Publications

Figure: The anti-tumor effects of STING agonists such as S100 are strikingly enhanced when combined with TLR agonists such as PAM3CSK4, or a suite of bacterial pathogens.

Summary: Bacteria have been used for +100 years as cancer therapies and continue to be used in the clinic today. Bacteria that reside in the cytosol are particularly useful tools for cancer, as they can deliver antigens to MHC-I. However, it has remained unknown how cytosolic bacteria activate innate immunity in tumors. Here, we find that these bacteria activate TLR pathways in tumors, and their anti-tumor effects are synergistically enhanced upon combining with STING agonists. This lays the groundwork for how to use small molecules or microbes for cancer immunotherapy: via the co-activation of STING and TLRs.

Legend: Depletion of GSH causes Rickettsia parkeri (green) to undergo chaining and altered actin-based motility (actin in red).

Summary: Spotted fever group Rickettsia obligately reside in the cytosol where they parasitize over fifty metabolites from their hosts. However, the roles for metabolite acquisition in pathogenesis and evading innate immunity remain unclear. Here, we observed with super-resolution microscopy that depletion of the abundant low molecular weight thiol glutathione (GSH) in host cells led to an impaired ability of Rickettsia parkeri to form plaques. Our data suggest that Rickettsia requires host GSH for cysteine metabolism to promote actin-based motility, evade ubiquitylation and autophagy, and survive in immune cells.

Summary: Why do arthropod-borne pathogens cause disease in humans, yet animal reservoirs in the wild are highly resistant to infection? Here, we show that the innate immune cytokines type I and type II interferon redundantly protect mice from the tick-borne pathogen Rickettsia parkeri, which causes skin lesions (eschars) and disseminated disease in humans. This study shows that human disease may be due to an insufficient interferon response and provides an improved mouse model to investigate vaccines and therapeutics.

Summary: Inflammasomes and interferons are two critical arms of innate immunity. Intracellular bacteria are generally restricted by the cytokine interferon-gamma whereas viruses are restricted by type I interferon. It has remained unclear how obligate cytosolic bacteria, which have a virus-like intracellular life cycle, interact with inflammasomes and interferons. Here, we show that the obligate bacterial pathogen Rickettsia parkeri exploits the inherent trade-off between inflammasome-mediated cell death and type I interferon production. These interactions between R. parkeri and innate immunity are more similar to viral interactions with innate immunity, suggesting that the innate immune system evolved mechanisms to target obligate pathogens.

Summary: Bacterial pathogens that reside in the eukaryotic cytosol must evade antibacterial autophagy to survive. Here, Engstrom and colleagues performed a forward genetic screen that identified the rickettsial factors mediating ubiquitylation avoidance. This work reveals that Rickettsia methylate their surface protein lysines, shielding from host ubiquitin and autophagy.

Figure: ompB mutant Rickettsia (green) are targeted by ubiquitin (red).

Summary: Here, Engstrom and colleagues find that the Rickettsia surface protein OmpB is essential for protecting against ubiquitylation and autophagy.

Summary: Rickettsia parasitize over 50 nutrients from their hosts, more than any other known bacteria. Here, Ahyong and colleagues discover that Rickettsia parasitize isoprenoids, which are critical for their survival, and that this process can be blocked with statins.

McFarland AP, Burke TP, Carletti AA, Glover RC, Tabakh H, Welch MD, Woodward JJ. RECON-Dependent Inflammation in Hepatocytes Enhances Listeria monocytogenes Cell-to-Cell Spread. mBio. 2018 May 15;9(3). doi: 10.1128/mBio.00526-18. PubMed PMID: 29764944; PubMed Central PMCID: PMC5954220.

Burke TP, Portnoy DA. SpoVG Is a Conserved RNA-Binding Protein That Regulates Listeria monocytogenes Lysozyme Resistance, Virulence, and Swarming Motility. mBio. 2016 Apr 5;7(2):e00240. doi: 10.1128/mBio.00240-16. PMID: 27048798; PMCID: PMC4959528.

Burke TP, Loukitcheva A, Zemansky J, Wheeler R, Boneca IG, Portnoy DA. Listeria monocytogenes is resistant to lysozyme through the regulation, not the acquisition, of cell wall-modifying enzymes. J Bacteriol. 2014 Nov;196(21):3756-67. doi: 10.1128/JB.02053-14. Epub 2014 Aug 25. PMID: 25157076; PMCID: PMC4248804.

Durack J, Burke TP, Portnoy DA. A prl mutation in SecY suppresses secretion and virulence defects of Listeria monocytogenes secA2 mutants. J Bacteriol. 2015 Mar;197(5):932-42. doi: 10.1128/JB.02284-14. Epub 2014 Dec 22. PMID: 25535272; PMCID: PMC4325107.

Witte CE, Whiteley AT, Burke TP, Sauer JD, Portnoy DA, Woodward JJ. Cyclic di-AMP is critical for Listeria monocytogenes growth, cell wall homeostasis, and establishment of infection. mBio. 2013 May 28;4(3):e00282-13. doi: 10.1128/mBio.00282-13. PubMed PMID: 23716572; PubMed Central PMCID: PMC3663569.

DeYoung BJ, Qi D, Kim SH, Burke TP, Innes RW. Activation of a plant nucleotide binding-leucine rich repeat disease resistance protein by a modified self protein. Cell Microbiol. 2012 Jul;14(7):1071-84. doi: 10.1111/j.1462-5822.2012.01779.x. Epub 2012 Mar 27. PMID: 22372664; PMCID: PMC3371279.

Sauer JD, Pereyre S, Archer KA, Burke TP, Hanson B, Lauer P, Portnoy DA. Listeria monocytogenes engineered to activate the Nlrc4 inflammasome are severely attenuated and are poor inducers of protective immunity. Proc Natl Acad Sci USA. 2011 Jul 26;108(30):12419-24. doi: 10.1073/pnas.1019041108. Epub 2011 Jul 11. PMID: 21746921; PMCID: PMC3145703.