discovery of genes not yet known to be expressed in sutures, reveal the commonalities and differences between sutures that may suggest new hypotheses of suture formation and differentiation, with wider significance for evolutionary studies of the vertebrate skull, and provide insight into the pathology of suture fusion.

 

Mapping cannabinoid biosynthesis networks

Cannabis sativa has been used for millennia as a source of fibre, oil- and protein-rich seeds and for its medicinal and psychoactive properties. There are few other plants that elicit so much controversy: it is currently the most widely consumed illegal drug worldwide yet it is legally used for its medicinal properties in many countries, including the USA. The unique effects of marijuana are due to the presence of cannabinoids, which include delta-9-tetrahydrocannabinol (THC) and more than 70 related chemicals. THC is responsible for the mood-altering effects of cannabis and exhibits diverse pharmacological activities including relief from pain and nausea, and appetite stimulation. Despite its widespread, government-approved use by patients, there is a lack of research on the cannabis plant and its medicinal effects. We previously produced the first genome and transcriptome assembly of Cannabis sativa and we are using these data to determine how cannabinoids are made. The underlying goal of this work is to better understand how cannabis produces medicinal compounds so that its potential to treat disease and alleviate suffering can be exploited.