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Jose Nakamoto- Institutionen för experimentell medicinsk vetenskap
Title: Finding the immune systems of bacteriophages
Main supervisor: Gemma C. Atkinson
Reviewers: Jenny J. Persson, Fredric Carlsson
Abstract
Background
Bacteria and bacteriophages (phages) are engaged in a continuous arms race, leading bacteria to obtain diverse antiphage defence systems. Defence systems are often clustered in genomic regions called defence islands. Emerging evidence shows that they are frequently hosted on mobile genetic elements (MGEs), such as transposons, prophages, and phage satellites. These MGEs can harbor multiple antiphage systems, influencing phage resistance profiles. Recent studies emphasize their role in inter-viral competition, with prophages acting as defence hotspots.
Toxin-antitoxin (TA) systems, found in bacteria and temperate phages, play a crucial role in antiphage defence through abortive infection. Among these, type II TAs use proteinaceous antitoxins to neutralize their toxins. Some type II TAs are part of tripartite toxin-antitoxin-chaperone (TAC) systems, involving a SecB-like chaperone for antitoxin stability. Recently, TACs encoded in prophage regions of E. coli have been confirmed as phage defence systems.
Research questions
This report presents two projects: a survey to identify new toxin-antitoxin-chaperone systems across bacteria and a search for novel antiphage defence systems by identifying variable regions within predicted prophages from Enterobacteriaceae.
Primary and preliminary results
We have performed large-scale screening for SecB homologues and analysed gene neighbourhood conservation. We have uncovered high sequence variation in TAC-associated SecBs in contrast to the more conservative classical SecB and found potential novel TAC systems. The results show that TACs are highly mobile and evolutionarily plastic systems.
For the Enterobacteriaceae prophages, I have predicted all the prophages from 1,018,366 Enterobacteriaceae genomes. So far, from a subset of 210,000 E. coli genomes, I have reannotated 710,000 predicted prophages to standardise protein annotation, clustered the protein sequences and identified multiple prophage communities.
Significance
Phage therapy is an alternative for treating antibiotic resistant bacterial infections. However, bacteria carry immune systems that protect them from phage infection. These immune systems are often encoded on prophages, viral sequences inserted into the bacterial genome. My PhD is focussed on bioinformatic methods to discover and classify these systems, as well as predict and validate their molecular mechanisms. This understanding will be important for the future engineering of therapeutic phages that can overcome the defences of pathogenic bacteria.
Manuscripts
- [Manuscript in preparation] Toxin Antitoxin Chaperone (TAC) systems diversity across bacteria.
Published Articles not included in this report
- Ernits K, Saha CK, Brodiazhenko T, Chouhan B, Shenoy A, Buttress JA, Duque-Pedraza JJ, Bojar V, Nakamoto JA, Kurata T, Egorov AA, Shyrokova L, Johansson MJO, Mets T, Rustamova A, Džigurski J, Tenson T, Garcia-Pino A, Strahl H, Elofsson A, Hauryliuk V, Atkinson GC. The structural basis of hyperpromiscuity in a core combinatorial network of type II toxin-antitoxin and related phage defense systems. Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2305393120. doi: 10.1073/pnas.2305393120. Epub 2023 Aug 9. PMID: 37556498; PMCID: PMC10440598.
- Mets T, Kurata T, Ernits K, Johansson MJO, Craig SZ, Medina-Evora G, Buttress JA, Odai R, Coppieters‘t Wallant K, Nakamoto JA, Shyrokova L, Egorov AA, Doering CR, Brodiazhenko T, Laub MT, Tenson T, Strahl H, Martens C, Harms A, Garcia-Pino A,*, Atkinson GC, Hauryliuk V. Mechanism of phage sensing and restriction by toxin-antitoxin-chaperone systems. [Cell Host Microbe - In press]
- Koller TO, Turnbull KJ, Vaitkevicius K, Crowe-McAuliffe C, Roghanian M, Bulvas O, Nakamoto JA, Kurata T, Julius C, Atkinson GC, Johansson J, Hauryliuk V, Wilson DN. Structural basis for HflXr-mediated antibiotic resistance in Listeria monocytogenes. Nucleic Acids Res. 2022 Oct 28;50(19):11285-11300. doi: 10.1093/nar/gkac934. PMID: 36300626; PMCID: PMC9638945.
- Svetlov MS, Dunand CF, Nakamoto JA, Atkinson GC, Safdari HA, Wilson DN, Vázquez-Laslop N, Mankin AS. Peptidyl-tRNA hydrolase is the nascent chain release factor in bacterial ribosome-associated quality control. Mol Cell. 2024 Feb 15;84(4):715-726.e5. doi: 10.1016/j.molcel.2023.12.002. Epub 2024 Jan 5. PMID: 38183984.
- Takada H, Paternoga H, Fujiwara K, Nakamoto JA, Park EN, Dimitrova-Partenoga L, Beckert B, Saarma M, Tenson T, Buskirk AR, Atkinson GC, Chiba S, Wilson DN, Hauryliuk V. A role for the S$-domain containing protein YlmH in ribosome-associated quality control in Bacillus subtilis. [Nucleic Acids Research - In Press]
Om evenemanget
Plats:
BMC I:1345 Sölvegatan 19, 223 62 Lund
Kontakt:
jose [dot] nakamoto [at] med [dot] lu [dot] se