Viruses and many bacteria must invade a cell to replicate, and cell entry is a step usefully accessible to inhibitors. Studies of pathogen entry have advanced our understanding of basic cell biological processes and led to discovery of new molecular mechanisms, while also providing opportunities to consider novel strategies for intervention. During the last decade, approaches using biochemistry, genetics, and real-time imaging have led to identification of a number of alternative modes of pathogen uptake, with sometimes subtle, yet critical differences in the way particular cellular structures are deployed. Direct fluorescence imaging of individual internalization events, combined when appropriate with pharmacological or genetic perturbation, resolves ambiguities associated with """"""""ensemble"""""""" measurements, and we rely on its use throughout this proposal. This project focuses on understanding the role of multiple modes of clathrin-mediated endocytosis for viral entry and how they relate to the destination of endocytosed virus, information that is relevant to strategies for inhibiting entry, to analysis of cell tropism and different outcomes for infection of different tissues, and to relating information from entry of pseudotyped viruses with heterologous envelope proteins to entry of authentic virions. This project also aims to understand the role of the clathrin endocytic machinery in infection by invasive and adherent bacterial pathogens.
This project will focus on early molecular events involving entry of infectious agents into target cells using real-time live cell imaging. The results of these studies will identify critical steps in the infectious process that may be targets for antimicrobial therapy.
|de Wispelaere, Melissanne; Lian, Wenlong; Potisopon, Supanee et al. (2018) Inhibition of Flaviviruses by Targeting a Conserved Pocket on the Viral Envelope Protein. Cell Chem Biol 25:1006-1016.e8|
|Huang, Nai-Jia; Pishesha, Novalia; Mukherjee, Jean et al. (2017) Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin. Nat Commun 8:423|
|Mertins, Philipp; Przybylski, Dariusz; Yosef, Nir et al. (2017) An Integrative Framework Reveals Signaling-to-Transcription Events in Toll-like Receptor Signaling. Cell Rep 19:2853-2866|
|Nair, Dhanalakshmi R; Chen, Ji; Monteiro, João M et al. (2017) A quinolinol-based small molecule with anti-MRSA activity that targets bacterial membrane and promotes fermentative metabolism. J Antibiot (Tokyo) 70:1009-1019|
|Choo, Min-Kyung; Sano, Yasuyo; Kim, Changhoon et al. (2017) TLR sensing of bacterial spore-associated RNA triggers host immune responses with detrimental effects. J Exp Med 214:1297-1311|
|de Wispelaere, Mélissanne; Carocci, Margot; Liang, Yanke et al. (2017) Discovery of host-targeted covalent inhibitors of dengue virus. Antiviral Res 139:171-179|
|Umetsu, Dale T (2017) Mechanisms by which obesity impacts upon asthma. Thorax 72:174-177|
|Zheng, Huiqing; Colvin, Christopher J; Johnson, Benjamin K et al. (2017) Inhibitors of Mycobacterium tuberculosis DosRST signaling and persistence. Nat Chem Biol 13:218-225|
|Coulson, Garry B; Johnson, Benjamin K; Zheng, Huiqing et al. (2017) Targeting Mycobacterium tuberculosis Sensitivity to Thiol Stress at Acidic pH Kills the Bacterium and Potentiates Antibiotics. Cell Chem Biol 24:993-1004.e4|
|Moayeri, Mahtab; Tremblay, Jacqueline M; Debatis, Michelle et al. (2016) Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice. Clin Vaccine Immunol 23:213-8|
Showing the most recent 10 out of 417 publications