Mechanisms of bacterial and protozoan pathogenesis, and host response against infectious microbes.
Ph. D., , University of California, San Francisco
B.S., , Yale University
Postdoc, , Harvard University
Awards and Academic Honors
Burroughs-Wellcome New Initiatives in Malaria
W. M. Keck Distinguished Young Scholar in Medicine
Hellman Faculty Fellow
Research in my laboratory is dedicated to understanding the basis of infectious disease at molecular and cellular levels. We focus on mechanisms by which virulence factors produced by pathogenic microbes interact with host cell targets and thereby modulate host cell behavior during infection. We study these interactions in structural detail (i.e., at the level of atomic resolution through X-ray crystallography) in order to carry out precise biochemical, genetic, and cell biological experiments aimed at elucidating the mechanism of action of bacterial virulence factors in their cellular context.
Our studies focus on the initial interaction between a pathogen and a host cell, and how this interaction resolves as induction of intracellular entry or inhibition of phagocytic uptake. Induction of intracellular entry is exemplified by studies on Listeria monocytogenes. We are delving into how the L. monocytogenes protein InlB activates the host cell receptor tyrosine kinase Met (hepatocyte growth factor receptor, HGFR) to effect host cell invasion. Met is a proto-oncogene and therefore we hope to understand general rules of regulation of such crucial mediators of host cell growth through studies of InlB. Inhibition of phagocytic uptake is being pursued through studies on the mechanism of protein translocation into host cells by the Yersinia pseudotuberculosis type III secretion system as well as on antiopsonic surface proteins of Group A Streptococcus. In a broader sense, macromolecular recognition is at the heart of all these processes, and we are pursuing diversity-generating retroelements and the massively sequence variable protein repertoires that they produce in order to understand the general rules underlying specificity in molecular recognition.
Primary Research Area
- Macheboeuf P, Buffalo C, Fu CY, Zinkernagel AS, Cole JN, Johnson JE, Nizet V, Ghosh P, "Streptococcal M1 protein constructs a pathological host fibrinogen network.", Nature, 2011, Vol. 472, Issue 7341, 64-8
- McNamara C, Zinkernagel AS, Macheboeuf P, Cunningham MW, Nizet V, Ghosh P, "Coiled-coil irregularities and instabilities in group A Streptococcus M1 are required for virulence.", Science, 2008, Vol. 319, Issue 5868, 1405-8
- Miller JL, Le Coq J, Hodes A, Barbalat R, Miller JF, Ghosh P, "Selective ligand recognition by a diversity-generating retroelement variable protein.", PLoS Biol, 2008, Vol. 6, Issue 6, e131
- Rodgers L, Gamez A, Riek R, Ghosh P, "The type III secretion chaperone SycE promotes a localized disorder-to-order transition in the natively unfolded effector YopE.", J Biol Chem, 2008, Vol. 283, Issue 30, 20857-63
- McMahon SA, Miller JL, Lawton JA, Kerkow DE, Hodes A, Marti-Renom MA, Doulatov S, Narayanan E, Sali A, Miller JF, Ghosh P, "The C-type lectin fold as an evolutionary solution for massive sequence variation.", Nat Struct Mol Biol, 2005, Vol. 12, Issue 10, 886-92
- Banerjee M, Copp J, Vuga D, Marino M, Chapman T, van der Geer P, Ghosh P, "GW domains of the Listeria monocytogenes invasion protein InlB are required for potentiation of Met activation.", Mol Microbiol, 2004, Vol. 52, Issue 1, 257-71
- Phillips RM, Six DA, Dennis EA, Ghosh P, "In vivo phospholipase activity of the Pseudomonas aeruginosa cytotoxin ExoU and protection of mammalian cells with phospholipase A2 inhibitors.", J Biol Chem, 2003, Vol. 278, Issue 42, 41326-32
- Birtalan SC, Phillips RM, Ghosh P, "Three-dimensional secretion signals in chaperone-effector complexes of bacterial pathogens.", Mol Cell, 2002, Vol. 9, Issue 5, 971-80
- Marino M, Banerjee M, Jonquières R, Cossart P, Ghosh P, "GW domains of the Listeria monocytogenes invasion protein InlB are SH3-like and mediate binding to host ligands.", EMBO J, 2002, Vol. 21, Issue 21, 5623-34