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					Host-Pathogen
Host Pathogen Interactions
               g
Research at Virginia Tech

     Brett Tyler, VBI
Animals and plants are healthy most of the time
   They have effective defense mechanisms


 Successful pathogens have specialized
    mechanisms for causing disease


 Complex networks of interactions among
pathogen and host genes determine disease
                 Hosts
                 H t



                            Computer
  Chemistry
                             Science


               Infectious
                Disease



Experimental                 Mathematics
  Biology
  Bi l                         St ti ti
                             & Statistics


               Microbes
                                                             Mukhopadhyay     VBI         VBI
Adelman          ENT       CALS      Humans        Vectors
Ahmed            BSPB      CVM                               Myles            ENT         CALS
Bassaganya-Riera VBI
       g y                 VBI
                                     Animals       Plants    Paulson          ENT         CALS
Bloomquist       ENT       CALS              H t
                                             Hosts           Popham           BIOLS       COS
Brewster         ENT       CALS                              Rathore          VBI         VBI
Carlier          CHEM      COS                               Schubot          BIOL        COS
Dickerman        VBI       VBI                               Schurig          BSPB        CVM
Falkinham        BIOL      COS                                     Computer CS
                                                             Setubal          VBI,        VBI, COE
             Chemistry
Gogal            BSPB      CVM                                      Science BIOL
                                                             Sharakov                     COS
Hawley           BIOL      COS                               Shulaev          VBI         VBI
Hoeschele        VBI,STAT VBI,COS                            Sobral           VBI, PPWS   VBI, CALS
Hong             PPWS      CALS                              Sriranganathan   BSPB        CVM
Inzana           BSPB      CVM            Infectious         Stevens          BIOLS       COS
Jelesko          PPWS      CALS            Disease           Sumner           FST         CALS
Klemba           BIOCH     CALS                              Su u
                                                             Suzuki            S
                                                                              BSPB        CVM
                                                                                          C
Kulkarni         PHYS      COS                               Tholl            BIOL        COS
Laubenbacher     VBI, MATH VBI,COS                           Tu               BIOCHEM     CALS
Lawrence Experimental
                 VBI, BIOL VBI,COS                           Tyson MathematicsBIOL        COS
Li
             Biology COS
             Bi BIOLS
                 l                                           Tyler            VBI,
                                                                         St tiVBI PPWS
                                                                      & Statistics
                                                                                ti        VBI,
                                                                                          VBI CALS
McDowell         PPWS      CALS                              Vinatzer         PPWS        CALS
Melville         BIOL      COS                               Wi               CHEM        COS
Mendes           VBI       VBI                               Winkel           BIOL        COS
Meng             BSPB      CVM             Microbes          Yuan             BSPB        CVM

                                     Bacteria     Fungi & oomycetes
                                     Viruses      Protists
                 Liwu Li, Biological Sciences, COS
             The laboratory of Innate Immunity and Inflammation


Define the complex molecular signaling network controlling innate immunity
and inflammation
Approaches:
        Experimental biology and biochemistry
        Computational simulation of complex signaling network
        Transgenic animal studies
Define the contribution of the inflammation network to the pathogenesis of
diseases
A      h
Approaches:
         Transgenic mouse models of atherosclerosis, diabetes, infection, and lupus
         Studies employing human patients
Explore the intervention of the inflammation network with small and novel
chemical compounds
Approaches:
        Screening of compound library
        Synthesis and modification of existing compounds
             Liwu Li: Signalling pathways in Innate Immunity

Signaling pathways spanning                                                        TLR (toll-like-receptor)
          from Tollip, IRAK-1 and related molecules           GPCR                                  Insulin receptor

                      feed-forward     feed-back
Positive and negative feed forward and feed back loops                      Tollip/IRAK 1
                                                                            Tollip/IRAK-1
                                                                Tau
Specialized cellular regulation in                              VASP                              Akt
          physiologically relevant cells and tissues
          (endothelial cells, mesangial cellls,
                                                     Cytoskeletal
          smooth muscle cells, macrophages)          rearrangementt                                      Glucose
Transcriptional regulation of key inflammatory                                                           metabolism,
                                                  Cytoplasm                                              transport
          gene expressions
                                                                                         Nucleus
Contribution of innate immunity pathways to
                                                                          T      i i f
                                                                          Transcription factors
           metabolic processes
(e.g. lipid transport, glucose metabolism, etc)                       (e.g. IRF NFAT C/EBP)




Innate Immunity pathways are
similar in plants and animals

                          Inflammatory mediators (e.g. cytokines, chemokines, adipokines, complement factors)
          Josep Bassaganya-Riera, VBI


                        Objectives
• To identify novel, naturally occurring, orally active
  immune modulators, especially those from food
  plants

• To elucidate the cellular and molecular mechanisms
  of action by which they prevent or ameliorate human
  disease

  Approach
• A      h
   – In vitro screening
   – Preclinical efficacy and safety testing
   – Phase I, II and III Clinical Testing of Novel Immune
     Modulators
                  Yasuhiro Suzuki
                             Pathobiology
     Biomedical Sciences and Pathobiology, CVM

                        p
• mechanism of host-pathogen g
  interactions in infection with
  Toxoplasma gondii
      l   l immuno-
• molecular i
  pathogenesis of cerebral
  toxoplasmosis
• factors in host resistance
• IFN-g-mediated immune
  response
• host genotype
  T.
• T gondii genotype
      John Tyson, Biological Sciences, COS




• Computational modeling of Programmed
  Cell Death (PCD)
               (    )
• PCD involved in defense against infection
  and cancer
• killing of pathogen infected cells in
  vertebrates and plants
         Brett Tyler, VBI & PPWS, CALS

 Systems Biology of Host-Pathogen Interactions




A single genetic network encompasses host and pathogen
Tyler: Genetic mapping of gene expression profiles
  associated with quantitative disease resistance

Population: V71-370 (G.max) x PI407162 (G. soja)
   – >7000 sequence polymorphisms mined from microarray data
   – At least 4 resistance QTLs
   – 297 RILs
   – F12 generation



             sample sites
                              Statistical Design
                              • RILs assayed in blocks of 24
                pathogen
                                  – harvested within 2 hour window
             visible lesion              t l        block
                              • 3 x 3 controls per bl k
                                   - (V71-370, VPRIL#9, Sloan)
                              • 30-50 plants pooled per experiment
                                Two        ll      i    t l li t
                              • T overall experimental replicates
 Day 5                        • 2600 Affymetrix micorarray chips
             Ina Hoeschele (Statistics & VBI)
          Statistical Genetics – Systems Genetics



• Systems Genetics SG: The integration and anchoring of
  multi-dimensional data-types (transcriptomic, proteomic,
   h      i     t b l i     ) to d l i           ti   i ti
  phenomic, metabolomic …) t underlying genetic variation

• Inference of causal networks among DNA
  polymorphisms, expressed genes, and (sub-) phenotypes
  of a complex disease using genetically randomized
        l ti
  populations
               Dorothea Tholl Biological Sciences, COS
  Biochemistry and Function of Volatiles in Plant- Pathogen/Insect Interactions


      Model:           Terpene Volatiles                 Direct or Indirect                   Biosynthesis
Arabidopsis thaliana
                                                         Defense against
                                                         D f           i t
                                                                                       Metabolic/Molecular
                                                           Insect Pests and                Regulation
                                                         Microbial Pathogens
                                                                                              F    ti
                                                                                              Function
                                         P. xylostella
                                                                                          External/Internal
                                                                                          Defense Signals

                                                            Aboveground
                                                                                      Genetic Engineering of
                                                                                        Volatile Emissions
                                             y g
                                         P. syringae
                       Leaves                                                               Development of
                                                                                            Alternative Pest
                                                            Belowground                         Controls
                       Roots
                                                                     Funding:
                                                Bradysia ssp.        NSF Advance VT              USDA-NRI
                                P. irregulare                        Kate Miller and Jeffress Memorial Trust Foundation
         Brenda Winkel, Biological Sciences, COS
 Cellular machinery of plant flavonoid chemical defense




The molecular basis of flavonoid
multi enzyme
multi-enzyme complex assembly –
new tools for metabolic engineering


                                      Dual localization in the cytoplasm
                                      and nucleus point to “moonlighting”
                                      roles for flavonoid enzymes           Fruits and vegetables
                                                                            have high levels of
                                                                            flavonoids,
                                                                            flavonoids which have
                              Interaction and expression networks are       well-known anti-
                                                                            cancer, anti-oxidant,
                              identifying functional links far outside
                                                                            and anti-microbial
                              the flavonoid pathway                         activities
    Reinhard Laubenbacher, VBI and Math, COS
Computer Models of Immune Response to Viral Pathogens



• Model of immune system dynamic response to
  pathogens
• Multi-scale, information-rich visualization
• Immune system simulation engine
   – Experiment with different outcomes based on
     varying infection and immune system parameters
PathSim interface: information display

				
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posted:10/21/2011
language:English
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