Professor, Department of Microbiology & Immunology
Harold and Muriel Block Faculty Scholar in Virology
My lab has two overarching goals. First, we seek to make a ‘molecular movie’ of the process by which the highly pathogenic Ebola and Marburg filoviruses gain entry into the cytoplasm of host cells, where all the ‘goodies’ for viral multiplication are located. Second, we seek to exploit this knowledge to develop new anti-filovirus therapeutics.
The filovirus entry mechanism is unusually complex (i.e., interesting!). It consists of multiple steps in which the virus interacts with and co-opts distinct host cell molecules, and is itself structurally transformed as a result. Over the last few years, others and we have found that filovirus entry is profoundly dependent upon the cellular endocytic pathway.
First as a postdoc, and then as a faculty member at Einstein, I have helped to identify endosomal host factors that are critical for filovirus entry and potential targets for antiviral therapy. In 2005, I showed that the endosomal cysteine proteases cathepsins B and L are required for viral entry and act by cleaving the viral glycoprotein. Very recently, grad students Tony Wong and Emily Miller in my lab have made a remarkable discovery. They have shown that the Niemann-Pick C1 protein, a highly studied cholesterol transporter in lysosomes, is an indispensable host factor for filovirus entry.
The discovery of a central role for NPC1 in filovirus entry promises to revolutionize our understanding of the filovirus infection cycle, in vivo viral pathogenesis, and the ecology and natural history of filovirus infections. Not least, NPC1 provides a new target for the development of anti-filovirus therapeutics.
Here are some questions we are currently exploring:
1. Why is the Niemann-Pick C1 (NPC1) protein required for filovirus entry? Our working hypothesis is that NPC1 induces structural changes in the viral glycoprotein that drive fusion of viral and endosomal lipid bilayers and bring about viral escape into the host cytoplasm.
2. What role does NPC1 play in filovirus in vivo pathogenesis? In collaboration with Steve Walkley’s lab at Einstein, and John Dye’s group at USAMRIID, we are asking if NPC1 is required for filovirus multiplication in vivo and for filovirus hemorrhagic fever.
3. How does the virus-NPC1 interaction influence filovirus host range, interspecies transmission, and virus-host coevolution?
4. Can antivirals targeting NPC1 be developed? With an industry partner, we are working to find small molecules that target NPC1 and block its capacity to support filovirus infection.
5. How do endosomal cysteine proteases mediate filovirus entry? We are using a combination of approaches to test our working hypothesis, which is that cleavage of the filovirus glycoprotein by cathepsins L and B acts in concert with NPC1 interaction to trigger viral membrane fusion.
6. What additional host factors and pathways are required for filovirus entry? We have identified additional endosomal host factors, including multiprotein complexes that are involved in the biogenesis and trafficking of specific endosomal compartments. We are exploring the roles of these endosomal factors in filovirus entry
7. What is the cascade of structural transformations in the viral glycoprotein that drives filovirus entry? In collaboration with Jon Lai’s lab at Einstein, we are using state-of-the-art synthetic antibody repertoires and phage display technology to develop monoclonal antibodies that bind to different conformational states of the filovirus glycoprotein and illuminate new frames in our molecular movie of viral entry.
Please go here for complete bibliography.
Frei JC, Nyakatura EK, Zak SE, Bakken RR, Chandran K, Dye JM, Lai JR§. 2016. Bispecific Antibody Affords Complete Post-Exposure Protection of Mice from Both Ebola (Zaire) and Sudan Viruses. Sci Rep 6:19193.
Ng M, Ndungo E, Kaczmarek ME, Herbert AS, Binger T, James R, Jangra RK, Hawkins JA, Gifford RJ, Biswas R, Demogines A, Kuehne AI, Yu M, Brummelkamp TR, Drosten C, Wang LF, Kuhn JH, Müller MA, Dye JM§, Sawyer SL§, and Chandran K§. 2015. NPC1 contributes to species-specific patterns of filovirus susceptibility in bats. eLife 4. pii: e11785
Basu A§, Mills DM, Mitchell D, Ndungo E, Williams JD, Herbert AS, Dye JM, Moir DT, Chandran K, Patterson JL, Rong L, Bowlin TL. 2015. Novel Small Molecule Entry Inhibitors of Ebola Virus. J Infect Dis 212 Suppl 2:S425-34.
Kleinfelter LM, Jangra RK, Jae LT, Herbert AS, Mittler E, Stiles KM, Wirchnianski AS, Kielian M, Brummelkamp TR, Dye JM§, and Chandran K§. 2015. Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion. MBio 6:e00801-15.
Herbert AS, Davidson C, Kuehne AI, Bakken R, Braigen SZ, Gunn KE, Whelan SP, Brummelkamp TR, Twenhafel NA, Chandran K§, Walkley SU§, and Dye JM§. 2015. Niemann-Pick C1 is essential for Ebola virus replication and pathogenesis in vivo. MBio 6:e00565-15.
Ng M, Ndungo E, Jangra RK, Cai Y, Postnikova E, Radoshitzky SR, Dye JM, Ramírez de Arellano E, Negredo A, Palacios G, Kuhn JH, Chandran K§. 2014. Cell entry by a novel European filovirus requires host endosomal cysteine proteases and Niemann-Pick C1. Virology 468-470:637-646.
Bhattacharyya S, Mulherkar N, Chandran K§. 2013. Endocytic pathways involved in filovirus entry: advances, implications and future directions. Viruses 4:3647-3664.
Koellhoffer JF, Chen G, Sandesara RG, Bale S, Saphire EO, Chandran K§, Sidhu SS§, Lai JR§. 2012. Two synthetic antibodies that recognize and neutralize distinct proteolytic forms of the Ebola virus envelope glycoprotein. Chembiochem 13:2549-2557. (pdf)
Miller EH and Chandran K§. 2012. Filovirus entry into cells – new insights. Curr Opin Virol 2:206-214. (pdf)
Miller EH, Obernosterer G, Raaben M, Herbert AS, Krishnan A, Ndungo E, Sandesara RG, Carette JE, Kuehne AI, Ruthel G, Dye JM§, Whelan SP§, Brummelkamp TR§, Chandran K§. 2012. Ebola virus entry requires the host-programmed recognition of an intracellular receptor. EMBO J 31:1947-1960. (pdf)
Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, Kuehne AI, Kranzusch PJ, Griffin AM, Ruthel G, Dal Cin P, Dye JM§, Whelan SP§, Chandran K§, Brummelkamp TR§. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature 477:340-343. (pdf)
Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Li Q, Ory D, Chandran K, Cunningham J§. Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection. Nature 477:344-348.(pdf)
Dias JM, Kuehne AI, Abelson DM, Wong AC, Halfmann P, Muhammad M, Kang E, Zak S, Fusco ML, Kawaoka Y, Chandran K, Dye JM§, Saphire EO§. A shared immunological solution for neutralization of ebolaviruses.Nature Struct. Mol. Biol. 18:1424-1427. (pdf) (Supplementary material)
Miller EH, Harrison JS, Radoshitzky SR, Higgins CD, Chi X, Dong L, Kuhn JH, Bavari S, Lai JR§, Chandran K§.Inhibition of Ebola virus entry by a C-peptide targeted to endosomes. J. Biol. Chem. 286:15854-15861.(pdf)
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Albert Einstein College of Medicine
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Wall Street Journal interviews Drs. Kartik Chandran and Steven Walkley about the connection between the rare genetic disease Niemann-Pick Type C and Ebola. (subscription)
The New York Daily News interviews Dr. Kartik Chandran about the evolving Ebola epidemic and the risk of airline travel.