Jere W. McBride, MS, PhD

The long-term objective of my research is to mechanistically define interkingdom molecular interplay between prokaryotes and eukaryotes involved in infection and immune evasion. The molecular host-pathogen interactions involved in the pathobiology of Ehrlichia spp. are not well defined. Our limited knowledge regarding the pathogen-host interactions and the molecular basis of these interactions is a major impediment for developing new therapeutics for infectious diseases. Ehrlichia spp. are useful model organisms to study intracellular survival and investigate how microbes with small genomes effectively engage and exploit complex eukaryotes and evade host defense mechanisms. The focus of my research for the past decade has been to understand the role of ehrlichial tandem repeat and ankyrin effectors in promoting infection. My research group identified the first type 1 secretion substrates identified in intracellular bacteria, and we have recently characterized molecular interactions between the type 1 secretion system (T1SS) tandem repeat protein (TRP) effectors and a large and diverse group of eukaryote targets, which are new to science. We have determined that Ehrlichia exploit several evolutionarily conserved host cell pathways to infect and evade innate host defenses and have performed numerous studies to understand the role of host signaling pathways in ehrlichial pathobiology. My laboratory is also investigating the role of post translational modifications of these effectors in mediating host-pathogen interactions and regulating cellular pathways. I have been trained in microbial pathogenesis, molecular biology, pathology and immunology and this broad training has allowed me to successfully pursue scientific investigations that involve these disciplines, and contribute significant scientific advances related to microbial pathogenesis, and cellular infection and immunity.

Ongoing and recently completed projects:

1R01 AI158422 (McBride, PI)
NIH/NIAID	11/01/2021 – 10/31/2026
“Ehrlichia Notch SLiM-activated oncoprotein inhibition of apoptosis” This project will define Ehrlichia Notch mimicry and mechanisms involved in apoptosis inhibition.

1R21 AI146637 (McBride, PI)
NIH/NIAID	09/01/2020 – 8/31/2022
“Ehrlichia TRP120 HECT ubiquitin ligase modulation of host cell pathways.” This research project will investigate Ehrlichia TRP120 HECT Ub ligase activity during infection.

1R21 AI149136 (McBride, PI)
NIH/NIAID	03/01/2020 – 2/28/2023
“Molecular basis of Wnt activation by Ehrlichia ligand mimics” This research project will identify Ehrlichia Wnt mimetic sequences that activate the Wnt pathway.

1R21 AI137779 (McBride, PI)
NIH/NIAID	11/21/2018 – 10/31/2022
“Sonic Hedgehog regulation of apoptosis during Ehrlichia infection” This research project will investigate the role of Sonic Hedgehog signaling in prevent apoptosis during Ehrlichia infection.

Completed Research Support (last 3 years)

U01 CK000512-01(Jere W. McBride, Lead, RP6)	12/31/2017-11/30/2021
Centers for Disease Control
“Western Gulf Center of Excellence for Vector-Borne Diseases” PI-Scott Weaver, “Ultrasensitive antibody and antigen detection for surveillance and diagnosis of human ehrlichiosis” The objective of this project is to understand to develop sensitive and specific antibody and antigen detection assays for the ehrlichioses.

1R21 AI123610 (PI- McBride)	01/05/2017-12/31/2020
NIH/NIAID
“Notch signaling and functional relevance during Ehrlichia infection” The objective of this project was to understand the role of the Wnt pathway in Ehrlichia infection and determine the pathogen-host interactions involved in exploitation.

1R01 AI106859 (JW McBride, PI)	03/01/2014-09/28/2019
NIH/NIAID
“Ehrlichia T1S effector regulation of host gene transcription” The objective of this proposal was to demonstrate that TRP120 is a dual-function transcription factor that has interplay with the Ub/SUMO pathway to mediate nuclear translocation and regulate host defense gene expression.

BS	Louisiana State University, Baton Rouge	Microbiology	1987
MS	Louisiana State University, Baton Rouge	Microbiology/Immunology	1993
PhD	University of California, Davis	Comparative Pathology	1997
Fellowship	University of Texas Medical Branch	Cellular Microbiology	1999

Positions and Employment

2012-present	Professor (tenured), Depts. of Pathology and Microbiology & Immunology, UTMB
2007-2012	Associate Professor, Dept. of Pathology, UTMB
2007-2012	Associate Professor (tenured), Dept. of Microbiology & Immunology, UTMB
2002-2007	Assistant Professor, Dept. of Microbiology & Immunology, UTMB
2002-2007	Assistant Professor, Dept. of Pathology, UTMB
1999-2002	Instructor, Dept. of Pathology, UTMB
1997-99	Postdoc Fellow-Dr. David Walker, Dept. of Pathology, Univ. Texas Med. Br. (UTMB)
1993-97	PhD Student-Dr. Bennie Osburn, Dept. of Path., Microbiol. & Immunol., UC Davis Vet. Med.
1990-93	Master Student-Dr. Richard Corstvet, Dept. of Microbiol. & Parasit., LSU Vet. Med.
1987-93	Research Associate, LSU School of Vet. Med.

Honors

2023-	Department of Pathology Researcher of the Year
2023-	The David Walker, MD Professor in Infectious Disease Pathogenesis
2023-	Member, UTMB Academy of Research Mentors
2023-	UTMB Graduate School for Biomedical Sciences Distinguished Faculty Service Award
2023-	Section Chief Editor, Frontiers in Cell Signaling,: Cell Signaling in Host-Microbe Interactions
2023-25	Editorial Board, Infection and Immunity (reappointed)
2019-21	Editorial Board, Infection and Immunity (reappointed)
2017-19	Editorial Board, Infection and Immunity
2017-	Editorial Board, npj Vaccines
2013-15	President, American Society for Rickettsiology
2012-13	Vice President, American Society for Rickettsiology
2012	Faculty Senate Chair (nominated)
2011	Leon Bromberg Professor for Excellence in Teaching (nominated)
2009	Department of Pathology, Researcher of the Year
2004	Department of Pathology Graduate Student Organization Award for Teaching and Mentoring
1999	James W. McLaughlin Award for Research Excellence in Infection and Immunity (Postdoctoral) University of Texas Medical Branch, Galveston

Other Professional Activities

2019	Reviewer, CDMRP Tick-Borne Diseases Research Program
2015-present	Pathology Executive Committee for Research
2013-present	Ad-Hoc Reviewer, National Institutes of Health (ZRG VH-G & IDM-B)
2011-present	Director, Experimental Pathology Graduate Program
2010-2011	Associate Director, Experimental Pathology Graduate Program
2010-present	Pathology Educational Leadership Committee
2009-present	Graduate School of Biomedical Sciences Executive Committee
2009-present	UTMB James W. McLaughlin Committee (Infectious Disease)
2002-present	Reviewer for >25+ scientific journals, including PLoS Pathogens, Nat. Rev., I&I, Cell. Micro.

American Society for Microbiology
American Society for Investigative Pathology
American Society for Rickettsiology
American Society for Cell Biology (ASCB)

Complete List of Published work in MyBibliography:

https://www.ncbi.nlm.nih.gov/myncbi/jere.mcbride.1/bibliography/public/

1) Immunomolecular analysis of protective Ehrlichia proteins, immunity, vaccines and diagnostics.

My laboratory has contributed significantly to the immunomolecular characterization of major immunoreactive proteins of agents associated with human and veterinary monocytic ehrlichioses, including E. chaffeensis and E. canis. Through these investigations, we have identified and characterized many of the known antigens that strongly reacted with antibody which included a group of tandem repeat proteins, performed epitope mapping studies to demonstrate that antibodies recognized species-specific linear and conformational epitopes, and demonstrated that antibodies directed at these epitopes are protective. These studies have provided a comprehensive group of antigens for development of subunit vaccines and for species-specific molecular immunodiagnostics for which I have extensive intellectual property and licensing agreements with industry.

a. Luo T, Patel JG, Zhang XF, Walker DH and McBride JW. Immunoreactive protein repertoires of Ehrlichia chaffeensis and E. canis reveal the dominance of hypothetical proteins and conformation-dependent antibody epitopes. Infect Immun, Oct 15;89(11):e0022421, doi: 10.1128/IAI.00224-21. Epub 2021 Aug 2. (Selected by the editors as an article of significant interest-“Spotlight”)
b. Luo T, Patel JG, Zhang XF, Walker DH, and McBride JW. Ehrlichia chaffeensis and E. canis hypothetical protein immunoanalysis reveals small secreted immunodominant proteins and conformation-dependent antibody epitopes. npj Vaccines. 2020; 5:85. doi:/10.1038/s41541-020-00231-1 PMCID:PMC7486380.
c. Velayutham TS, Kumar S, Zhang XF, Kose N, Walker DH, Winslow G, Crowe JE, and McBride JW. Ehrlichia chaffeensis outer membrane protein 1-specific human antibody-mediated immunity is defined by intracellular TRIM21-dependent innate immune activation and extracellular neutralization. Infect. Immun. 2019 87: e00383-19. PMCID: PMC6867850. (Selected by the editors as an article of significant interest-“Spotlight”)
d. Kuriakose J, Zhang XF, Luo T and McBride JW. Molecular basis of antibody mediated immunity to Ehrlichia chaffeensis involves species-specific linear epitopes in tandem repeat proteins. Microbes Infect. 2012; 14:1054-63. PMCID: 3445803

2) Identification and functional analysis of Ehrlichia proteins.

My group has also identified and performed functional analysis of Ehrlichia proteins that play a role in ehrlichial survival in the host cell. Proteins such as disulfide bond formation protein (DsbA), ferric binding protein (Fbp) and TRP120, the first ehrichial HECT-type ubiquitin ligase effector. In these studies, we determined that the E. chaffeensis Dsb functions consistent with E. coli Dsb. Our characterization of Fbp revealed differences in iron acquision of Ehrlichia compared to other gram-negative bacteria. We have recently determined the TRP120 effector is a HECT ubiquitin ligase that primarily targets host cell nuclear proteins for degradation to promote ehrlichial survival.

a. Zhu B, Das S, Mitra S, Farris TR, McBride JW. Ehrlichia chaffeensis TRP120 moonlights as a HECT E3 ligase involved in self- and host ubiquitination to influence protein interactions and stability for intracellular survival. Infect. Immun. 2017 85:1-16 pii: e00290-17. doi: 10.1128/IAI.00290-17 PMCID: PMC28630068.
b. McBride JW, Ndip L, Popov VL, Walker DH. Identification and functional analysis of an immunoreactive DsbA-like thio-disulfide oxidoreductase of Ehrlichia spp. Infect Immun. 2002; 70:2700-2703. PMCID: PMC127935
c. Doyle CK, Zhang X, Popov VL, McBride JW. An immunoreactive 38-kilodalton protein of Ehrlichia canis shares structural homology and iron-binding capacity with the ferric-ion binding protein family. Infect Immun. 2005; 73:62-69. PMCID: PMC538948

3) Identification of Ehrlichia effector proteins, secretion mechanisms and molecular pathogen-host interactions.

My laboratory has concentrated effort to understanding the prokaryote-eukaryote interface as we have determined that many ehrlichial proteins we identified as major immunoreactive proteins are secreted and contain tandem repeat and ankyrin domains. We utilized yeast-two-hybrid assays to define molecular protein-protein interactions with ehrlichial TRPs and reported the first defined host protein targets of these ehrlichial effectors. Further studies established that ehrlichial effectors interact with a diverse array of host proteins associated with important cellular processes. We have further determined that these host proteins have a direct connection to ehrlichial intracellular survival. We have determined that Ehrlichia TRP effectors are substrates of the type 1 secretion system, the first such description for an obligately intracellular bacterium.

a. Wakeel A, Kuriakose J, and McBride JW. An Ehrlichia chaffeensis tandem repeat protein interacts with multiple host targets involved in cell signaling, transcriptional regulation and vesicle trafficking. Infect. Immun. 2009; 76:1572-1580. (Selected by the editors as an article of significant interest-“Spotlight” p.1721) PMCID: 2681728
b. Luo T and McBride JW. Ehrlichia chaffeensis TRP32 interacts with host cell targets that influence intracellular survival. Infect. Immun. 2012; 80:2297-2306. PMCID: 3416477
c. Zhu B, Das S, Mitra S, Farris TR, McBride JW. Ehrlichia chaffeensis TRP120 moonlights as a HECT E3 ligase involved in self- and host ubiquitination to influence protein interactions and stability for intracellular survival. Infect. Immun. 2017 85:1-16 pii: e00290-17. doi: 10.1128/IAI.00290-17 PMCID: PMC5563569.
d. Wakeel A, den Dulk-Ras A, Hooykas PJJ, McBride JW. Ehrlichia chaffeensis tandem repeat proteins are type 1 secretion system substrates related to the repeats-in-toxin exoprotein family. Front. Cell. Infect. Microbio. 2011; 1:1-19. PMCID: PMC3417381

4) Ehrlichia-host DNA interactions and host transcriptional regulation.

In addition to effector-host interactions defined by our laboratory, we have also determined that four ehrlichial effectors, TRP120, TRP32, TRP47 and Ank200 are nucleomodulins that interact with host cell DNA. The TRP120 has a novel DNA binding domain defined by the tandem repeats that directly binds DNA. We utilized ChIPSeq with next generation sequencing to define target genes and DNA binding motifs of these effectors, and are currently investigating mechanisms of nuclear trafficking, and mechanisms of direct and indirect transcriptional regulation by TRPs.

a. Zhu B, Nethery KA, Kuriakose JA, Zhang, XF, and McBride JW. Nuclear translocated Ehrlichia chaffeensis ankyrin repeat protein interacts with the mid-A stretch of host promoter and intronic Alu elements. Infect Immun 2009; 77:4243-4255. (Selected by the editors as an article of significant interest-“Spotlight” p.4181) PMCID: PMC2747939
b. Zhu B, Kuriakose JA, Luo T, Ballesteros E, Gupta S, Fofanov Y, and McBride JW. Ehrlichia chaffeensis TRP120 bind a G+C-rich motif in host cell DNA and exhibits eukaryotic transcriptional activator function. Infect. Immun. 2011; 79:4370-4381. PMCID: PMC3257946
c. Mitra S, Dunphy PS, Das S, Zhu B, Luo T, McBride JW. Ehrlichia chaffeensis TRP120 effector targets and recruits host polycomb group proteins for degradation to promote intracellular infection. Infect. Immun. 86:e00845-17. PMCID: PMC29358333.
d. Farris TR, Dunphy PS, Zhu B, Kibler CE, and McBride JW. Ehrlichia chaffeensis TRP32 is a nucleomodulin that directly regulates expression of host genes governing differentiation and proliferation. Infect. Immun. 2016; 84: 3182-3194. Aug 29. pii: IAI.00657-16 (Selected by the editors as an article of significant interest-“Spotlight” p.3093). PMCID: PMC5067751.

5) Ehrlichia exploitation of eukaryote pathways for survival.

To further extend our understanding of how microbes seamlessly interact with the eukaryotic host, we have more recently investigated how multiple host proteins can interact with a single bacterial effector. Post translational modifications extend the functional properties of both eukaryote and prokaryote proteins, and thus, can partially explain how a single effector protein can interact with multiple eukaryote targets. Moreover, Ehrlichia have small genomes, so PTMs may be particularly important for expansion of effector function and interaction and modulation of eukaryote pathways. We identified the first sumolyated bacterial protein/effector and determined its role in protein-protein interactions. Current studies are further extending these investigations to understand the full repertoire of ehrlichial effector PTMs and their role in effector function in various cellular contexts. We have shown that Ehrlichia activate host cellular pathways (Wnt and Notch) using short liner motifs (SLiMs) to subvert innate host defenses of the mononuclear phagocyte.

a. Wang JY, Zhu B, Patterson LL, Rogan MR, Kibler CE and McBride JW. Ehrlichia chaffeensis TRP120 mediated ubiquitination and proteasomal degradation of tumor suppressor FBW7 increases oncoprotein stability and promotes infection. 2020; PLoS Pathogens 16: e1008541 PMCID: PMC7217479.
b. Luo T, Dunphy PS, Lina TT, McBride JW. Ehrlichia chaffeensis exploits canonical and noncanonical host Wnt signaling pathways to stimulate phagocytosis and promote intracellular survival. Infect. Immun. 2016; 84:686-700. PMCID: PMC4771358 (Selected by the editors as an article of significant interest-“Spotlight” p.611).
c. Lina TT, Dunphy PS, Luo T, McBride JW. Ehrlichia chaffeensis TRP120 activates canonical
Notch signaling to downregulate TLR2/4 expression and promote intracellular survival. mBio 2016; 7: e00672-16 PMCID: PMC4958247
d. Lina T, Lou T, Velayutham T, McBride JW. Ehrlichia activation of Wnt-PI3K-mTOR signaling inhibits autolysosome generation and autophagic destruction by the mononuclear phagocyte. Infect. Immun. 2017 Oct 9. pii: IAI.00690-17. doi: 10.1128/IAI.00690-17. PMCID: PMC 5695117.

Jere W. McBride, PhD, MSDavid Walker, MD Professor in Infectious Disease Pathogenesis