Bacterial Lipoproteins as Players in Host-Pathogen and Host-Commensal Communication
Martin Caffrey
Membrane Structural and Functional Biology Group, School of Medicine and School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Bacterial lipoproteins reside in the cell envelope and have activities that range from functioning as enzymes and inhibitors to serving critical structural roles. As agonists of Toll-like Receptor 2 (TLR2) most lipoproteins are adjuvants of the innate immune system. Some are potent antigens that play a role in acquired immunity. Several lipoprotein posttranslational processing enzymes are essential in pathogenic bacteria and, with no mammalian equivalents, are targets for the design and development of much needed antibiotics. Because the enzymes and their lipid and protein substrates and products reside in the membrane, they present formidable challenges when it comes to establishing their assorted structures and activities. We have implanted an experimental programme to do just that. In the past few years, the structures of three of the lipoprotein processing enzymes have been solved by the group using macromolecular X-ray crystallography at close to atomic resolution with insights into mechanism of action and antibiotic design and discovery. A new and logical direction for the team is to explore the downstream host immune activities of the various innate agonists generated by these enzymes integral to both pathogenic and commensal bacteria. In the spirit of this conference, we hope to explore opportunities to collaborate with immunologists to address ‘urgent questions’ in the host-pathogen and host-commensal communication fields as they relate to bacterial lipoproteins.
References
Vogeley, L., El Arnaout, T., Bailey, J., Stansfeld, P.J., Boland, C., & Caffrey, M. Structural basis of lipoprotein signal peptidase II action and inhibition by the antibiotic globomycin. Science 351:876-880 (2016)
Wiktor, M., Weichert, D., Howe, N., Huang, C-Y., Olieric, V., Boland, C., Bailey, J., Vogeley, L., Stansfeld, P. J., Buddelmeijer, N., Wang, M., & Caffrey, M. Structural insights into the mechanism of the membrane integral N-acyltransferase step in bacterial lipoprotein synthesis. Nat. Commun. 8:15952 (2017)
Olatunji, S., Yu, X., Bailey, J., Huang, C-Y., Zapotoczna, M., Bowen, K., Remškar, M., Müller, R., Scanlan, E. M., Geoghegan, J. A., Olieric, V., & Caffrey, M. Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin. Nat. Commun. 11:140 (2020)
Olatunji, S., Bowen, K., Huang, C-Y., Weichert, D., Singh, W., Tikhonova, I. G., Scanlan, E. M., Olieric, V., & Caffrey, M. Structural basis of the membrane intramolecular transacylase reaction responsible for lyso-form lipoprotein synthesis. Nat. Commun. 12:4254 (2021)
Funded in part by Science Foundation Ireland

**Bacterial Lipoproteins as Players in Host-Pathogen and Host-Commensal Communication**
Martin Caffrey
Membrane Structural and Functional Biology Group, School of Medicine and School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
Bacterial lipoproteins reside in the cell envelope and have activities that range from functioning as enzymes and inhibitors to serving critical structural roles. As agonists of Toll-like Receptor 2 (TLR2) most lipoproteins are adjuvants of the innate immune system. Some are potent antigens that play a role in acquired immunity. Several lipoprotein posttranslational processing enzymes are essential in pathogenic bacteria and, with no mammalian equivalents, are targets for the design and development of much needed antibiotics. Because the enzymes and their lipid and protein substrates and products reside in the membrane, they present formidable challenges when it comes to establishing their assorted structures and activities. We have implanted an experimental programme to do just that. In the past few years, the structures of three of the lipoprotein processing enzymes have been solved by the group using macromolecular X-ray crystallography at close to atomic resolution with insights into mechanism of action and antibiotic design and discovery. A new and logical direction for the team is to explore the downstream host immune activities of the various innate agonists generated by these enzymes integral to both pathogenic and commensal bacteria. In the spirit of this conference, we hope to explore opportunities to collaborate with immunologists to address ‘urgent questions’ in the host-pathogen and host-commensal communication fields as they relate to bacterial lipoproteins.
References
Vogeley, L., El Arnaout, T., Bailey, J., Stansfeld, P.J., Boland, C., & Caffrey, M. Structural basis of lipoprotein signal peptidase II action and inhibition by the antibiotic globomycin. Science 351:876-880 (2016)
Wiktor, M., Weichert, D., Howe, N., Huang, C-Y., Olieric, V., Boland, C., Bailey, J., Vogeley, L., Stansfeld, P. J., Buddelmeijer, N., Wang, M., & Caffrey, M. Structural insights into the mechanism of the membrane integral N-acyltransferase step in bacterial lipoprotein synthesis. Nat. Commun. 8:15952 (2017)
Olatunji, S., Yu, X., Bailey, J., Huang, C-Y., Zapotoczna, M., Bowen, K., Remškar, M., Müller, R., Scanlan, E. M., Geoghegan, J. A., Olieric, V., & Caffrey, M. Structures of lipoprotein signal peptidase II from Staphylococcus aureus complexed with antibiotics globomycin and myxovirescin. Nat. Commun. 11:140 (2020)
Olatunji, S., Bowen, K., Huang, C-Y., Weichert, D., Singh, W., Tikhonova, I. G., Scanlan, E. M., Olieric, V., & Caffrey, M. Structural basis of the membrane intramolecular transacylase reaction responsible for lyso-form lipoprotein synthesis. Nat. Commun. 12:4254 (2021)
_Funded in part by Science Foundation Ireland_

Bacterial Lipoproteins as Players in Host-Pathogen and Host-Commensal Communication

Exploring the intricacies of host-pathogen communication is vital in order to understand why
some microbes persist within a host, while others are effectively cleared. As such,
host-pathogen communication is an urgent area of research underpinning human health
and disease, especially given the emerging concerns of antibiotic resistance.
Understanding host-pathogen pathways requires intricate knowledge in the fields of both
microbiology and immunology.

Living in a world of specialists, where scientists sometimes invest their whole career
studying one organism, a specific pathway or a protein, multidisciplinary discussions of
host-pathogen interactions are highly needed. This international conference will provide
such a forum for scientific exchange at the highest level, between scientists from different
research areas related to host-pathogen interactions, with the aim to trigger fruitful
collaborations addressing the urgent questions in the field.

This meeting has an additional special focus of bringing researchers from Ireland, Denmark
and Israel together to learn about cutting edge biology and form new collaborations.
Thus, the conference will be a showcase for the exciting and original research emanating
from these three small but innovative countries.