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Raphael Valdivia

Vice Dean of Basic Sciences and Associate Professor
Molecular Genetics and Microbiology
Research Interest: 
Membranes and organelles
Microbiology and virology
Research Summary: 
Biochemical, functional genomic and cell biological approaches to understand how intracellular bacterial pathogens manipulate their host cells.
Research Description: 

Our laboratory is interested in understanding how obligate bacterial pathogens modulate the internal architecture of their host cells to promote pathogen replication and disable innate immune pathways. We focus our studies on Chlamydia trachomatis, the most common sexually transmitted pathogen and the leading cause of infectious blindness worldwide.
Current projects include:
1. Mechanism of effector protein secretion. We are interested in identifying the proteins secreted by Chlamydia into its eukaryotic host. These proteins, termed “effectors” are directly responsible for controlling actin dynamics, signaling, membrane transport and host cell survival. We study how these proteins are recognized by Chlamydia's protein secretion system, how a hierarchy of effector secretion is established, and the function of accessory secretion chaperones in regulating effector delivery into the host cell.
2. Cell biology of Chlamydia infections. We study the series of events that regulate actin reorganization during Chlamydia entry into cells and the strategies used by the pathogen to maintain the integrity of the pathogen containing vacuole (“inclusion”), and to acquire nutrients through its extensive interactions with the host endomembrane system.
3. Development of systems for genetic analysis in “intractable” pathogens. Chlamydia, unlike many model bacterial pathogens, is not amenable to routine molecular genetic manipulation. As a result, loss-of-function approaches are of limited use. We have developed methods to perform genetic analysis in pathogens like Chlamydia, based on chemical mutagens and next generation DNA sequencing technologies. As a result it is now possible to implement forward and reverse genetic approaches in support of projects 1 and 2.
4. The cell biology of innate immune signaling. Infected cells detect the presence of Chlamydia and initiate signaling pathways in an attempt to activate cell autonomous defense mechanism. We have identified ligand(s) recognized by cytosolic microbial surveillance pathways and study how the trafficking – and ultimate signaling output- of these host receptors is modulated by bacterial products. In parallel, we study the role Lipid Droplets, an organelle which is targeted by Chlamydia, plays in initiating and regulating innate immune responses.

Quantitative proteomics reveals metabolic and pathogenic properties of Chlamydia trachomatis developmental forms.
Saka HA, Thompson JW, Chen YS, Kumar Y, Dubois LG, Moseley MA, Valdivia RH.
Mol Microbiol. 2011. 82:1185-203.

The Chlamydia protease CPAF regulates host and bacterial proteins to maintain pathogen vacuole integrity and promote virulence.
Jorgensen I, Bednar MM, Amin V, Davis BK, Ting JP, McCafferty DG, Valdivia RH.
Cell Host Microbe. 2011. 10:21-32.

The Chlamydia type III secretion system C-ring engages a chaperone-effector protein complex.
Spaeth KE, Chen YS, Valdivia RH.
PLoS Pathog. 2009. 5:e1000579.

Actin and intermediate filaments stabilize the Chlamydia trachomatis vacuole by forming dynamic structural scaffolds.
Kumar Y, Valdivia RH.
Cell Host Microbe. 2008. 4:159-69.

Cytoplasmic lipid droplets are translocated into the lumen of the Chlamydia trachomatis parasitophorous vacuole.
Cocchiaro JL, Kumar Y, Fischer ER, Hackstadt T, Valdivia RH.
Proc Natl Acad Sci U S A. 2008. 105:9379-84.