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How does the immune system detect a pathogen?

Our research group is broadly interested in how bacteria and viruses interact with, and often subvert, their host’s immune system.ÌýAn infection can be viewed like a race. The host immune system has to detect an invading pathogen and respond, whileÌýpathogens like bacteria and viruses must evade detection and replicate. Who wins that race determines the outcome of disease.

InÌýmammals, detection of pathogenic bacteria and viruses starts with receptors of the innate immune system that sense microbe-derived chemical signals. Innate immune signaling activates the rest of the immune system to sterilize the infection. Identification ofÌýligands (chemical signals) that activate the innate immune system has led to a better understanding of vaccines and the design ofÌýnovel adjuvants. What’s more, some of these chemicals activate the immune system to fight cancer.

Our lab studies the innate immune system, the microbe-derived ligands important for immune activation, and general bacterialÌýpathogenesis. We are particularly focused on immune pathways that use nucleotide second messengers to amplify signaling.ÌýOne of the most exciting characteristics of these pathways is that they are found in both animal and bacterial cells. The sameÌýmolecular machinery that allows eukaryotes to respond to DNA viruses (called the cGAS-STING pathway), is also found inÌýbacteria. cGAS-like enzymes in bacteria are important for defense against viruses that infect bacteria, phages.

The finding that bacterial antiphage genes are homologous to human antiviral genes has led to the unexpectedÌýhypothesis that early eukaryotes must have assimilated and repurposed bacterial phage defense genes. This new paradigm inÌýevolution of the immune system establishes bacterium-phage interactions as a relevant and highly tractable model system. Our lab isÌýinterested in identifying other elements of the human immune system that can be found in bacteria, understanding molecularÌýmechanisms of phage/virus detection, and distilling these findings identify generalizable characteristics of immune systems.

The ultimate goal of our work is to better understand human immune signaling and inform the development of therapeutics,Ìýcontributing to the goal of defeating human pathogens and cancers.

SeeÌýÌýfor a full and up-to-date list

• Conte AN, Ridgeway SM, Ruchel ME, Kibby EM, Nagy TA, Whiteley AT. Phage detection by a bacterial NLR-related protein is mediated by DnaJ. bioRxiv. 2024 Jun 4;. doi: 10.1101/2024.06.04.597415. PubMed PMID: 38895412; PubMed Central PMCID: PMC11185742.
• Ledvina HE, Whiteley AT. Conservation and similarity of bacterial and eukaryotic innate immunity. Nat Rev Microbiol. 2024 Jul;22(7):420-434. doi: 10.1038/s41579-024-01017-1. Epub 2024 Feb 28. Review. PubMed PMID: 38418927; PubMed Central PMCID: PMC11389603.
• Kibby EM, Conte AN, Burroughs AM, Nagy TA, Vargas JA, Whalen LA, Aravind L, Whiteley AT.Bacterial NLR-related proteins protect against phage. Cell. 2023 May 25;186(11):2410-2424.e18. doi: 10.1016/j.cell.2023.04.015. Epub 2023 May 8. PubMed PMID: 37160116; PubMed Central PMCID: PMC10294775.
• Ledvina HE*, Ye Q*, Gu Y, Sullivan AE, Quan Y, Lau RK, Zhou H, Corbett KD†, Whiteley AT† (*equal contribution, †co-cor. author). An E1-E2 fusion protein primes antiviral immune signalling in bacteria. Nature. 2023 Apr;616(7956):319-325. doi: 10.1038/s41586-022-05647-4. Epub 2023 Feb 8. PubMed PMID: 36755092; PubMed Central PMCID: PMC10292035.