Targeting of a Chlamydial Protease Impedes Intracellular Bacterial Growth

Christian, Jan G.; Heymann, Julia; Paschen, Stefan A.; Vier, Juliane; Schauenburg, Linda; Rupp, Jan; Meyer, Thomas F.; Häcker, Georg; Heuer, Dagmar

doi:10.1371/journal.ppat.1002283

Cited by 44 publications

(69 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Certain bacteria have a propensity for intracellular infection in host cells, and they regulate host cells by targeting their proteins in the host (Christian et al, 2011). During intracellular E. coli infection, proteins will be released directly into the host cell and these proteins will become a part of the host cell.…”

Section: Introductionmentioning

confidence: 99%

In SilicoPrediction ofEscherichia coliProteins Targeting the Host Cell Nucleus, with Special Reference to Their Role in Colon Cancer Etiology

Khan

2014

Journal of Computational Biology

View full text Add to dashboard Cite

The potential role of Escherichia coli in the development of colorectal carcinoma (CRC) has been investigated in many studies. Although the exact mechanism is not clear, chronic inflammation caused by E. coli and other related events are suggested as possible causes behind E. coli-induced colon cancer. It has been found that CRC cells, but not normal cells, are colonized by an intracellular form of E. coli. We predicted nuclear targeting of bacterial proteins in the host cell through computational tools nuclear localization signal (NLS) mapper and balanced subcellular localization predictor (BaCeILo). During intracellular E. coli residence, such targeting is highly likely and may have a possible role in colon cancer etiology. We observed that several gene expression-associated proteins of E. coli can migrate to the host nucleus during intracellular infections. This situation provides an opportunity for competitive interaction of host and pathogen proteins with similar cellular substrates, thereby increasing the chances of development of colon cancer. Moreover, the results indicated that proteins localized in the membrane of E. coli mostly act as secretary proteins in host cells. No exact correlation was observed between NLS prediction and nuclear localization prediction by BaCeILo. This is partly because of a number of reasons, including that only 30% of nuclear proteins carry NLS and that proteins <40 kDa molecular weight can passively target the host nucleus. This study concludes that detection of gene expression-specific E. coli proteins and their targeting of the nucleus may have a profound impact on CRC etiology.

show abstract

Section: Introductionmentioning

confidence: 99%

In SilicoPrediction ofEscherichia coliProteins Targeting the Host Cell Nucleus, with Special Reference to Their Role in Colon Cancer Etiology

Khan

2014

Journal of Computational Biology

View full text Add to dashboard Cite

show abstract

“…Pathogenic chlamydiae have been reported to degrade several cellular matrixes, actin or intermediate fibre filaments required for inclusion formation, which is regulated via the activation of chlamydia-associated protease factor (CPAF) (Christian et al, 2011;Jorgensen et al, 2011;Zhong, 2011). Because recent genome research has demonstrated the presence of a gene homologue in P. acanthamoebae, the CPAF-like enzyme is a potential candidate for causing this modification (Horn, 2008).…”

Section: Discussionmentioning

confidence: 99%

A domino-like chlamydial attachment process: concurrent Parachlamydia acanthamoebae attachment to amoebae is required for several amoebal released molecules and serine protease activity

et al. 2012

View full text Add to dashboard Cite

A domino-like chlamydial attachment process: concurrent Parachlamydia acanthamoebae attachment to amoebae is required for several amoebal released molecules and serine protease activity Parachlamydia acanthamoebae is an obligate intracellular bacterium that infects free-living amoebae (Acanthamoeba), and is a potential human pathogen associated with hospital-acquired pneumonia. The attachment mechanism of this bacteria to host cells is crucial in bacterial pathogenesis, yet remains undetermined. Hence, we obtained monoclonal antibodies (mAbs) specific to either P. acanthamoebae or amoebae in an attempt to elucidate the attachment mechanism involved. Hybridomas of 954 clones were assessed, and we found that four mAbs (mAb38, mAb300, mAb311, mAb562) that were reactive to the amoebae significantly inhibited bacterial attachment. All mAbs recognized amoebal released molecules, and mAb311 also recognized the amoebal surface. mAbs reacted with the bacteria not only within amoebae, but also when they were released from amoebae (except mAb311). Furthermore, a serine protease inhibitor had an inhibitory effect on the bacterial attachment to amoebae, although none of the mAbs had any synergistic effect on the inhibition of attachment by the protease inhibitor. Taken together, we conclude that concurrent P. acanthoamebae attachment to amoebae is required for several amoebal released molecules and serine protease activity, implying the existence of a complicated host-parasite relationship. INTRODUCTIONChlamydiae, which are obligate intracellular bacterial pathogens, have been reclassified into the order Chlamydiales, which includes four families, Chlamydiaceae, Parachlamydiaceae, Waddliaceae and Simkaniaceae (Horn, 2008). The family Chlamydiaceae, which is broadly distributed among mammals, including humans, includes two major human pathogens designated the pathogenic chlamydiae. Chlamydophila pneumoniae is a causal agent of common respiratory infection (Bartlett, 2008) and is also suspected of being involved in certain chronic diseases, such as asthma (Sutherland & Martin, 2007) and atherosclerosis (Watson & Alp, 2008), while Chlamydia trachomatis is responsible for sexually transmitted disease and preventable blindness (Jordan et al., 2011). Furthermore, Parachlamydiaceae, Waddliaceae and Simkaniaceae have only recently been recognized as environmental chlamydiae, and exhibit a wide distribution in natural environments, such as in rivers and soil (Greub, 2009;Horn et al., 2004). These species can grow and survive within the free-living amoeba Acanthamoeba, which is the most abundant genus of amoebae (Khan, 2006).Abbreviations: AIU, amoeba-infectious units; HRP, horseradish peroxidase; PAS, Page's modified Neff's amoeba saline.A supplementary table, showing a summary of monoclonal antibodies directed to either P. acanthamoebae or amoebae, is available with the online version of this paper. Microbiology

show abstract

“…This chlamydial effector protein is known to be secreted from the infection vacuole once effective replication has been established and, as its name indicates, cleave host cell proteins for the chlamydial favour [17]. In 2011, Christian et al reported on findings demonstrating the ability of C. pneumoniae CPAF to induce Golgi fragmentation [18]. This feature was reported to be vital for C .…”

Section: Lead Discovery Strategiesmentioning

confidence: 99%

Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors

Hanski

Vuorela

2016

Microorganisms

View full text Add to dashboard Cite

Throughout its known history, the gram-negative bacterium Chlamydia pneumoniae has remained a challenging target for antibacterial chemotherapy and drug discovery. Owing to its well-known propensity for persistence and recent reports on antimicrobial resistence within closely related species, new approaches for targeting this ubiquitous human pathogen are urgently needed. In this review, we describe the strategies that have been successfully applied for the identification of nonconventional antichlamydial agents, including target-based and ligand-based virtual screening, ethnopharmacological approach and pharmacophore-based design of antimicrobial peptide-mimicking compounds. Among the antichlamydial agents identified via these strategies, most translational work has been carried out with plant phenolics. Thus, currently available data on their properties as antichlamydial agents are described, highlighting their potential mechanisms of action. In this context, the role of mitogen-activated protein kinase activation in the intracellular growth and survival of C. pneumoniae is discussed. Owing to the complex and often complementary pathways applied by C. pneumoniae in the different stages of its life cycle, multitargeted therapy approaches are expected to provide better tools for antichlamydial therapy than agents with a single molecular target.

show abstract

Targeting of a Chlamydial Protease Impedes Intracellular Bacterial Growth

Cited by 44 publications

References 28 publications

In SilicoPrediction ofEscherichia coliProteins Targeting the Host Cell Nucleus, with Special Reference to Their Role in Colon Cancer Etiology

In SilicoPrediction ofEscherichia coliProteins Targeting the Host Cell Nucleus, with Special Reference to Their Role in Colon Cancer Etiology

A domino-like chlamydial attachment process: concurrent Parachlamydia acanthamoebae attachment to amoebae is required for several amoebal released molecules and serine protease activity

Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors

Contact Info

Product

Resources

About