James E. Cassat, M.D., Ph.D.

Assistant Professor

jim.cassat@vanderbilt.edu

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Faculty Appointments
Assistant Professor of Pediatrics Assistant Professor of Biomedical EngineeringAssistant Professor of Pathology, Microbiology and Immunology
Education
M.D., University of Arkansas, Little Rock, ArkansasPh.D., Microbiology and Immunology, University of Arkansas, Little Rock, ArkansasB.S., University of Arkansas, Little Rock, Arkansas
Research Description
The major focus of my research is to understand the interaction between host and pathogen during invasive bacterial infections. Specifically, we seek to define the bacterial virulence mechanisms and host defenses employed during osteomyelitis, an invasive infection of bone common in both children and adults. Risk factors and protective immune responses for osteomyelitis are poorly defined, and bone infections are notoriously recalcitrant to antimicrobial therapy due to both pathogen-induced bone destruction and the emergence of multi-drug resistant pathogens. Therefore, we have created new tools to investigate the host-pathogen interface during osteomyelitis. As Staphylococcus aureus is by far the most common cause of osteomyelitis, we have focused our efforts on identifying the mechanisms by which S. aureus causes bone infection and resulting bone destruction, as well as the host defenses that protect against staphylococcal infection. Using a combination of bone cell culture models, proteomic analyses of bacterial virulence factors, and a new quantitative in vivo model of staphylococcal osteomyelitis, we have uncovered specific bacterial factors that contribute to the pathogenesis of osteomyelitis by triggering osteoblast cell death and bone destruction in vivo. We have also identified staphylococcal genes necessary for survival within the bone. By further defining the mechanisms by which S. aureus survives within bone and ultimately triggers bone destruction, we hope to identify new therapeutic targets to treat osteomyelitis and to limit the morbidity associated with this invasive infection. Moreover, by characterizing the host responses to bacterial pathogens in the bone, we seek to define protective correlates of innate immunity in bone and potentially uncover risk factors for the development of osteomyelitis in otherwise healthy children. Finally, by investigating how bacterial pathogens perturb bone cell physiology, we wish to enhance an understanding of changes in bone remodeling in the face of infectious and inflammatory insults.

Emerging research areas in the lab also include: 1) Investigation of microbiota-dependent regulation of bone remodeling; 2) Mechanisms of bone loss during systemic inflammatory disorders like inflammatory bowel disease, and 3) Investigation of microbe-microbe interactions during polymicrobial infection.
Research Keywords
Bacterial pathogenesis; Host-pathogen interactions; osteomyelitis; bone biology; In vivo imaging; osteoblast; osteoclast; pattern recognition receptor; osteoimmunology; Staphylococcus aureus; virulence; animal models; imaging; rheumatology; microbiome; microbial ecology; inflammatory bowel disease
Clinical Research Keywords
Pediatric Infectious Diseases; Bone infections; osteomyelitis; invasive staphylococcal infection
Publications
Frazier SB, Katz S, Wood JB, Cassat JE. An Unusual Source of Sepsis in Two Previously Healthy Children. Clin Pediatr (Phila) [print-electronic]. 2017 Oct 10/1/2017; 9922817738349. PMID: 29084446, DOI: 10.1177/0009922817738349, ISSN: 1938-2707.

Ford CA, Cassat JE. Advances in the local and targeted delivery of anti-infective agents for management of osteomyelitis. Expert Rev Anti Infect Ther [print-electronic]. 2017 Sep; 15(9): 851-60. PMID: 28837368, DOI: 10.1080/14787210.2017.1372192, ISSN: 1744-8336.

Thomsen IP, Sapparapu G, James DB, Cassat JE, Nagarsheth M, Kose N, Putnam N, Boguslawski KM, Jones LS, Wood JB, Creech CB, Torres VJ, Crowe JE. Monoclonal antibodies against the Staphylococcus aureus bicomponent leukotoxin AB (LukAB) isolated following invasive human infection reveal diverse binding and modes of action. J. Infect. Dis [print-electronic]. 2017 Feb 2/10/2017; PMID: 28186295, PII: 2982058, DOI: 10.1093/infdis/jix071, ISSN: 1537-6613.

Mendoza Bertelli A, Delpino MV, Lattar S, Giai C, Llana MN, Sanjuan N, Cassat JE, Sordelli D, Gómez MI. Staphylococcus aureus protein A enhances osteoclastogenesis via TNFR1 and EGFR signaling. Biochim. Biophys. Acta [print-electronic]. 2016 Oct; 1862(10): 1975-83. PMID: 27475257, PII: S0925-4439(16)30184-3, DOI: 10.1016/j.bbadis.2016.07.016, ISSN: 0006-3002.

Hendrix AS, Spoonmore TJ, Wilde AD, Putnam NE, Hammer ND, Snyder DJ, Guelcher SA, Skaar EP, Cassat JE. Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis. Antimicrob. Agents Chemother [electronic-print]. 2016 Sep; 60(9): 5322-30. PMID: 27324764, PMCID: PMC4997817, PII: AAC.00834-16, DOI: 10.1128/AAC.00834-16, ISSN: 1098-6596.

Loughran AJ, Gaddy D, Beenken KE, Meeker DG, Morello R, Zhao H, Byrum SD, Tackett AJ, Cassat JE, Smeltzer MS. Impact of sarA and Phenol-Soluble Modulins on the Pathogenesis of Osteomyelitis in Diverse Clinical Isolates of Staphylococcus aureus. Infect. Immun [electronic-print]. 2016 Sep; 84(9): 2586-94. PMID: 27354444, PMCID: PMC4995912, PII: IAI.00152-16, DOI: 10.1128/IAI.00152-16, ISSN: 1098-5522.

Wilde AD, Snyder DJ, Putnam NE, Valentino MD, Hammer ND, Lonergan ZR, Hinger SA, Aysanoa EE, Blanchard C, Dunman PM, Wasserman GA, Chen J, Shopsin B, Gilmore MS, Skaar EP, Cassat JE. Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection. PLoS Pathog. 2015 Dec; 11(12): e1005341. PMID: 26684646, PMCID: PMC4684308, PII: PPATHOGENS-D-15-02340, DOI: 10.1371/journal.ppat.1005341, ISSN: 1553-7374.

Hammer ND, Cassat JE, Noto MJ, Lojek LJ, Chadha AD, Schmitz JE, Creech CB, Skaar EP. Inter- and intraspecies metabolite exchange promotes virulence of antibiotic-resistant Staphylococcus aureus. Cell Host Microbe. 2014 Oct 10/8/2014; 16(4): 531-7. PMID: 25299336, PMCID: PMC4197139, PII: S1931-3128(14)00335-7, DOI: 10.1016/j.chom.2014.09.002, ISSN: 1934-6069.

Gillon JE, Cassat JE, Di Pentima MC. Validation of two vancomycin nomograms in patients 10 years of age and older. J Clin Pharmacol [print-electronic]. 2014 Jan; 54(1): 35-8. PMID: 24249098, DOI: 10.1002/jcph.173, ISSN: 1552-4604.

Cassat JE, Smeltzer MS, Lee CY. Investigation of biofilm formation in clinical isolates of Staphylococcus aureus. Methods Mol. Biol. 2014; 1085: 195-211. PMID: 24085698, DOI: 10.1007/978-1-62703-664-1_12, ISSN: 1940-6029.

Cassat JE, Skaar EP. Recent advances in experimental models of osteomyelitis [editorial]. Expert Rev Anti Infect Ther. 2013 Dec; 11(12): 1263-5. PMID: 24215241, DOI: 10.1586/14787210.2013.858600, ISSN: 1744-8336.

Attia AS, Cassat JE, Aranmolate SO, Zimmerman LJ, Boyd KL, Skaar EP. Analysis of the Staphylococcus aureus abscess proteome identifies antimicrobial host proteins and bacterial stress responses at the host-pathogen interface. Pathog Dis [print-electronic]. 2013 Jul 7/11/2013; PMID: 23847107, PMCID: PMC3877740, DOI: 10.1111/2049-632X.12063, ISSN: 2049-632X.

Cassat JE, Hammer ND, Campbell JP, Benson MA, Perrien DS, Mrak LN, Smeltzer MS, Torres VJ, Skaar EP. A secreted bacterial protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis. Cell Host Microbe. 2013 Jun 6/12/2013; 13(6): 759-72. PMID: 23768499, PMCID: PMC3721972, PII: S1931-3128(13)00185-6, DOI: 10.1016/j.chom.2013.05.003, ISSN: 1934-6069.

Cassat JE, Skaar EP. Iron in infection and immunity. Cell Host Microbe. 2013 May 5/15/2013; 13(5): 509-19. PMID: 23684303, PMCID: PMC3676888, PII: S1931-3128(13)00152-2, DOI: 10.1016/j.chom.2013.04.010, ISSN: 1934-6069.

Hammer ND, Reniere ML, Cassat JE, Zhang Y, Hirsch AO, Indriati Hood M, Skaar EP. Two heme-dependent terminal oxidases power Staphylococcus aureus organ-specific colonization of the vertebrate host. MBio. 2013; 4(4): PMID: 23900169, PMCID: PMC3735196, PII: mBio.00241-13, DOI: 10.1128/mBio.00241-13, ISSN: 2150-7511.

Cassat JE, Skaar EP. Metal ion acquisition in Staphylococcus aureus: overcoming nutritional immunity. Semin Immunopathol [print-electronic]. 2012 Mar; 34(2): 215-35. PMID: 22048835, PMCID: PMC3796439, DOI: 10.1007/s00281-011-0294-4, ISSN: 1863-2300.

Stenz L, François P, Fischer A, Huyghe A, Tangomo M, Hernandez D, Cassat J, Linder P, Schrenzel J. Impact of oleic acid (cis-9-octadecenoic acid) on bacterial viability and biofilm production in Staphylococcus aureus. FEMS Microbiol. Lett [print-electronic]. 2008 Oct; 287(2): 149-55. PMID: 18754790, PII: FML1316, DOI: 10.1111/j.1574-6968.2008.01316.x, ISSN: 0378-1097.

Tsang LH, Cassat JE, Shaw LN, Beenken KE, Smeltzer MS. Factors contributing to the biofilm-deficient phenotype of Staphylococcus aureus sarA mutants. PLoS ONE [print-electronic]. 2008; 3(10): e3361. PMID: 18846215, PMCID: PMC2556392, DOI: 10.1371/journal.pone.0003361, ISSN: 1932-6203.

Rice KC, Mann EE, Endres JL, Weiss EC, Cassat JE, Smeltzer MS, Bayles KW. The cidA murein hydrolase regulator contributes to DNA release and biofilm development in Staphylococcus aureus. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2007 May 5/8/2007; 104(19): 8113-8. PMID: 17452642, PMCID: PMC1876580, PII: 0610226104, DOI: 10.1073/pnas.0610226104, ISSN: 0027-8424.

Cassat JE, Lee CY, Smeltzer MS. Investigation of biofilm formation in clinical isolates of Staphylococcus aureus. Methods Mol. Biol. 2007; 391: 127-44. PMID: 18025674, PMCID: PMC4098860, PII: 1-59745-468-0:127, DOI: 10.1007/978-1-59745-468-1_10, ISSN: 1064-3745.

Cassat J, Dunman PM, Murphy E, Projan SJ, Beenken KE, Palm KJ, Yang SJ, Rice KC, Bayles KW, Smeltzer MS. Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390. Microbiology (Reading, Engl.). 2006 Oct; 152(Pt 10): 3075-90. PMID: 17005987, PII: 152/10/3075, DOI: 10.1099/mic.0.29033-0, ISSN: 1350-0872.

Cassat JE, Dunman PM, McAleese F, Murphy E, Projan SJ, Smeltzer MS. Comparative genomics of Staphylococcus aureus musculoskeletal isolates. J. Bacteriol. 2005 Jan; 187(2): 576-92. PMID: 15629929, PMCID: PMC543526, PII: 187/2/576, DOI: 10.1128/JB.187.2.576-592.2005, ISSN: 0021-9193.

Kaiser JR, Cassat JE, Lewno MJ. Should antibiotics be discontinued at 48 hours for negative late-onset sepsis evaluations in the neonatal intensive care unit?. J Perinatol. 2002 Sep; 22(6): 445-7. PMID: 12168120, DOI: 10.1038/sj.jp.7210764, ISSN: 0743-8346.