Saturday, November 23, 2024
11/23/2024
There is a critical need for improved human tissue models to study infectious diseases. Animal models often fail to reproduce human physiology, and are similarly poor predictors of drug efficacy when translated to humans. This proposal describes the MIT Center for Human Tissue Models for Infectious Diseases (MIT.HTMID), which will focus on two dimensional human neural cells and three dimensional human cerebral organoids to study virus infections. The project is sited entirely at The Massachusetts Institute of Technology. The three investigators are: Lee Gehrke (Virology and Infectious Diseases), Rudolf Jaenisch (Tissue Engineering, Cell Biology, and Stem Cells) and David Sabatini (Genetics and Screening Technologies). The Center will also include three Cores; that is, Administrative, Virology, and Human Cells and Tissues. The themes of the two interrelated Research Projects of this U19 proposal are: Project 1: Human tissue models to study infectious diseases: Human 2D and 3D neural cultures for studying virus tropism and infection phenotypes, and Project 2: Use of 2D cultures and 3D organoids to identify candidate antiviral compounds; to use genetic approaches to identify and validate host genes that promote or protect against flavivirus infection. The experimental use of organoids is significant because the three dimensional architecture and differentiation from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells provide nearphysiological functions in tissue organization, tissue renewal, and responses to pathogen infections. Indeed, human organoids have been generated for a wide range of tissues and uses in studying development and diseases, including virus infections. The project will compare the infections of five different neural or microglial cell types (neuronal progenitors, neurons, oligodendrocytes, astrocytes, microglia) with three flaviviruses (Zika Virus, West Nile Virus, or Dengue virus). The research goals of MIT.HTMID address the Zika virus global health crisis, toward understanding how related flaviviruses can cause very different diseases, including microcephaly and Guillain Barre Syndrome. The virus work will be extended beyond flaviviruses to include other neurotropic viruses; that is, pseudotyped vesicular stomatitis viruses (VSV) that carry the envelopes of select agent encephalitic viruses (Eastern Equine Encephalitis, Western Equine Encephalitis, and Venezuelan Equine Encephalitis). We will use cell and molecular methods to define and compare the infection phenotypes of the cells and viruses. Tissue engineering and genetics will be combined by performing CRISPRCas9 screens to identify genes that regulate or are regulated by virus infection, and then generating “knockout” organoids to test function in a threedimensional tissue. The organoid human tissue model will also be used to evaluate a number of antiviral compounds to validate its potential use as a drug testing platform. If successful, this Center will yield significant new data and be an integral component of a network of Human Tissue Models for Infectious Diseases.
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