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Kartik Chandran: Chemistry Kid

Associate Professor, Department of Microbiology & Immunology, Albert Einstein College of Medicine, Age: 38

By | September 1, 2012

image: Kartik Chandran: Chemistry Kid dustin fenstermacher

In high school in Bangalore, India, Kartik Chandran did some admittedly crazy experiments with his fellow chemistry club members, including distilling nitric acid to make explosive guncotton (nitrocellulose), which they used to blow up a Coke can. “The chemistry club was really adventurous,” he recalls. “The safety standards [in Indian high schools] are not what they are here” in the United States.

Wanting to learn more about chemistry, Kartik applied for and received a full scholarship to Lafayette College in Pennsylvania. Getting an advanced science degree “is really difficult in India,” he says. “If I stayed in India, it wouldn’t work out."

METHODS: After college Chandran joined virologist Max Nibert’s lab at the University of Wisconsin, Madison, where he dove into the study of how mammalian reoviruses enter host cells. The viruses were known to be taken up into a cell’s endosomes, but such compartments were typically thought of as virus “graveyards,” Chandran says.

Virus entry was typically studied using a process called reverse genetics, in which a researcher uses living cells to construct a virus made with selectively mutated viral genes. But because the reovirus genome consists of 10 different pieces of double-stranded RNA, and “no one had figured out how to take these 10 RNAs, put them in cells, and get virus back . . . you couldn’t make mutations in [the] virus,” Chandran says.

So he devised a system to strip away the virus’s three surface proteins, recoating it with altered proteins. “That’s a very useful technique because it lets us essentially do genetics on all three of the outer capsid proteins,” says Nibert. Chandran found that the viruses cross the endosome membrane by tricking endosomal proteases into exposing a hydrophobic region of a viral capsid protein.1

RESULTS: After earning his PhD, Chandran followed Nibert to Harvard Medical School as a postdoc, then crossed the street to work with virologist Jim Cunningham at Brigham and Women’s Hospital. Chandran decided to work on Ebola entry, which had stumped researchers who were unable to identify a cell-surface receptor for the virus.

It turns out that Ebola, a filovirus, has taken a page from the book of reoviruses, co-opting the cell’s endosome, where proteases degrade part of the virus’s surface to allow it to enter the cytoplasm.2

DISCUSSION: Now in his own lab at the Albert Einstein College of Medicine, Chandran continues to study Ebola. Collaborating with Sean Whalen at Harvard and Thijn Brummelkamp at the Whitehead Institute for Biomedical Research, he screened human cells for mutations that affected Ebola entry, identifying the Niemann-Pick C1 (NPC1) gene, which, when mutated, is known to cause a fatal neurodegenerative disease. Meanwhile, Cunningham’s group investigated hits ID’d in a small-molecule screen for Ebola entry inhibitors that Chandran had performed, and also identified the NPC1 protein as a target. The two studies, each coauthored by Chandran, were published in side-by-side Nature papers last year.3,4

Chandran has gone on to show that the normal NPC1 protein is indeed necessary for viral escape from the endosome, but that it can only bind viruses that have been cleaved by endosomal proteases—just as he and his colleagues had predicted. “It’s elegant,” Cunningham says. “Largely from the work that started with Kartik, the host factors for Ebola have likely been found.”

LITERATURE CITED:


  1. K. Chandran et al., “Strategy for nonenveloped virus entry: a hydrophobic conformer of the reovirus membrane penetration protein µ1 mediates membrane disruption,” J Virol, 76:9920-33, 2002. (Cited 93 times)

  2. K. Chandran et al., “Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection,” Science, 308:1643-45, 2005. (Cited 251 times)

  3. J.E. Carette et al., “Ebola virus entry requires the cholesterol transporter Niemann-Pick C1,” Nature, 477:340-43, 2011. (Cited 25 times)

  4. M. Côté et al., “Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection,” Nature, 477:344-48, 2011. (Cited 21 times)

 

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