The host-microbe inter-phase as a target for anti-infective therapy. Jordi Vila Department of Microbiology, Hospital Clinic, School of Medicine, University of Barcelona Barcelona, Spain. 5th ESCMID School of Clinical Microbiology and Infectious Diseases
Department of Microbiology, Hospital Clinic,
School of Medicine, University of Barcelona
5th ESCMID School of Clinical Microbiology and Infectious
Santander, Spain June 10-16, 2006
HOST DEFENSES AND
VIRULENCE FACTORS TISSUE INJURY
Most bacteria must first adhere to host cell surfaces to cause infection
Many pathogenic bacteria express specialized surface proteins called adhesins which mediate their binding to the cells.COLONIZATION
Long filamentous structures called cause infectionpili or fimbriae --. The adhesin may be:
Proteins at the tip
Pilin subunit itself
Afimbrial adhesins – tighter adherence
Non-fibrillar adhesin, i.e: Protein F in S. pyogenesADHESINS
* In Gram-negative bacteria:
* In Gram-positive bacteria
Carbohydrate residues of glycoproteins or glycolipids cause infection(Protein-carbohydrate interaction)
- This binding is quite specific
Extracellular matrix proteins. (Protein-protein interaction)
- I.e. Fibronectin
In some cases the pathogen injects its own protein receptor into the host cell.
It is common for a pathogen to express and utilize more than one adhesinHOST CELL RECEPTORS FOR ADHESINS
G cause infection
The pap operon
Regulation Major Assembling Minor subunits
Chembiochem (2001) 12: 915
PNAS (2000) 97: 5510
Autoinducers: cause infectionHomoserine lactones
lasR/lasI ----- enhances the transcription of genes encoding VF in P. aeruginosa
rhlR/rhlI ----- enhances the transcription of other VF in P. aeruginosa
More than 600 P.aeruginosa genes are QS-controlled.
There is an interplay of these three moleculesQUORUM SENSING SYSTEMS AND BIOFILMS
Givskov et al. (1996) J. Bacteriol. 178: 6618. cause infection
Halogenated furanones produced by a marine algae which are structurally similar to the bacterial acylhomoserine lactonesQUORUM SENSING INHIBITORS
homoserine - cause infection
Synthesis of the
Can inhibition of a single individual step or factor in the disease process result in effective therapy?
Would disruption of pathogenesis lead to bacterial death, either directly or by host defense system clearance?
Could a virulence inhibitor be used in combination therapy with current antibiotics or immune system enhancers for therapy?FINAL QUESTIONS TO BE ANSWERED
Prevention or prophylaxis disease process result in effective therapy?
Treatment of enteric infections caused by some toxigenic bacteria
In conjunction with conventional therapeutic strategiesIN WHAT CONTEXT COULD ANTIVIRULENCE AGENTS BE USED?