Epigenetic reprogramming of innate immunity during uropathogenic E. coli infection in surrogate insect model

• Applicant: Dr. Krishnendu Mukherjee, Ph.D.
• Subject Area: Reproductive Medicine, Urology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 299244350

Pathogen infection in humans involves specific pro- and anti-inflammatory innate immune responses the transcription of which is regulated by epigenetic mechanisms such as DNA methylation and histone acetylation. Thus, epigenetic mechanisms are being increasingly considered to combat complicated infections such as in the urinary tract of humans by ExPEC. However, this requires extensive screening of strains, serotypes, and virulence factors in a whole animal high-throughput screening system which is cost effective, ethically unrestricted, with short generation times and correlates the results to humans. Insects fit to these criteria and share innate immunity and conserved epigenetic mechanisms with humans. The prime objective of the proposed project is to identify epigenetic alterations that are induced through UPEC infection in a surrogate insect host to expedite the development of epigenetic based anti-infective strategies for clinical application. UPEC and other ExPEC strains that are responsible for causing UTIs in humans impose an annual healthcare budget of over 2.5 billion dollar in the USA and Europe and can infect the greater wax moth G. mellonella at 37°C. This provides scope to explore this insect model for elucidating novel aspects of mechanisms leading to UPEC virulence and antimicrobial resistance. In addition, G. mellonella offer a number of advantages over mammalian models including the study of complex interacting parameters such as fecundity, longevity, gender ratio even at the transgenerational level. We hypothesize that UPEC infects G. mellonella by targeting epigenetic mechanisms in order to repress transcriptional activation of bactericidal host responses. This will be tested by analyzing innate immunity and epigenetic alterations induced through methylating cytosines and acetylating/ deacetylating histones following exposure to uropathogenic and non-pathogenic E. coli. The potential impact of such bacteria induced epigenetic regulations on the expression host defense molecules across generations will be investigated in G. mellonella larvae.

• DFG Programme: Research Grants