Power, David; (1998) Gene targeting as a tool to investigate granulocyte function. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Neutrophils provide the body's first line of defence against infection by bacteria and fungi. The aim of this project was to use gene targeting to determine the effect of disrupting three genes thought to be important in neutrophil function. Mice lacking p47phox. a component of the NADPH oxidase, were found to suffer from a condition identical to the human disorder chronic granulomatous disease (CGD). Like sufferers of CGD the mutant mice lacked the activity of the NADPH oxidase, developed granulomas and were extremely susceptible to infection by C.albicans. Mice deficient in grancalcin, an EF hand calcium binding protein expressed in neutrophils, were healthy and fertile. Neutrophils from the mutant mice could kill S.aureus and migrate to the peritoneum normally. The mutant mice themselves were able to resolve infection by S.aureus in an identical manner to wild type mice. Further research will be required using the mutant mice to define the role of grancalcin. Mice lacking Csk specifically in their neutrophils were generated using conditional gene targeting and found to suffer from pneumonia. Csk is thought to down regulate the Src family of tyrosine kinases and the tenfold elevation in tyrosine phosphorylation in the neutrophils of the mutant mice implied that Csk actively plays this role in neutrophils. The results obtained not only show how essential p47phox and Csk are for normal neutrophil function but how essential neutrophils are to the immune system.

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