Raphael Valdivia

Overview:

My laboratory is interested in how microbes influence human health, both in the context of host-pathogen and host-commensal interactions.  For many pathogens, and certainly for most commensal microbes, it is is poorly understood what is the molecular basis for how host and microbial factors contribute to a beneficial outcome for us. We currently focus on two experimental systems:

Chlamydia trachomatis infections are responsible for the bulk of sexually transmitted bacterial diseases and are the leading cause of infectious blindness (trachoma) in the world. Chlamydia  resides within a membrane bound compartment (“inclusion”). From this location, the pathogen manipulates the cytoskeleton, inhibits lysosomal recognition of the inclusion, activates signaling pathways, re-routes lipid transport, and prevents the onset of programmed cell death. Our laboratory focuses on identifying and characterizing the bacterial factors that are secreted into the host cell cytoplasm to manipulate eukaryotic cellular functions. We use a combination of cell biological techniques, biochemistry, genetics, genomics, live cell microscopy, proteomics and molecular biology to determining the function of virulence factors that reveal novel facets of the cell biology of host-pathogen interactions.  Our ultimate goal is to understand how these obligate intracellular bacterial pathogens manipulate host cellular functions to replicate, disseminate and cause disease.

A second area of focus in my research group is the development of new methods to perform genetic analysis in many of the microbes that reside in our gut. Understanding how the collection of genetic information of microbes associated with our bodies (microbiomes) impact our health is one of the new frontiers in microbiology. We are currently studying how one specific bacterium, Akkermansia muciniphila, proliferates in the mucus layers of our lower gastrointestinal tract and contribute to nutrient homeostasis and human immunological health.


Positions:

Nanaline H. Duke Distinguished Professor of Molecular Genetics and Microbiology

Integrative Immunobiology
School of Medicine

Professor in Integrative Immunobiology

Integrative Immunobiology
School of Medicine

Chair, Department of Immunology

Integrative Immunobiology
School of Medicine

Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1998

Stanford University

Postdoctoral Fellow

Stanford University

Postdoctoral Fellow

University of California - Berkeley

Grants:

IsoCyte Laser Scanning Plate Cytometer for High-throughput, High-content Assays

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Major User
Start Date
End Date

Live cell widefield fluorescence microscope with activation and bleaching lasers

Administered By
Biology
Awarded By
National Institutes of Health
Role
Major User
Start Date
End Date

Interferon-driven ubiquitin response targets Chlamydia inclusions in human cells

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Enzymology of Chlamydial Pathogenesis

Administered By
Chemistry
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Integrated instrument systems for maintenance and delivery of RNAi libraries

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Publications:

The bacterial effector GarD shields Chlamydia trachomatis inclusions from RNF213-mediated ubiquitylation and destruction.

Chlamydia trachomatis is the leading cause of sexually transmitted bacterial infections and a major threat to women's reproductive health in particular. This obligate intracellular pathogen resides and replicates within a cellular compartment termed an inclusion, where it is sheltered by unknown mechanisms from gamma-interferon (IFNγ)-induced cell-autonomous host immunity. Through a genetic screen, we uncovered the Chlamydia inclusion membrane protein gamma resistance determinant (GarD) as a bacterial factor protecting inclusions from cell-autonomous immunity. In IFNγ-primed human cells, inclusions formed by garD loss-of-function mutants become decorated with linear ubiquitin and are eliminated. Leveraging cellular genome-wide association data, we identified the ubiquitin E3 ligase RNF213 as a candidate anti-Chlamydia protein. We demonstrate that IFNγ-inducible RNF213 facilitates the ubiquitylation and destruction of GarD-deficient inclusions. Furthermore, we show that GarD operates as a cis-acting stealth factor barring RNF213 from targeting inclusions, thus functionally defining GarD as an RNF213 antagonist essential for chlamydial growth during IFNγ-stimulated immunity.
Authors
Walsh, SC; Reitano, JR; Dickinson, MS; Kutsch, M; Hernandez, D; Barnes, AB; Schott, BH; Wang, L; Ko, DC; Kim, SY; Valdivia, RH; Bastidas, RJ; Coers, J
MLA Citation
Walsh, Stephen C., et al. “The bacterial effector GarD shields Chlamydia trachomatis inclusions from RNF213-mediated ubiquitylation and destruction.Cell Host Microbe, vol. 30, no. 12, Dec. 2022, pp. 1671-1684.e9. Pubmed, doi:10.1016/j.chom.2022.08.008.
URI
https://scholars.duke.edu/individual/pub1546629
PMID
36084633
Source
pubmed
Published In
Cell Host Microbe
Volume
30
Published Date
Start Page
1671
End Page
1684.e9
DOI
10.1016/j.chom.2022.08.008

Chlamydia repurposes the actin-binding protein EPS8 to disassemble epithelial tight junctions and promote infection.

Invasive microbial pathogens often disrupt epithelial barriers, yet the mechanisms used to dismantle tight junctions are poorly understood. Here, we show that the obligate pathogen Chlamydia trachomatis uses the effector protein TepP to transiently disassemble tight junctions early during infection. TepP alters the tyrosine phosphorylation status of host proteins involved in cytoskeletal regulation, including the filamentous actin-binding protein EPS8. We determined that TepP and EPS8 are necessary and sufficient to remodel tight junctions and that the ensuing disruption of epithelial barrier function promotes secondary invasion events. The genetic deletion of EPS8 renders epithelial cells and endometrial organoids resistant to TepP-mediated tight junction remodeling. Finally, TepP and EPS8 promote infection in murine models of infections, with TepP mutants displaying defects in ascension to the upper genital tract. These findings reveal a non-canonical function of EPS8 in the disassembly of epithelial junctions and an important role for Chlamydia pathogenesis.
Authors
Dolat, L; Carpenter, VK; Chen, Y-S; Suzuki, M; Smith, EP; Kuddar, O; Valdivia, RH
MLA Citation
Dolat, Lee, et al. “Chlamydia repurposes the actin-binding protein EPS8 to disassemble epithelial tight junctions and promote infection.Cell Host Microbe, vol. 30, no. 12, Dec. 2022, pp. 1685-1700.e10. Pubmed, doi:10.1016/j.chom.2022.10.013.
URI
https://scholars.duke.edu/individual/pub1557146
PMID
36395759
Source
pubmed
Published In
Cell Host Microbe
Volume
30
Published Date
Start Page
1685
End Page
1700.e10
DOI
10.1016/j.chom.2022.10.013

Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment.

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Antibiotic treatment to eradicate A. muciniphila before caloric restriction preserved colonic mucus, whereas A. muciniphila reintroduction restored mucus thinning. Caloric restriction of unirradiated mice raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila in vitro with propionate reduced utilization of mucin as well as of fucose. Treating irradiated mice with an antibiotic targeting A. muciniphila or propionate preserved the mucus layer, suppressed translocation of flagellin, reduced inflammatory cytokines in the colon, and improved thermoregulation. These results suggest that diet, metabolites, and colonic mucus link the microbiome to neutropenic fever and may guide future microbiome-based preventive strategies.
Authors
Schwabkey, ZI; Wiesnoski, DH; Chang, C-C; Tsai, W-B; Pham, D; Ahmed, SS; Hayase, T; Ortega Turrubiates, MR; El-Himri, RK; Sanchez, CA; Hayase, E; Frenk Oquendo, AC; Miyama, T; Halsey, TM; Heckel, BE; Brown, AN; Jin, Y; Raybaud, M; Prasad, R; Flores, I; McDaniel, L; Chapa, V; Lorenzi, PL; Warmoes, MO; Tan, L; Swennes, AG; Fowler, S; Conner, M; McHugh, K; Graf, T; Jensen, VB; Peterson, CB; Do, K-A; Zhang, L; Shi, Y; Wang, Y; Galloway-Pena, JR; Okhuysen, PC; Daniel-MacDougall, CR; Shono, Y; Burgos da Silva, M; Peled, JU; van den Brink, MRM; Ajami, N; Wargo, JA; Reddy, P; Valdivia, RH; Davey, L; Rondon, G; Srour, SA; Mehta, RS; Alousi, AM; Shpall, EJ; Champlin, RE; Shelburne, SA; Molldrem, JJ; Jamal, MA; Karmouch, JL; Jenq, RR
MLA Citation
Schwabkey, Zaker I., et al. “Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment.Sci Transl Med, vol. 14, no. 671, Nov. 2022, p. eabo3445. Pubmed, doi:10.1126/scitranslmed.abo3445.
URI
https://scholars.duke.edu/individual/pub1556939
PMID
36383683
Source
pubmed
Published In
Sci Transl Med
Volume
14
Published Date
Start Page
eabo3445
DOI
10.1126/scitranslmed.abo3445