M.S. Pierre and Marie Curie Univ., Paris, 1993
Ph.D. Pierre and Marie Curie Univ., Paris, 1997
Postdoc. Weill Cornell Medical College, 1998-2001
Dr. Seveau’s research is focused on understanding, at the molecular level, host-pathogen interactions and the host responses to bacterial toxins. The results of her research provide a molecular basis for the logical design of new anti-microbial therapeutics. Specific projects currently are to:
Establish how Listeria monocytogenes invades and establishes infections of mammalian cells and tissues.
L. monocytogenes is a food-borne intracellular bacterial pathogen that causes gastroenteritis, meningitis, encephalitis and fetal infections of humans. L. monocytogenes lives inside host cells, and its ability to invade mammalian cells facilitates both its initial transit through the epithelial barrier of the digestive tract, and subsequent colonization of many organs. State-of-the-art quantitative fluorescence microscopy is used as the primary approach to investigate and quantify L. monocytogenes infections of live host cells. The complex dynamics of the signaling events that lead to L. monocytogenes uptake by epithelial cells and macrophages are being determined and characterized.
Determine the molecular basis, and outcome of host-cell signaling induced by cholesterol-dependent cytolysin (CDCs) toxins.
CDCs are a family of closely-related pore-forming bacterial toxins produced by many Gram-positive Listeria, Streptococcus, Bacillus and Clostridium species. 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-signaling remain unknown. To gain this information, we are investigating the signaling properties of listeriolysin O, a CDC and the major virulence factor of L. 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 human defensin antimicrobial peptides.
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 clear L. monocytogenes infection. The mechanisms involved in the neutralization of listeriolysin O and increase antimicrobial activity of macrophages by defensins are currently under investigation.
- Vadia S & Seveau S. Fluxes of Ca2+ and K+ are required for the LLO-dependent internalizationpathwayof Listeria monocytogenes. (Manuscript under revision)
- Arnett E, Vadia S, Nackerman CC, Oghumu S, Satoskar AR, McLeish KR, Uriarte SM &Seveau S. Listeriolysin O is degraded by neutrophil metalloprotease 8 and fails to mediate Listeria monocytogenes intracellular survival in neutrophils. (Journal of Immunology, accepted)
- Habyarimana F, Swearingen MC, Young GM, Seveau S & Ahmer BMM. Yersinia enterocolitica inhibits Salmonella enterica and Listeria monocytogenes cellular uptake. (Infection and Immunity, accepted)
- Rogers TE, Sandro FA, Dare K, Katz A, Seveau S, Roy H & Ibba M. (2012). A pseudo-tRNA modulates antibiotic resistance in Bacillus cereus. Plos One. 7(7):e41248.
- 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. (2012). Critical role for PI3Kγ in parasite invasion and disease progression of cutaneous leishmaniasis. Proc Natl Acad Sci U S A. 109(4):1251-6.
- Arnett E & Seveau S. (2011) The Multifaceted Activities of Mammalian Defensins. Current Pharm Design. In Press
- Vadia S, Arnett E, Haghighat AC, Wilson-Kubalek EM, Tweten RK, Seveau S. (2011). The Pore-Forming Toxin Listeriolysin O Mediates a Novel Entry Pathway of L. monocytogenes into Human Hepatocytes. Plos Pathog. 7(11):e1002356
- Arnett E, Lehrer RI, Pratikhya P, Lu W & Seveau S. (2011). Defensins enable macrophages to inhibit the intracellular proliferation of Listeria monocytogenes. Cell Microbiol. 13 (4): 635-51
- Haghighat AC & Seveau S. (2010). Quantification of host-microbes interactions by automated fluorescence microscopy. J Immunol Methods. 31, 186-91.
- Hoppe AD, Seveau S & Swanson JA. (2009). Live cell fluorescence microscopy to study microbial pathogenesis. Cell Microbiol. 11, 540-50.
- Seveau S, Tham TN, Payrastre B, Hoppe AD, Swanson JA & Cossart P. (2007). A FRET analysis to unravel the role of cholesterol in Rac1 and PI 3-kinase activation in the InIB/Met signalling pathway. Cell Microbiol. 9, 790-803.
- Seveau S, Pizzaro-Cerda J & Cossart P. (2007). Molecular mechanisms exploited by Listeria monocytogenes during host cell invasion. Microbes Infect. 9, 1167-75.
- Hamon M, Batsche E, Muchardt C, Nam TT, Seveau S & Cossart, P. (2007). Histone modifications induced by a family of bacterial toxins. Proc Natl Acad Sci U S A. 104, 13467-72.
- Diakonova M, Helfer E, Seveau S, Swanson JA, Kocks C, Rui L, Carlier M & Carter-Su C. (2007). Adapter protein SH2-Bß stimulates Actin-based motility of Listeria monocytogenes in a VASP-dependent fashion. Infect Immunity. 7, 3581.
- Seveau S, Tham TN, Payrastre B, Hoppe AD, Swanson J & Cossart P. (2007). A FRET analysis to unravel the role of cholesterol in Rac1 and PI 3-kinase activation in the InlB/Met signalling pathway. Cell Microbiol. 9:790-803
- Martinez JJ, Seveau S, Veiga-Chacon E, Matsuyama S & Cossart P. (2005). Ku70, a component of DNA-dependent protein kinase, is a receptor involved in Rickettsia conorii invasion of mammalian cells. Cell. 123,1013-23.
- Nusbaum P, Lainé C, Bouaouina M, Seveau S, Cramer EM, Masse JM, Lesavre P & Halbwachs-Mecarelli L. (2005). Distinct signaling pathways are involved in leukosialin (CD43) downregulation, membrane blebbing and phospholipids scrambling during neutrophil apoptosis. J Biol Chem. 280(7):5843-53.
- Seveau S, Bierne H, Giroux S, Prevost MC & Cossart P. (2004). Role of lipid rafts in E-cadherin- and HGF-R/Met-mediated entry of Listeria monocytogenes into host cells. J Cell Biol. 166, 743-53.
- Nusbaum P, Laine C, Seveau S, Lesavre P & Halbwachs-Mecarelli L. (2004). Early membrane events in polymorphonuclear cell (PMN) apoptosis: membrane blebbing and vesicle release, CD43 and CD16 down-regulation and phosphatidylserine externalization. Biochem Soc Trans. 32:477-9.
- Dehghani ZA, Seveau S, Halbwachs-Mecarelli L & Keller HU. (2003). Chemotactically-induced redistribution of CD43 as related to polarity and locomotion of human polymorphonuclear leucocytes. Biol Cell. 95(5):265-73.
- Pierini LM, Eddy RJ, Fuortes M, Seveau S, Casulo C & Maxfield FR. (2003). Membrane lipid organization is critical for human neutrophil polarization. J Biol Chem. 278(12):10831-41.
- Seveau S, Eddy RJ, Maxfield FR & Pierini LM. (2001). Cytoskeleton-dependent membrane domain segregation during neutrophil polarization. Mol Biol Cell. 12:3550-62.
- Seveau S, Keller H, Maxfield FR, Piller F & Halbwachs-Mecarelli L. (2000) Neutrophil polarity and locomotion are associated with surface redistribution of leukosialin (CD43), an anti-adhesive membrane molecule. Blood. 95:2462-70.
- Lopez S, Seveau S, Lesavre P, Robinson MK & Halbwachs-Mecarelli L. (1998). 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. 5(2):151-60.
- Seveau S, Lopez S, Lesavre P, Guichard J, Cramer EM & Halbwachs-Mecarelli L. (1997). 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.110:1465-75.