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Höflich, Jörg (2005): Genetic and functional characterization of Caenorhabditis elegans srf-3, a gene involved in regulating surface antigenicity. Dissertation, LMU München: Faculty of Biology
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Abstract

The widespread emergence of pathogens resistant to the majority of available antibiotics makes it necessary to find new ways to combat the corresponding microorganisms. Adaptive immunity is specific to vertebrates but the mechanisms of innate immunity are ancient and highly conserved during evolution. Therefore it is reasonable to use model organisms to study the molecular mechanisms of host defence and the corresponding mechanisms of pathogenicity. Microbacterium nematophilum adheres to the rectum of a Caenorhabditis elegans animal inducing a localized non-lethal response that causes swelling of the underlying hypodermal tissue. The aim of this thesis was to gain a first insight into the molecular mechanisms underlying the resistance of srf-3 animals to the bacterial pathogens Microbacterium nematophilum and Yersinia pestis/pseudotuberculosis. M. nematophilum adheres to the cuticle of wild type animals but fails to adhere to the surface of srf-3 worms. This is a novel type of resistance because pathogens like P. aeruginosa or Salmonella typhimurium do not adhere to the cuticle but kill C. elegans by colonization and accumulation in the intestine. Molecular cloning of srf-3 showed that this gene codes for a type III transmembrane protein similar to the family of UDP-galactose transporters. Expression analysis revealed that SRF-3 is expressed in a set of active secretory cells consistent with a function of this gene in cuticle or surface modification. A functional characterization of SRF-3 revealed that this protein can function as a nucleotide sugar transporter. The protein showed multisubstrate specificity capable of translocating UDP-galactose and UDP-N-acetylglucosamine in vitro as judged by transport assays done with Golgi/ER enriched vesicles, as well as in vivo, as shown by the phenotypic correction of mutants defective in UDP-galactose or UDP-N-acetylglucosamine transport. The data presented in this thesis emphasize the importance of glycosylation in regulating the surface antigenicity of C. elegans. This can help to understand the process of pathogen adherence, the first step in the establishment of an infection, as well as how parasitic nematodes modulate the surface in order to escape the host response.