Host-Pathogen Interactions Initiative

Host-Pathogen Interaction

As recently as twenty years ago, some prominent scientists declared the impending end of infectious diseases as a serious threat to human health. The subsequent emergence and re-emergence of a variety of infectious diseases, including AIDS, antibiotic-resistant bacterial infections, tuberculosis, gastrointestinal ulcers, virus-induced cancers, and West Nile virus encephalitis, to name a few, provide dramatic proof that this prediction was premature. Moreover, there is now a pressing need for increased understanding of microbial pathogens that might be used for biowarfare purposes such as the anthrax bacillus.  The University of Michigan Medical School already possesses considerable expertise in microbial pathogenesis and the host response to infectious agents. However, the EBS has determined that certain strategic investments could propel Michigan past its competitors in the area of host-pathogen interactions. These investments form the core of the EBS Host-Pathogens Interactions Initiative. In support of the Host-Pathogen Interactions Initiative, the EBS has approved funding for:

  • Recruitment of faculty within specific disciplines that would complement existing areas of expertise and fill deficits in our capabilities in the area of host-pathogen interactions;
  • Construction of an Animal Biosafety Level-3 Facility;
  • Upgrades of the existing Biosafety Level-3 (BSL-3) wet lab;
  • Development of a gnotobiotic animal facility;
  • Support to the Live Cell Fluorescent Imaging Facility for a fast 4D FRET microscope for imaging protein interactions in living cells
  • And support to fund pilot proposals in biodefense and vaccinology.

The establishment of this initiative was timely with respect to the previous interest in the fields of biodefense and vaccinology and the fact that the NIH earmarked substantial funding for research in these areas. Now, the Host-Pathogen Initiative, which brings together faculty members from all nine of the participating units in the EBS, leveraged these resources to propose The Host Microbiome Initiative, funded by the University of Michigan Medical School as a part of its strategic plan.

Host Microbiome Initiative

Indigenous microbiota are essential components of the modern concept of human health, but the composition and functional characteristics of a healthy microbiome remain to be elucidated. Different patterns of microbial colonization associated with disease states have been documented, but the patterns of microbial colonization and functional characteristics associated with health are less clear. A healthy microbiome could be described (i) in terms of ecologic stability (i.e., the ability to resist community structure change under stress, or to rapidly return to baseline following a stress-related change), (ii) by an idealized (presumably healthier) composition, or (iii) by a desirable functional profile (including metabolic and synthetic activity). Currently, there is no widely accepted description of a healthy microbiome. Elucidation of the properties of a healthy microbiota would provide a target for dietary interventions and microbial modifications aimed at sustaining health in generally healthy populations, and improving the health status of people exhibiting disrupted microbiome and associated diseases [2]. For this discussion, the "microbiome" will be defined as the host-associated bacteria, fungi, archeae, viruses, phage and protozoa, functioning as mutualists, commensals and pathogens.  The "host" will include a focus on mucosal immunity and systemic immunity that is impacted by alterations in the microbiome (systems immunology).

The underpinning of this proposal is to leverage the rich academic and translational research resources at the University Michigan Medical School, including the well-established nationally renowned investigators in the fields of microbiology, immunology, and pathophysiology throughout multiple departments at the University.  The existing faculty is a strength of the Host-Microbiome initiative and their expertise in microbial pathogenesis and the microbiome will be leveraged in this initiative.  On the host side, we will establish a mucosal immunology and autoimmunity consortium that will provide an interface with the pathogenesis and microbiome researchers. A central part of this is the establishment of the Microbiome Research Laboratory, as well as leveraging existing strengths in microbiology and host response research here at the University of Michigan.
The goals of the proposal are the following:

  • Conduct comprehensive host-microbiome scientific projects using the common framework outlined in this application
  • bring in new technology and expand resources relevant to the mission;
  • re-organize current facilities to service proposed work;
  • provide ongoing training for laboratory staff in use of these technologies or resources AND provide staff/platform scientists that know how to use this new technology;
  • provide training for laboratory staff in advanced data analysis and provide staff/platform scientists trained in advanced data analysis;
  • bring in new perspectives and approaches, based on other fields outside of biomedical science, to be applied to cutting-edge questions in host-microbiome research;
  • identify targeted faculty recruitments in specific need areas of the Host-Microbiome Initiative; and
  • provide an administrative and financial structure to oversee this cross-departmental interdisciplinary program.

Scientific teams have been assembled and have developed novel scientific initiatives that will be accelerated by the Host Microbiome Initiative, which includes targeted faculty recruitments, rapid bioinformatics capabilities, and an administrative structure that will streamline these advances.  Specific scientific projects have been organized around the framework of: A) Mucosal Microbiome Inflammatory Interactions (mucosal vaccination against inflammatory disease, medical device microbiome and prevention of device-related infection, microbiome/metabolome interaction in gastrointestinal disease); B) Host-Pathogen Interactions (virulence gene discovery in U of M hospital pathogens; effects of persistent viral infections on the microbiome of the gastrointestinal, respiratory, and urinary tracts); C) Gene-nutrient Interactions in the Human Gut Microbiome
The Host Microbiome Initiative will contain the following programs and facilities:

  1. Advanced microbial cultivation facilities ("in vitro cultivation").
  2. Microbial biorepository - an inventory of relevant microbial isolates and defined microbial populations ("defined flora") for study. 
  3. Gnotobiotic mouse research laboratory ("in vivo cultivation") - this leverages the current Germ-free facility (through the Unit for Laboratory Animal Medicine), which will be expanded and re-organized with increased flexibility and a research arm to develop new methods and provide an educational/training resource for in vivo microbiome manipulation that can be passed on to investigators interested in the role of the microbiome in their specific field of research.
  4. Microbial sequencing research laboratory- the goal is to develop a laboratory whose focus is on research and development of new methods for utilizing the constantly evolving sequencing technology for analysis of the microbiome (16S, bacterial genomics, metagenomics and metatranscriptomics).  These new methods can be developed into standard operating procedures that are passed on to the UM DNA Sequencing Core for distribution to investigators interested in the role of the microbiome in their specific field of research and utilization of these methods by the UM DNA sequencing core. 
  5. Microbial bioinformatics and computational biology - most notably, team scientists ("platform scientists").   This will include an interface with the Department of Computational Medicine and Bioinformatics for faculty, staff scientists and educational/workshop initiatives to resolve this major bottleneck.

Specific instructional and research track faculty recruitment targeted for the Host-Microbiome Initiative will include experts in Microbial physiology, Microbiome structure-function, Comparative microbial genomics, Microbial bioinformatics, and Computational modeling of microbe-microbe, host-microbe and host-host interactions.