The long-term goal of my research is to deepen our understanding of interkingdom molecular interactions between prokaryotes and eukaryotes, particularly those involved in infection and immune evasion. Our current knowledge of the interactions between obligately intracellular bacteria and their hosts—especially the molecular mechanisms underlying these interactions—remains limited. This gap presents a significant barrier to developing rationally designed therapeutics for diseases caused by these pathogens.

 Ehrlichia spp. serve as an excellent model system for studying intracellular survival and investigating how microbes with limited genomes can effectively interact with complex eukaryotic hosts. Over the past two decades, my research has focused on unraveling the role of ehrlichial effectors in the bacterium’s molecular pathobiology. My team was the first to identify and describe Type 1 secretion system (T1SS) effectors in intracellular bacteria, a breakthrough that has led to the characterization of numerous novel molecular interactions between these effectors and a wide array of eukaryotic cellular targets. More recently, we have explored how Ehrlichia exploits conserved host cell signaling pathways—such as Wnt, Notch, Hedgehog, and Hippo—both to infect host cells and to evade innate immune defenses. This work has revealed several novel short linear motifs (SLiMs) within ehrlichial effectors that mimic host signaling pathway ligands, further expanding our understanding of how pathogens manipulate host cellular machinery. My laboratory is also investigating the role of post-translational modifications of these effectors in mediating host-pathogen interactions and modulating host signaling and transcriptional pathways. These efforts aim to illuminate key molecular strategies that enable Ehrlichia and similar pathogens to persist within their hosts and evade immune surveillance.

I have been trained across the disciplines of microbial pathogenesis, molecular and cell biology, pathology, and immunology, and this interdisciplinary expertise has been instrumental in my ability to pursue complex investigations in infection biology. My research has led to significant advances in our understanding of cellular infection, microbial pathogenesis, immunopathogenesis, and immune modulation, and I am committed to continuing this work which will lead to new therapeutic strategies for combating infectious diseases. 

Ongoing and recently completed projects:

NIH/NIAID 1R01AI192966                   08/01/2025 – 7/31/2030
"Ehrlichia modulation of RNA splicing to influence KIRREL1-regulated Hippo signaling”

NIH/NIAID 1R01 AI158422                   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.

Completed Research Support (last 3 years)

NIH/NIAID 1R21 AI146637                   09/01/2020 – 8/31/2023
“Ehrlichia TRP120 HECT ubiquitin ligase modulation of host cell pathways.” 
This research project will investigate Ehrlichia TRP120 HECT Ub ligase activity during infection.  

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

NIH/NIAID 1R21 AI137779                   11/21/2018 – 10/31/2023
“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.

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.