Most tissue damage from infectious disease is caused by secondary inflammation elicited in the host.  Furthermore, identical pro-inflammatory stimuli from the same pathogen load causes markedly different amounts of inflammation in different species, different hosts, and even within a single individual.   Given the prominent role of inflammation in most infections, tolerance to this inflammation is a likely major determinant of outcome and survival. As a study of the Glue Grant(www.gluegrant.org),we identified tremendous differences in host response to injury and infections between human patients and mouse models. 

In SPIRIT program, we screened at least 10 mammalian species including 4 or more non-human primates specifically chosen to vary widely in their in vivo tolerance to endotoxin challenge. We identified tolerant populations, and then evaluated these populations in comparison to relevant control populations using transcriptomic, proteomic, metabolomic, lipidomic, and epigenetic techniques. Those tasks are and will be accomplished by multiple centers: MGH (prime), T.H. Chan Harvard School of Public Health, University of Montreal, University of California at San Francisco, University of Maryland, Southwest National Primate Research Center, Pacific Northwest National Laboratories (proteomics, metaolomics, lipidomics), Expression Analysis, Inc. (sequencing for transcriptomics).

 

Our Bioinformatics Core will be a cornerstone of the SPIRIT program. All data from different arms of the project will feed into the core, and then will feed back out to each of the sites. We are dedicated to 

• Establish the data center for SPIRIT, including setup of Integrated Laboratory Information Management System(LIMS) and setup of web based ‘Omics Data Management System (ODMS);
• Analysis and identification of tolerance mechanisms using all sorts of data from SPIRIT;
• >Development and validation of algorithms and tools focusing on interspecies comparisons;
• Collect and integrate retrospective datasets. For example, we do comparison of data of SPIRIT and other THoR studies with retrospective omics datasets. Also, we collect and mine the literature to discover new genomic, proteomic and other ‘omic’ relationships.

 

We seek to identify target genes, pathways and drugs based upon the mechanisms. These targets and drugs will be further be validated in silico (e.g drug repositioning), in vitro, and in vivo. Our overarching goal is to have a treatment ready for clinical trials at the end of the project.

 

 

Dr. Feifei Han is in charge of this project, in collaboration with Li-Yuan Hung.