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. 2017 Nov 27;12(11):e0188071.
doi: 10.1371/journal.pone.0188071. eCollection 2017.

Mechanisms of Action of Coxiella Burnetii Effectors Inferred From Host-Pathogen Protein Interactions

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Free PMC article

Mechanisms of Action of Coxiella Burnetii Effectors Inferred From Host-Pathogen Protein Interactions

Anders Wallqvist et al. PLoS One. .
Free PMC article

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Abstract

Coxiella burnetii is an obligate Gram-negative intracellular pathogen and the etiological agent of Q fever. Successful infection requires a functional Type IV secretion system, which translocates more than 100 effector proteins into the host cytosol to establish the infection, restructure the intracellular host environment, and create a parasitophorous vacuole where the replicating bacteria reside. We used yeast two-hybrid (Y2H) screening of 33 selected C. burnetii effectors against whole genome human and murine proteome libraries to generate a map of potential host-pathogen protein-protein interactions (PPIs). We detected 273 unique interactions between 20 pathogen and 247 human proteins, and 157 between 17 pathogen and 137 murine proteins. We used orthology to combine the data and create a single host-pathogen interaction network containing 415 unique interactions between 25 C. burnetii and 363 human proteins. We further performed complementary pairwise Y2H testing of 43 out of 91 C. burnetii-human interactions involving five pathogen proteins. We used the combined data to 1) perform enrichment analyses of target host cellular processes and pathways, 2) examine effectors with known infection phenotypes, and 3) infer potential mechanisms of action for four effectors with uncharacterized functions. The host-pathogen interaction profiles supported known Coxiella phenotypes, such as adapting cell morphology through cytoskeletal re-arrangements, protein processing and trafficking, organelle generation, cholesterol processing, innate immune modulation, and interactions with the ubiquitin and proteasome pathways. The generated dataset of PPIs-the largest collection of unbiased Coxiella host-pathogen interactions to date-represents a rich source of information with respect to secreted pathogen effector proteins and their interactions with human host proteins.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Yeast two-hybrid (Y2H) host-pathogen protein-protein interactions.
Using Y2H screens against whole human and murine proteome libraries, we detected 273 unique interactions between 20 Coxiella burnetii and 247 human proteins and 157 unique interactions between 17 C. burnetii and 137 murine proteins. We used these data to construct a single host-pathogen protein interaction network, based on murine/human orthology, containing 415 unique interactions between 25 C. burnetii and 363 human proteins. Green nodes represent C. burnetii proteins, whereas pink and red nodes represent host proteins. Twelve C. burnetii proteins interacted with both hosts, three of which participated in conserved interactions (i.e., they interacted with both human proteins and their murine orthologs; shown as red nodes and connected with thick grey edges).
Fig 2
Fig 2. Coxiella interactions in the endoplasmic reticulum protein-processing pathway.
The interacting host proteins are highlighted in red text and the pathogen proteins are superimposed as named yellow circles and located close to their interacting host partners. Overlaying the interacting C. burnetii proteins onto their human partners in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways illustrates intervention points of nine screened Coxiella effectors that could affect human-host protein processing in the endoplasmic reticulum (ER). Pathogen proteins can multiply their effect by interacting with multiple host proteins or focus their effect by using different pathogen proteins to target the same host protein. The potential effect of these interactions could influence multiple processes, such as protein export, COPII-mediated vesicle formation, initiation of apoptosis, and ER-assisted protein degradation. In this pathway representation, CBUA0014 interacts with Hsp40 and Skp1; CBU1379a with BiP; CirA with PERK; CirC with ERManI; CBU0794 with Calpain and Sec23/24; CBU1724 with Cul1; and CBU1457 with Cul1. The underlying network graph is reprinted from KEGG [40] under a CC BY license, with permission from the Kanehisa Laboratories, original copyright 2016.
Fig 3
Fig 3. Host pathways targeted by Coxiella.
C. burnetii-interacting host proteins are present in interconnected Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with the potential to affect multiple cellular processes of the host. The pathways are grouped into five major categories: RNA processing, protein processing, degradation pathways, signaling (including signaling events related to the immune response), and metabolism. The size of a star indicates the number of targeted host proteins in each pathway. ECM, extracellular matrix; ER, endoplasmic reticulum; ErbB, erythroblastic leukemia viral oncogene; ESCRT, endosomal sorting complexes required for transport; MAPK, mitogen-activated protein kinase; NOD, nucleotide-binding oligomerization domain; PIK3, phosphatidylinositol-3-kinases; TCA, tricarboxylic acid; TGF, transforming growth factor.

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References

    1. Raoult D, Marrie T, Mege J (2005) Natural history and pathophysiology of Q fever. Lancet Infect Dis 5: 219–226. doi: 10.1016/S1473-3099(05)70052-9 - DOI - PubMed
    1. Larson CL, Martinez E, Beare PA, Jeffrey B, Heinzen RA, Bonazzi M (2016) Right on Q: genetics begin to unravel Coxiella burnetii host cell interactions. Future Microbiol 11: 919–939. doi: 10.2217/fmb-2016-0044 - DOI - PMC - PubMed
    1. van Schaik EJ, Chen C, Mertens K, Weber MM, Samuel JE (2013) Molecular pathogenesis of the obligate intracellular bacterium Coxiella burnetii. Nat Rev Microbiol 11: 561–573. doi: 10.1038/nrmicro3049 - DOI - PMC - PubMed
    1. Eldin C, Melenotte C, Mediannikov O, Ghigo E, Million M, Edouard S, et al. (2017) From Q fever to Coxiella burnetii infection: a paradigm change. Clin Microbiol Rev 30: 115–190. doi: 10.1128/CMR.00045-16 - DOI - PMC - PubMed
    1. Kersh GJ, Wolfe TM, Fitzpatrick KA, Candee AJ, Oliver LD, Patterson NE, et al. (2010) Presence of Coxiella burnetii DNA in the environment of the United States, 2006 to 2008. Appl Environ Microbiol 76: 4469–4475. doi: 10.1128/AEM.00042-10 - DOI - PMC - PubMed

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Grant support

This work was supported by U.S. Defense Threat Reduction Agency Award CBS.MEDBIO.02.10.BH.021 (JR) and by the U.S. Army Medical Research and Materiel Command (Ft. Detrick, MD) (JR) as part of the U.S. Army’s Network Science Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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