Hacker within! Ehrlichia chaffeensis Effector Driven Phagocyte Reprogramming Strategy

Lina, Taslima T.; Farris, Tierra R.; Luo, Tian; Mitra, Shubhajit; Zhu, Bing; McBride, Jere W.

doi:10.3389/fcimb.2016.00058

Cited by 37 publications

(41 citation statements)

References 143 publications

(224 reference statements)

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“…lar trafficking and cytoskeletal organization, and apoptosis (4,5). Most recently, E. chaffeensis via the TRP120 effector was shown to activate Wnt and Notch signaling pathways to promote intracellular survival (6,7).…”

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confidence: 99%

Ehrlichia chaffeensis TRP120 Moonlights as a HECT E3 Ligase Involved in Self- and Host Ubiquitination To Influence Protein Interactions and Stability for Intracellular Survival

et al. 2017

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Ehrlichia chaffeensis secretes tandem repeat protein (TRP) effectors that are involved in a diverse array of host cell interactions, some of which directly activate cell signaling pathways and reprogram host gene transcription to promote survival in the mononuclear phagocyte. However, the molecular details of these effectorhost interactions and roles in pathobiology are incompletely understood. In this study, we determined that the E. chaffeensis effector TRP120 is posttranslationally modified by ubiquitin (Ub) and that ubiquitination occurs through intrinsic and host-mediated HECT ligase activity. A functional HECT E3 ligase domain with a conserved catalytic site was identified in the C-terminal region of TRP120, and TRP120 autoubiquitination occurred in vitro in the presence of host UbcH5b/c E2 enzymes. TRP120 ubiquitination sites were mapped using a high-density microfluidic peptide array and confirmed by ectopic expression of TRP120 lysine mutants in cells. Moreover, we determined that the HECT E3 ubiquitin ligase, Nedd4L, interacts with TRP120 during infection and also mediates TRP120 ubiquitination. Nedd4L knockdown resulted in the reduction of TRP120-Ub, decreased ehrlichial infection, and reduced recruitment of a known TRP120-interacting host protein, PCGF5, to ehrlichial inclusions. TRP120-mediated PCGF5 polyubiquitination was associated with a reduction in PCGF5 levels. Inhibition of ubiquitination with small molecules also significantly decreased ehrlichial infection, indicating that the Ub pathway is critical for ehrlichial intracellular replication and survival. The current study identified a novel E. chaffeensis ubiquitin ligase and revealed an important role for the ubiquitin pathway in effector-host interactions and pathogen-mediated host protein stability in order to promote intracellular survival.

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confidence: 99%

Ehrlichia chaffeensis TRP120 Moonlights as a HECT E3 Ligase Involved in Self- and Host Ubiquitination To Influence Protein Interactions and Stability for Intracellular Survival

et al. 2017

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“…Ankyrin repeats mediate protein–protein interactions, provide scaffolding for signalling pathways and localize molecules to subcellular compartments in eukaryotes 88 . Ankyrin-repeat containing proteins (Anks) in A. phagocytophilum and E. chaffeensis were shown to mediate host epigenetic changes to promote bacterial survival 69,89 . Elucidating the function of conserved Anks in obligate intracellular bacteria can provide insight into host signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

Engineering of obligate intracellular bacteria: progress, challenges and paradigms

et al. 2017

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It is estimated that approximately one billion people are at risk of infection with obligate intracellular bacteria, but little is known about the underlying mechanisms that govern their life cycles. The difficulty in studying Chlamydia spp., Coxiella spp., Rickettsia spp., Anaplasma spp., Ehrlichia spp. and Orientia spp. is, in part, due to their genetic intractability Recently, genetic tools have been developed; however, optimizing the genomic manipulation of obligate intracellular bacteria remains challenging. In this Review, we describe the progress in, as well as the constraints that hinder, the systematic development of a genetic toolbox for obligate intracellular bacteria. We highlight how the use of genetically manipulated pathogens has facilitated a better understanding of microbial pathogenesis and immunity and how the engineering of obligate intracellular bacteria could enable the discovery of novel signalling circuits in host–pathogen interactions.

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“…A homolog of Erum1110 was previously implicated with attachment to tick cells (De la Fuente et al, 2004). Previous studies have reported that TR-proteins elicit a strong protective antibody response during infection that is directed at continuous species-specific epitopes located at the TR region (Lina et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, these genes may possibly be ideal targets for CTL immunity. Lina et al (2016) reviewed that pathogenicity-associated genes (e.g. type IV secretion system proteins (T4SS)) play an important role in the in E. chaffeensis growth and virulence.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of Ehrlichia ruminantium during the developmental stages in bovine and tick cell culture

Tjale

Pretorius

Josemans

et al. 2018

Ticks and Tick-borne Diseases

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The use of bioinformatics tools to search for possible vaccine candidates has been successful in recent years. In an attempt to search for additional vaccine candidates or improve the current heartwater vaccine design, a genome-wide transcriptional profile of E. ruminantium (Welgevonden strain) replicating in bovine endothelial cells (BA886) and Ixodes scapularis embryonic tick cells (IDE8) was performed. The RNA was collected from the infective extracellular form, the elementary bodies (EBs) and vegetative intracellular form, reticulate bodies (RBs) and was used for transcriptome sequencing. Several genes previously implicated with adhesion, attachment and pathogenicity were exclusively up-regulated in the EBs from bovine and tick cells. Similarly, genes involved in adaptation or survival of E. ruminantium in the host cells were up-regulated in the RBs from bovine cells. Thus, it was concluded that those genes expressed in the EBs might be important for infection of mammalian and tick host cells and these may be targets for both cell and humoral mediated immune responses. Alternatively, those exclusively expressed in the RBs may be important for survival in the host cells. Exported or secreted proteins exclusively expressed at this stage are ideal targets for the stimulation of cytotoxic T-lymphocyte (CTL) immune responses in the host.

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Hacker within! Ehrlichia chaffeensis Effector Driven Phagocyte Reprogramming Strategy

Cited by 37 publications

References 143 publications

Ehrlichia chaffeensis TRP120 Moonlights as a HECT E3 Ligase Involved in Self- and Host Ubiquitination To Influence Protein Interactions and Stability for Intracellular Survival

Ehrlichia chaffeensis TRP120 Moonlights as a HECT E3 Ligase Involved in Self- and Host Ubiquitination To Influence Protein Interactions and Stability for Intracellular Survival

Engineering of obligate intracellular bacteria: progress, challenges and paradigms

Transcriptomic analysis of Ehrlichia ruminantium during the developmental stages in bovine and tick cell culture

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