Systems Biology of Host Pathogen interactions.

Hancock, R.E.W.

Dept. Microbiology and Immunology, U. British Columbia, Vancouver, BC, V6T 1Z3 Canada.

Antibiotics are the underpinning of all modern medicine, but are being undermined by an explosion of (multidrug) resistance, and a dearth of new antibiotics. We have proposed that manipulation of natural innate immunity will serve as a new therapeutic strategy against antibiotic-resistant infections. However to understand the assets and potential deficits of such a strategy we need to understand the extremely complex process of innate immunity (involving 1500 to 5000 gene products, small RNA species etc). To understand the complexity of host immune responses to pathogens, we have developed new bioinformatic tools for studying the systems biology of innate immunity including a database of innate immunity proteins and their interactions (InnateDB) and new network visualization strategies (Cerebral). These have enabled systems level investigations enabling more in depth understanding of the immediate host responses to pathogenic challenge, and the development of new therapeutic strategies. Cationic host defence (antimicrobial) peptides are produced by virtually all organisms, ranging from plants and insects to humans, as a major part of their immediate, relatively non-specific (innate) immune defences against infection. Although originally noted for their modest direct antimicrobial activity, it was recently demonstrated that host defence peptides profoundly modulate innate immunity. Microarrays, sophisticated bioinformatics, and pathway and transcription factor studies have demonstrated that these peptides stimulate innate immunity in a unique fashion, boosting protective immunity while suppressing potentially harmful inflammation/sepsis. Using the principle of selective boosting of innate immunity we have developed novel small innate defence regulator peptides with no direct antibacterial activity, that are nevertheless able to protect in animal models against many different microbial infections, including antibiotic resistant infections and malaria, providing a new concept in anti-infective therapy.

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