Microbial – Host interactions and Antimicrobial Resistance

The BRC is involved in two main collaborative areas of Biomedical research aimed at 1) identifying and studying genetic pathways and signal molecules related to microbial–host interactions and pathogenesis and 2) investigating mechanisms of resistance to anti-microbial agents/antibiotics.

In order to identify effective target areas for the development of new strategies for anti-microbial pharmacology, an understanding of the cascade of events leading to colonisation, persistence and ultimately the pathogenesis of an invading microorganism in response to the host environment is essential. In the BIOMERIT Research Centre, investigations are being carried out to identify and characterise genetic elements related to microbial pathogenesis. Specifically, Pseudomonas aeruginosa is an important pathogen involved in chronic broncho-pulmonary disease in cystic fibrosis (CF) patients and is being used as a representative Gram-negative pathogen of clinical relevance. On going research in the BRC involves utilising GeneChip and Proteomics technologies to study in situ pathogenesis in relation to bi-directional signalling and bacterial interactions with human lung epithelial cells (Fig. 6).

Microbial Host (Fig 6)

A specific research area involves investigating i) the effect of microbial infection on the co-ordinated expression of host genes involved in the immune response and ii) the effect of microbial infection of CF and normal lung epithelial cells on molecular and physiological aspects of microbial pathogenesis. In vitro co-culture systems have been developed whereby human lung epithelial cells are infected with Pseudomonas aeruginosa strains and the molecular and physiological response of the host and bacteria are studied. This research is closely linked to our Functional Genomics Research and we have identified several regulatory cascades that play a key role in the response to Microbial – Host interactions. As an extension of this research in vivo infection models are used to study the complexity of acute versus chronic infections.

A related research interest in the BIOMERIT Research Centre is investigating the mechanism of resistance of P. aeruginosa to host Cationic Antimicrobial Peptides (CAMPs) and antibiotics in general. This research has arisen in response to the global public health issue of the emergence of multi-drug resistant microorganisms. Currently within Ireland, hospital acquired MRSA is proving to be a major health care problem with medical, financial and litigation implications. Recently, multi-drug resistance (MDR) Gram-negative human pathogens, including Pseudomonas aeruginosa, are also emerging in hospital acquired infections. This has led to an increased interest for cationic antimicrobial peptides (CAMPs) as potential therapeutic molecules. CAMPs are ubiquitous in nature, and are key components of the innate immune response. The CAMP Colistin, (polymyxin E) was first introduced as an antibiotic in the 1950s, but was gradually abandoned in the early 1980s because of the reported high incidence of nephrotoxicity. Recent studies have highlighted the effectiveness of colistin and shown that it has considerably less toxicity than previously reported and it has since re-emerged as an alternative treatment of infections with multidrug resistant Gram negative bacteria. In a HRB funded study in the BRC we are investigating molecular mechanisms associated with the microbial response to, and subsequently the development of resistance to the CAMP Colistin.

In a separate study, in collaboration with Dr. Jim Clair in the Mercy University Hospital, we are studying the range and mechanism of multi drug resistance in hospital isolates, most particularly focusing on B-lactam resistance. Resistance to all classes of B-lactam antibiotics has been observed among Gram-negative clinical isolates and this resistance threatens the effective treatment of infections by narrowing treatment options and promoting resistance to currently effective antimicrobials.

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