| Description |
Viruses have been long known to exploit host cellular factors to facilitate various steps of their replication cycle. While viruses like HIV have available although exorbitantly expensive therapies, others like Influenza virus are rapidly developing drug-resistance and yet others like the Filoviridae family of Ebola and Marburg viruses, which are known to cause acute hemorrhagic fever, have no effective therapy or licensed vaccines currently available. I am interested in studying the interactions of viruses that pose a major global threat, with their host cells and designing effective strategies to block them. Our collaborative genome-wide siRNA screening efforts have led to the identification of 295 cellular factors required for influenza virus entry. Also, using multiple approaches in the form of chemical inhibitors, dominant-negative proteins and RNAi, our studies have uncovered a novel beta-arrestin 1 (ARRB1) and adaptor-related protein complex 1 (AP-1) dependent pathway in the clathrin-mediated entry of Influenza virus. We have also examined the role of the clathrin endocytic pathway in Ebola and Marburg glycoprotein (GP) mediated viral entry. To monitor virus infection, we employed reporter viruses encoding either the green fluorescent protein (GFP) or the Renilla luciferase gene and expression of these genes was examined as a marker for viral entry. These studies have revealed an important role for clathrin-mediated endocytosis in filovirus entry and have shown that Ebola and Marburg virus have differential requirements for key components of this cellular endocytic pathway. Our results indicate that there may be differences in Ebola virus versus Marburg virus receptor and/or co-receptor interactions during cellular entry. Also, requirements for Marburg GP mediated entry are strikingly similar to Influenza virus entry suggesting that further characterization of this ARRB1 and AP-1 dependent pathway could reveal a major pathogen entry mechanism. Additionally, using state-of-the-art deconvolution microscopy, we observed that Ebola GP, which is known to be severely cytotoxic, accumulates in the endoplasmic reticulum (ER) in close proximity to the nuclear membrane, when transiently expressed in cells. This finding is intriguing and could have important therapeutic implications because filoviruses complete their replication cycle in the cytoplasm and are not known to enter the nucleus. Therefore, future studies investigating the correlation between Ebola GP accumulation in the ER and its cytotoxic property may be useful in designing inhibitors to block this cytotoxic effect during infection and/or potentially reduce the severe pathogenic effects that these patients experience.
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