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The goal of this project, funded by an NIH NIAID U19 network award, is to develop improved human models for studying infectious diseases.  The Gehrke laboratory provides virology expertise and manages the Virology Core, while Rudolf Jaenisch'slaboratory at the Whitehead Institute provides stem cell expertise and manages the Stem Cell Core, and David Sabatini's laboratory at the Whitehead Institute provides screening expertise and runs the CRISPR-cas screening platform.


A number of the flaviviruses, including for example Zika, West Nile, Powassan, Japanese Encephalitis, are neurotropic and therefore infect nerve cells and/or supporting glial cells.  The Zika virus outbreak in 2015 was striking because of the correlation between virus infections of pregnant women and the birth of babies with small heads (microcephaly).  The molecular mechanisms underlying neuropathologies caused by flaviviruses are poorly understood.



To develop improved models for understanding infectious diseases, we are using organoidsderived from human embryonic stem cells (approved on the NIH registry) or induced pluripotent stem cells.  Organoids have been shown to be remarkable in recapitulating the morphology and gene expression pattern of human tissues. Organoids represent an experimental platform that has improved relevance for understanding human biology as compared to transformed cell lines that have been passaged for decades in the laboratory. The illustration at the left shows a human cerebral organoid.  Like the human brain, cerebral organoids have ventricles that are surrounded by proliferating progenitor cells (stained pink-purple in the figure). The cellular layering found in the human brain is also approximated in the cerebral organoid model. 


Unlike Zika and Dengue viruses that are transmitted by mosquitoes, some emerging flaviviruses, such as Powassan virus and Deer Tick Virus are transmitted by ticks.  Powassan virus is transmitted by the same tick ...Ixodes scapularis... (right) that transmits carries Lyme disease. These ticks are prevalent in the Northeast (including Cape Cod) and in the Great Lakes area. Powassan infections can cause a serious encephalitis, and we are working to define the specific cells that become infected, and to understand how the virus affects the host cell physiology.


Working in the M.I.T. environment is advantageous because new technologies are being developed constantly.  We are benefiting from two technologies that were developed in our building in the Institute for Medical Engineering and Science (IMES). The first is an imaging method called "CLARITY" or "SHIELD" that was developed by Kwanghun Chung. The image on the left shows two organoids, top and bottom.  The bottom organoid has been treated to remove lipids (fats) from the organoid, rendering it optically transparent. This transparency allows us to look at the internal structures of the organoid without slicing into sections.  The resulting data can be computationally reconstructed to yield a three-dimensional picture of organoids with and without virus infection. The method allows us to follow virus infections with time and to define the specific cells that become infected. 

The second technology allows us to study virus infections at the level of single cells, using a method called "SeqWell" to determine the nucleotide sequence of the messenger RNA transcriptome of infected and uninfected cells. Seqwell was developed by Christopher Love and Alex Shalek, and the essential components of the method are presented in the image at the right.  A microscope slide is patterned with thousands of tiny wells that are just large enough for a cell to occupy with a nanobead that binds the messenger RNAs for processing culminating in next generation sequence analysis. 


This approach is important because it allows us to look specifically at cells that are infected or are not virus-infected so that we can identify the specific changes in gene expression that are associated with virus infections. This information can tell us how the cell reacts to block infection, and how the virus also reacts to counter cellular mechanisms. The results have potential both for understanding the basic science of virus-host interactions, and also for defining potential targets for drugs that might block virus replication. 

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