Listeria monocytogenesis an intracellular bacterial pathogen responsible for the life-threatening disease, listeriosis. This bacterium is generally transmitted through contaminated food andcrosses the intestinal, placental, and blood-brain barriers to colonize multiple tissues and organs, causing gastroenteritis, meningitis, encephalitis and fetal infections of humans. Our laboratory studies the molecular machineries underlying host cell invasion and intracellular replication ofL. monocytogenes. The results of our research are expected to provide a molecular basis for the logical design of new anti-microbial therapeutics. Specific projects currently are to:
Establish howL. monocytogenesinvades mammalian cells and tissues.
We use quantitative fluorescence microscopy to establish the complex dynamics of the signaling events orchestrated byL. monocytogenesvirulence factors during host cell invasion. Our experimental models include immortalized human cell lines, primary human cells (hepatocytes and placental cells), and term placental explants infected byL. monocytogenes.
Determine the molecular basis and outcomes of host-cell signaling induced by cholesterol-dependent cytolysin (CDCs).
CDCs are a family of pore-forming toxins produced by numerous Gram-positiveListeria,Streptococcus,BacillusandClostridiumspecies. At concentrations below those that cause host-cell lysis, these virulence factors function as signaling molecules but the underlying molecular biology and the host cell responses to this toxin remain poorly understood. To gain this information, we are investigating the signaling properties of listeriolysin O, the CDC and the major virulence factor ofL. monocytogenes.Structure-function dissection of listeriolysin O is being combined with live-cell imaging to establish how this toxin affects host-cell signaling during the course of a bacterial infection.
Determine the mechanisms underlying the anti-toxin and immunomodulatory functions of defensins.
Defensins are cysteine-rich and cationic antimicrobial peptides that display a large array of antimicrobial and anti-toxin activities as well as immunomodulatory functions. Understanding the molecular basis of defensins activities is a promising avenue of research for the logical design of anti-microbial therapeutics. Current antimicrobial treatments include drugs that target pathogens and vaccines. An alternative to these strategies is the development of drugs that target the pathogen while potentiating the host immune responses. It is expected that pathogens will develop limited resistance to such multifunctional drugs. In this line of investigation, we found that not only defensins exert direct anti-listerial and listeriolysin O toxin neutralization activities; they also unable macrophages to clearL. monocytogenesinfection. Mechanisms involved in the neutralization of listeriolysin O and increase antimicrobial activity of macrophages by defensins are currently under investigation.
- Seveau S. Multifaceted activity of Listeriolysin O, the cholesterol-dependent cytolysin of Listeria monocytogenes. Subcellular Biochemistry. 2014; 80:161-95.Book Chapter.
- Arnett E, Vadia S, Nackerman CC, Oghumu S, Satoskar AR, McLeish KR, Silvia M. Uriarte &Seveau S. Listeriolysin O is degraded by the neutrophil metalloprotease MMP-8 and fails to protect Listeria monocytogenes from intracellular killing in neutrophils. Journal of Immunology. 2014; 192 (1): 234-44.
- Vadia S & Seveau S. Fluxes of Ca2+ and K+ are required for the LLO-dependent internalization pathway of Listeria monocytogenes. Infection and Immunity.2014; 82 (3): 1084-91.
- Bayer A, Delorme-Axford E, Sleigher C, Frey TK, Trobaugh DW, Klimstra WB, Emert-Sedlak LA, Smithgall TE, Kinchington PR, Vadia S, Seveau S, Boyle JP, Coyne CB &Sadovsky Y. Human trophoblasts confer resistance to viruses implicated in perinatal infection. American Journal of Obstetrics and Gynecology. 2014; August 26.
- Habyarimana F, Swearingen MC, Young GM, Seveau S& Ahmer BM. Yersinia enterocolitica inhibits Salmonella enterica and Listeria monocytogenes cellular uptake. Infection and Immunity. 2014; 82 (1): 174-83.
- Dare K, Shepherd J, Roy H, Seveau S& Ibba M. LysPGS formation in Listeria monocytogenes has broad roles in maintaining membrane integrity beyond antimicrobial peptide resistance. Virulence. 2014; 6; 5(4).
- Cummings H, Barbi J, Reville P, Zorko N, Oghumu S, Sarkar A, Keiser T, Lu B, Rückle T, Lezama-Davila C, Wewers M, Whitacre C, Radzioch D, Rommel C, Seveau S& Satoskar AR. Critical role for PI3Kγ in parasite invasion and disease progression of cutaneous leishmaniasis. Proc Natl Acad Sci U S A. 2012; 109(4):1251-6. Cited in Faculty of 1,000.
- Rogers TE, Sandro FA, Dare K, Katz A, Seveau S, Roy H & Ibba M. A pseudo-tRNA modulates antibiotic resistance in Bacillus cereus. Plos One. 2012; 7(7): e41248.
- Arnett E, Lehrer RI, Pratikhya P, Lu W &Seveau S. Defensins enable macrophages to inhibit the intracellular proliferation of Listeria monocytogenes. Cell Microbiol. 2011; (4): 635-51.
- Vadia S, Arnett E, Haghighat AC, Wilson-Kubalek EM, Tweten RK &Seveau S. The pore-forming toxin listeriolysin O mediates a novel entry pathway of L. monocytogenes into human hepatocytes. Plos Pathog. 2011; 7(11): e1002356. Cited in Faculty of 1,000.
- Arnett E &Seveau S. The Multifaceted Activities of Mammalian Defensins.Current Pharmaceutical Design. 2011; 17(38): 4254-69.
- Haghighat AC & Seveau S. Quantification of host-microbe interactions by automated fluorescence microscopy. J Immunol Methods. 2010; 352(1-2):186-91.
- Hoppe AD, Seveau S & Swanson JA. Live Cell Fluorescence Microscopy to study microbial pathogenesis. Cell Microbiol. 2009; 11(4): 540-50.
Other Relevant Publications
- Seveau S, Tham TN, Payrastre B, Hoppe AD, Swanson J & Cossart P. A FRET analysis to unravel the role of cholesterol in Rac1 and PI 3-kinase activation in the InlB/Met signalling pathway. Cell Microbiol. 2007; 9:790-803.
- Seveau S, Pizarro-Cerda J &Cossart P. Molecular mechanisms exploited by Listeria monocytogenes during host cell invasion. Microbes Infect. 2007; 10:1167-75.
- Diakonova M, Helfer E, Seveau S, Swanson JA, Kocks C, Rui L, Carlier MF &Carter-Su C. Adapter Protein SH2-B Stimulates Actin-based Motility of Listeria monocytogenes in a VASP-dependent Fashion. Infect Immun. 2007; 75:3581-3593.
- Hamon MA, Batsché E, Régnault B, Tham TN, Seveau S, Muchardt C &Cossart P. Histone modifications induced by a family of bacterial toxins. Proc Natl Acad Sci USA. 2007; 104 (44):17555. Cited in Faculty of 1,000.
- Nusbaum P, Lainé C, Bouaouina M, Seveau S, Cramer EM, Masse JM, Lesavre P & Halbwachs-Mecarelli L. Distinct signaling pathways are involved in leukosialin (CD43) downregulation, membrane blebbing and phospholipids scrambling during neutrophil apoptosis. J Biol Chem. 2005; 280(7):5843-53.
- Martinez JJ, Seveau S, Veiga-Chacon E, Matsuyama S & Cossart P. Ku70, a component of DNA-dependent protein kinase, is a receptor involved in Rickettsia conorii invasion of mammalian cells. Cell. 2005; 123(6):1013-23. cited in Faculty of 1,000.
- Seveau S, Bierne H, Giroux S, Prevost MC & Cossart P. Role of lipid rafts in E-cadherin- and HGF-R/Met-mediated entry of Listeria monocytogenes into host cells. J Cell Biol. 2004; 166(5):743-53.
- Nusbaum P, Laine C, Seveau S, Lesavre P & Halbwachs-Mecarelli L. Early membrane events in polymorphonuclear cell (PMN) apoptosis: membrane blebbing and vesicle release, CD43 and CD16 down-regulation and phosphatidylserine externalization. Biochem Soc Trans. 2004; 32:477-9.
- Dehghani ZA, Seveau S, Halbwachs-Mecarelli L & Keller HU. Chemotactically-induced redistribution of CD43 as related to polarity and locomotion of human polymorphonuclear leucocytes. Biol Cell. 2003; 95(5): 265-73.
- Pierini LM, Eddy RJ, Fuortes M, Seveau S, Casulo C & Maxfield FR. Membrane lipid organization is critical for human neutrophil polarization.J Biol Chem. 2003; 278(12): 10831-41.
- Seveau S, Eddy RJ, Maxfield FR & Pierini LM. Cytoskeleton-dependent membrane domain segregation during neutrophil polarization. Mol Biol Cell. 2001; 12: 3550-62.
- Seveau S, Keller H, Maxfield FR, Piller F & Halbwachs-Mecarelli L. Neutrophil polarity and locomotion are associated with surface redistribution of leukosialin (CD43), an anti-adhesive membrane molecule. Blood. 2000; 95: 2462-70.
- Lopez S, Seveau S, Lesavre P, Robinson MK & Halbwachs-Mecarelli L. CD43 (sialophorin, leukosialin) shedding is an initial event during neutrophil migration, which could be closely related to the spreading of adherent cells. Cell Adhes Commun. 1998; 5(2): 151-60.
- Seveau S, Lopez S, Lesavre P, Guichard J, Cramer EM & Halbwachs-Mecarelli L. Leukosialin (CD43, sialophorin) redistribution in uropods of polarized neutrophils is induced by CD43 cross-linking by antibodies, by colchicine or by chemotactic peptides. J Cell Sci. 1997; 110: 1465-75.