John A. T. Young
Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis
Nomis Foundation Chair
John A. T. Young, a Professor in the Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, studies the cell biology of virus infection and anthrax intoxication. His laboratory is identifying and characterizing cellular factors that contribute to the early steps of infection by HIV and other retroviruses, influenza virus, and filoviruses such as Ebola virus. These studies are giving novel insights into virus-host interactions and are suggesting new therapeutic strategies for combating virus infection. The Young laboratory has also identified both known cellular receptors for anthrax toxin. Current research in the lab is aimed at understanding how these receptors, along with other cellular factors, regulate anthrax toxin entry into cells. Soluble versions of a cellular receptor are also being developed as receptor decoys to efficiently neutralize anthrax toxin.
"A major goal of our work is to reveal how host cell proteins either contribute to or defend against infection by important human microbial pathogens, such as HIV, influenza virus, Ebola virus and the bacterium that causes anthrax. Knowledge of the roles played by this cellular machinery provides new insights into the cell biology of microbial infections and could suggest new broad-spectrum antimicrobial approaches."
A major focus of Young's work is on the HIV virus. HIV/AIDS continues to be a serious global problem. The virus can remain "hidden" in a latent form in infected individuals for years, even after long-term suppression with highly active antiretroviral therapy. Moreover, viral drug resistance represents a formidable problem, creating an urgent need for new classes of antiretrovirals.
HIV begins its assault by injecting its core, which contains single-stranded RNA, into a host cell. Once inside, the viral RNA is converted into double-stranded DNA—a process known as reverse transcription—and the original viral RNA is degraded. Another enzyme, integrase, mediates the final step of the genome conversion, where the viral double-stranded DNA slips into the host's DNA, allowing it to take advantage of the host cell's genetic machinery to replicate and propagate itself. During these early steps of infection, the virus relies heavily on its host cell to lend a helping hand, which makes it particularly vulnerable to antivirals and host defense mechanisms.
To identify cellular processes that either facilitate or defend against HIV-1 infection, Young and his collaborators use systems biology approaches to investigate the roles played by individual genes in the genome of host cells. These experiments have uncovered ZASC1, a new regulator of virus gene expression. They have also revealed that sulfonation—a type of chemical modification— regulates viral gene expression. A number of cellular factors they have identified restrict HIV infection, some of which play known roles in innate immunity, one of the body's defense mechanisms that protect against microbial infections. In addition, virus countermeasures of these host defenses are being identified. Young anticipates that these discoveries will open up new avenues for the development of drugs that specifically interfere with HIV replication.
Left to right: From left to right: Rose Pilpa, T Morrell, Shannon Seidel, Artuo Diaz, Jeff Murry, John Young, John Naughton, John Marlett, Sebastien Landry, Justine Swann, Melissa Rodgers
Bruce, J.W., Ahlquist P., and Young, J.A.T. (2008) The host cell sulfonation pathway contributes to retroviral infection at a step coincident with provirus establishment. PLoS Pathogens November; 4(11): e1000207.
König, R., Zhou, Y., Elleder, D., Diamond, T.L., Bonamy, G. M.C., Irelan, J.T., Chiang, C., Tu, B.P., De Jesus, P.D., Lilley, C.E., Seidel, S., Opaluch, A.M., Caldwell, J.S., Weitzman, M.D., Kuhen, K.L., Bandyopadhyay, S., Ideker, T., Orth, A.P., Miraglia, L.J., Bushman, F.D., Young, J.A.T., Chanda, S.K. (2008) Global analysis of host-pathogen interactions that regulate early stage HIV-1 Replication. Cell. Volume 135, Issue 1, 49-60.
Scobie, H.M., Marlett, J.M., Thomas, D., Rainey, G.J.A., Lacy, D.B., Collier, R.J. and Young, J.A.T. 2007. Anthrax toxin receptor 2 determinants that dictate the pH threshold of toxin pore formation. PLoS ONE. 2:e329.
Scobie H.M., Wigelsworth D.J., Marlett J.M., Thomas D., Rainey, G.J.A., Lacy D.B., Manchester, M. and Young J.A.T. 2006. Anthrax Toxin Receptor 2-Dependent Lethal Toxin Killing in vivo. PLoS Pathogens. 2:e111.
Rainey, G.J., Wigelsworth, D.J., Ryan, P.L., Scobie, H.M., Collier, R.J. and Young, J.A.T. 2005. Receptor- specific Requirements for Anthrax Toxin Delivery into Cells. Proc. Natl. Acad. Sci. U.S.A. 102(37):13278-13283.
Narayan, S. and Young, J.A.T. 2004. Reconstitution of Retroviral Fusion and Uncoating in a Cell-free System. Proc. Natl. Acad. Sci. U.S.A. 101:7721-7726.
Scobie, H.M., Rainey, G.J.A., Bradley, K.A. and Young, J.A.T. 2003. Human Capillary Morphogenesis Protein 2 Functions as an Anthrax Toxin Receptor. Proc. Natl. Acad. Sci. U.S.A. 100:5170-5174.
Bradley, K.A., Mogridge, J., Mourez, M., Collier, R.J. and Young, J.A.T. 2001. Identification of the Cellular Receptor for Anthrax Toxin. Nature. 414:225-229.
Mothes, W., Boerger A.L., Narayan, S., Cunningham, J.M. and Young, J.A.T. 2000. Retroviral Entry Mediated by Receptor Priming and Low pH Triggering of an Envelope Glycoprotein. Cell. 103:679-689.
Salk News Releases
Potent mechanism helps viruses shut down body's defense system against infection
August 14, 2013
Salk Institute and Sanford-Burnham study selected most-cited paper in Molecular Biology & Genetics
January 4, 2011
NIH awards $21 million grant to study early stages of HIV-1 infection
August 12, 2010
Nomis Foundation's $6.5 million gift supports research in Immunobiology; Salk ends fundraising year above $31-million mark
June 28, 2010
Novel regulatory step during HIV replication
November 13, 2008
What HIV Needs
October 2, 2008
Innovative dual action anthrax vaccine-antitoxin combination
October 5, 2007
Unexpected features of anthrax toxin may lead to new types of therapies
August 29, 2005
Several minute intermediate stage in virus-cell fusion discovered; possible window of opportunity for drug development
June 8, 2005
A New View of HIV
June 7, 2004
Awards and Honors
- Eli Lilly and Company Research Award in Microbiology and Immunology
- Fellow, American Academy of Microbiology
NIH awards $21 million grant to study early stages of HIV-1 infection
August 16, 2010
A multi-institutional team headed by John Young, Ph.D., a professor at the Salk Institute for Biological Studies, and Sumit Chanda, Ph.D., an associate professor at Sanford-Burnham Medical Research Institute, has been awarded a $21 million Program Project Grant to dissect the early innate immune response to HIV infection using a systems biology approach.
The project will bring together a multidisciplinary team that draws on the expertise of 13 research groups at seven institutions to uncover the cellular protein machinery that represents the first line of defense against HIV, the cause of AIDS. Read more>>