Megan Stanifer, Ph.D.
Impact of cellular polarity on virus sensing
Intestinal epithelial cells are in constant contact with the ever-present commensal flora. This leaves them with a complex task of maintaining a fine balance between tolerating the microbiota and being ready to respond to invading pathogens. Intestinal cells are polarized with an apical side facing the lumen of the gut and a basolateral side facing the sterile lamina propria. Our work has uncovered that one method used by human intestinal epithelial cells (hIECs) to avoid over stimulation is that they polarize the pathogen-recognition receptor TLR‑3 to the basolateral side of hIECs to avoid over detection of the commensal bacteria. Our group continues to investigate the molecular mechanisms used by hIECs to maintain immune-homeostasis and how these mechanisms are mis-regulated in patients with inflammatory bowel disease. Additionally, we are now extending our observations in hIECs to additional mucosal tissues (e.g. the lung and genital tract) to determine if all tissues that act as a protect barrier use similar mechanisms to detect and fight invading pathogens while tolerating the presence of the commensal flora.
Stanifer, ML, Mukenhirn, M, Muenchau, S, Pervolaraki, K, Kanaya, T, Albrecht, D, Odendall, C, Kagan, J, Bartfeld, S, Ohno, H Boulant, S. Asymmetric distribution of TLR3 leads to a polarized immune response in human intestinal epithelial cells Nature Microbiology. 2019 Nov 4. doi.org/10.1038/s41564-019‑0594‑3.
Rihn, S; Aziz, M; Stewart, D; Hughes, J; Turnbull, M; Varela, M; Sugrue, E; Herd, C; Stanifer, M; Sinkins, S; Palmarini, M and Wilson, S. TRIM69 inhibits Vesicular Stomatitis Indiana Virus (VSIV). Journal of Virology. 2019 Aug 2. pii: JVI.00951–19.
Pervolaraki, K, Guo, C, Albrecht, D, Stanifer, ML, Boulant, S. Interdependence of type I and type III interferons. J. of Interferon and Cytokine Research 2019 Jun 13.
Muenchau, S; Deutsch, R; Albrecht, D; Niesler, B, Stanifer, ML, Boulant, S. miRNA 16 and 340 regulate barrier function in human intestinal epithelial cells under low oxygen conditions. Molecular Cell Biology 2019 May 6.
Stanifer, ML, Pervolaraki, K, Boulant, S. Differential regulation of type I and type III interferon signaling, International Journal of Molecular Sciences 2019 Mar 21;20(6).
Fakhiri, J; Schneider, M; Puschhof, J; Stanifer, M; Schildgen,V; Holderbach,S; Voss, Y; El Andari, J; Schildgen, O; Boulant, S; Meister, M; Clevers, H Qiu,Y; Grimm, D. Novel chimeric gene therapy vectors based on Adeno-associated virus (AAV) and four different mammalian bocaviruses (BoV). Molecular Therapy — Methods & Clinical Development, 2019 Jan 18;12:202–222.
Pervolakari, K; Rastgou, S; Albrecht, D; Bormann, F; Hoefer, T; Stanifer, ML; Boulant, S. Kinetics of antiviral action of type III interferon is independent of receptor level. Plos Pathogen 2018 Nov 28;14(11).
Stanifer, ML, Kischnick, C, Boulant, S. MRV ISVPs counteract immune induction by blocking cellular transcription. Scientific Reports, 2017 Sep 7;7(1):10873.
Shah, NM; Stanifer, ML; Höhn, K; Engel, U; Haselmann, U; Bartenschlager, R; Kräusslich, HG; Krijnse-Locker, J; Boulant S. Genome packaging of reovirus is mediated by the scaffolding property of the microtubule network. Cell Microbiol. 2017 Dec;19(12).
Stanifer, ML, Pervolarki, K, Muenchau, S, Grimm, D, Renn, L, Rabin, R, Boulant, S. Type I and type III interferons display different dependency on MAPKs to mount an antiviral state in the human gut. Frontiers Immunology, 2017.
Kim, IS; Jenni, S; Stanifer, ML; Roth, E; Whelan SPJ; van Oijen, A; Harrison, SC. Mechanisms of membrane fusion induced by vesicular stomatitis virus G protein. PNAS. 017 Jan 3;114(1):E28-E36.
Martinez, C; Rodino-Janeiro, B; Lobo, B; Stanifer, ML; Klaus, B; Gransow, M; Alonso-Cotoner, C; Pigrau, M; Roeth, R; Rappold, G; Huber, W; Gonzalez Siloz, R; Lorenzo, J’ Azpiroz, F; Boulant, S; Vicario, M; Niesler, B; Snatos, J. miR16 and miR-125b are involved in barrier function dysregulation through the modulation of claudin‑2 and cingulin expression in the jejunum in irritable bowel syndrome with diarrhea. Gut, 2017 Jan 12
Stanifer ML, Rippert A, Kazakov A, Willemsen J, Bucher D, Bender S, Bartenschlager R, Binder M, Boulant S. Reovirus intermediate subviral particles constitute a strategy to infect intestinal epithelial cells by exploiting TGF‑β dependent pro-survival signaling. Cell Microbiol. 2016 Jun 8
Boulant S, Stanifer M, Lozach PY. Dynamics of virus-receptor interactions in virus binding, signaling, and endocytosis. Viruses. 2015 Jun 2;7(6):2794–815
Boulant S, Stanifer M, Kural C, Cureton DK, Massol R, Nibert ML, Kirchhausen T. Similar uptake but different trafficking and escape routes of reovirus virions and infectious subvirion particles imaged in polarized Madin-Darby canine kidney cells. Mol Biol Cell. 2013 Apr;24(8):1196–207
Stanifer, ML; Cureton, DK; Whelan SPJ. A recombinant vesicular stomatitis virus bearing a lethal mutation in the glycoprotein gene, uncovers a second site suppressor that restores fusion. J.Virology. 2011 Aug;85(16):8105–15.
Gee, GV; Stanifer, ML; Christensen, BC; Atwood, WJ, Ugoini,I; Nelson, HH, Marsit, CJ; Kelsey, KT. SV40 associated miRNA is not detectable in mesotheliomas. British Journal of Cancer. 2010 Sep 7;103(6):885–8.
Gasparovic, ML; Maginnis, MS; O’Hara, B; Dugan, AS; and Atwood, WJ. Modulation of PML protein expression both negatively and positively regulates JCV infection. Virology. 2009 Aug 1;390(2):279–88.
Gasparovic, ML; Gee, GV; Atwood, WJ. The JC Virus (JCV) Minor Capsid Proteins Vp2 and Vp3 are Essential for Virus Propagation. J Virol. 2006 Nov; 80(21):10858–61.
Elphick, G.F.; Querbes, W.; Jordan, J.A.; Gee, G.V.; Eash, S.; Manley, K.; Dugan, A.; Stanifer, M.; Roth, B.L.; and W.J. Atwood. The Human Polyomavirus, JCV, Uses Serotonin Receptors to Infect Cells. Science 2004 Nov 19; 306 (5700): 1380–3.