Involvement of matrix metalloproteinases in chronic Q fever

Jansen, Annemarie; Schoffelen, Teske; Textoris, Julien; Mège, Jean‐Louis; Bleeker‐Rovers, Chantal P.; Roest, H.I.J.; Wever, Peter C.; Joosten, Leo A. B.; Netea, Mihai G.; Vosse, Esther van de; Deuren, Marcel van

doi:10.1016/j.cmi.2017.01.022

“…The transcriptome data show that Cm infection in OE-WT cells substantially up regulates these ECM genes, and thereby can trigger or disrupt cellular processes that are essential for processes including cellular growth, wound healing, and fibrosis, but are highly suggestive that Chlamydia infection can also have impact on processes such as cell migration, gene expression, and cellular differentiation in macrophages and other hematopoietically-derived cells [73,74]. Our findings support the investigations of others who have implicated several members of this subset of ECM proteins in various disorders associated with genital tract Chlamydia infections such as oviduct fibrosis and scarring, uterus and oviduct distention, and tubal damage caused by ectopic pregnancy [75–80]. Because the transcriptome data show that TLR3-deficiency causes dysregulation in the gene expression levels of most of the ECM proteins identified by IPA, these data provides insight into a possible mechanism that expounds our recent report demonstrating thatTLR3 deficient mice suffer more severe genital tract pathology than wild-type mice during Cm infection [59].…”

Section: Discussionsupporting

confidence: 86%

TLR3 Deficiency Leads to a Dysregulation in the Global Gene-Expression Profile in Murine Oviduct Epithelial Cells Infected with Chlamydia muridarum

Kumar¹,

Derbigny²

2018

Int J Microbiol Curr Res

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Chlamydia trachomatis replicates primarily in the epithelial cells lining the genital tract and induces the innate immune response by triggering cellular pathogen recognition receptors (PRRs). Our previous studies showed that Toll-like receptor 3 (TLR3) is expressed in murine oviduct epithelial (OE) cells, is the primary PRR triggered by C. muridarum (Cm) early during infection to induce IFN-β synthesis, and that TLR3 signaling regulates the chlamydial induced synthesis of a plethora of other innate inflammatory modulators including IL-6, CXCL10, CXCL16 and CCL5. We also showed that the expression of these cytokines induced by Chlamydia was severely diminished during TLR3 deficiency; however, the replication of Chlamydiain TLR3 deficient OE cells was more robust than in WT cells. These data suggested that TLR3 had a biological impact on the inflammatory response to Chlamydia infection; however, the global effects of TLR3 signaling in the cellular response to Chlamydia infection in murine OE cells has not yet been investigated. To determine the impact of TLR3 signaling on Chlamydia infection in OE cell at the transcriptome level, we infected wild-type (OE-WT) and TLR3-deficient (OE-TLR3KO) cells with Cm, and performed transcriptome analyses using microarray. Genome-wide expression and ingenuity pathway analysis (IPA) identified enhanced expression of host genes encoding for components found in multiple cellular processes encompassing: (1) pro-inflammatory, (2) cell adhesion, (3) chemoattraction, (4) cellular matrix and small molecule transport, (5) apoptosis, and (6) antigen-processing and presentation. These results support a role for TLR3 in modulating the host cellular responses to Cm infection that extend beyond inflammation and fibrosis, and shows that TLR3 could serve a potential therapeutic target for drug and/or vaccine development.

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“…The transcriptome data show that Cm infection in OE-WT cells substantially up regulates these ECM genes, and thereby can trigger or disrupt cellular processes that are essential for processes including cellular growth, wound healing, and fibrosis, but are highly suggestive that Chlamydia infection can also have impact on processes such as cell migration, gene expression, and cellular differentiation in macrophages and other hematopoietically-derived cells [73,74]. Our findings support the investigations of others who have implicated several members of this subset of ECM proteins in various disorders associated with genital tract Chlamydia infections such as oviduct fibrosis and scarring, uterus and oviduct distention, and tubal damage caused by ectopic pregnancy [75][76][77][78][79][80]. Because the transcriptome data show that TLR3-deficiency causes dysregulation in the gene expression levels of most of the ECM proteins identified by IPA, these data provides insight into a possible mechanism that expounds our recent report demonstrating thatTLR3 deficient mice suffer more severe genital tract pathology than wild-type mice during Cm infection [59].…”

Section: Discussionsupporting

confidence: 85%

Untitled

2019

Int J Microbiol Curr Res

0

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Chlamydia trachomatis replicates primarily in the epithelial cells lining the genital tract and induces the innate immune response by triggering cellular pathogen recognition receptors (PRRs). Our previous studies showed that Toll-like receptor 3 (TLR3) is expressed in murine oviduct epithelial (OE) cells, is the primary PRR triggered by C. muridarum (Cm) early during infection to induce IFN-β synthesis, and that TLR3 signaling regulates the chlamydial induced synthesis of a plethora of other innate inflammatory modulators including IL-6, CXCL10, CXCL16 and CCL5. We also showed that the expression of these cytokines induced by Chlamydia was severely diminished during TLR3 deficiency; however, the replication of Chlamydiain TLR3 deficient OE cells was more robust than in WT cells. These data suggested that TLR3 had a biological impact on the inflammatory response to Chlamydia infection; however, the global effects of TLR3 signaling in the cellular response to Chlamydia infection in murine OE cells has not yet been investigated. To determine the impact of TLR3 signaling on Chlamydia infection in OE cell at the transcriptome level, we infected wild-type (OE-WT) and TLR3-deficient (OE-TLR3KO) cells with Cm, and performed transcriptome analyses using microarray. Genome-wide expression and ingenuity pathway analysis (IPA) identified enhanced expression of host genes encoding for components found in multiple cellular processes encompassing: (1) pro-inflammatory, (2) cell adhesion, (3) chemoattraction, (4) cellular matrix and small molecule transport, (5) apoptosis, and (6) antigen-processing and presentation. These results support a role for TLR3 in modulating the host cellular responses to Cm infection that extend beyond inflammation and fibrosis, and shows that TLR3 could serve a potential therapeutic target for drug and/or vaccine development.

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“…In the literature the proteolytic cleavage of E-cad was reported for a number of sheddases, including zinc-dependent matrix metalloproteinases (MMP-2, -3, -7, -9 and -14), members of the disintegrin family (adamalysin/ADAM-10 and−15), bacterial proteases gingipains (HRgpA, RgpB, and Kgp), B. fragilis toxin/fragilysin, cysteine cathepsins (B, L, and S), serine protease Kallikrein-7 (KLK7), plasmin serine protease, aspartic proteinases BACE1 and BACE2, and malaria parasite serine proteinases PfSUB2n, PfROM1, and PfROM 4 (Grabowska and Day, 2012). One possible candidate for E-cad cleavage during C. burnetii infections could be the human MMP-9, since: (i) MMP-9 levels were reported elevated in the sera of patients with endocarditis (Thuny et al, 2012), and patients with acute Q fever (Krajinović et al, 2012); (ii) its production was induced in PBMCs of healthy persons following in vitro exposure to C. burnetii ; (iii) MMP-9 SNP was found more frequently in patients with persistent Q fever (Jansen et al, 2017); and (iv) MMP-9 was recently identified as a key gene in mantle cell lymphoma (Yan et al, 2018). Experiments are under progress in our laboratory to investigate whether C. burnetii infection induces the activation of a human cellular protease from the sheddase family or if C. burnetii itself encodes for a sheddase.…”

Section: Discussionmentioning

confidence: 99%

“…The matrix metalloproteinases (MMP) family, count among the inducible human sheddases that catalyze the proteolysis of cadherins (cad), a group of cell-surface adhesion molecules that includes E-cadherin (E-cad) and belongs to the superfamily of CAM (Grabowska and Day, 2012). Recently, we reported (Jansen et al, 2017) that C. burnetii induces the sheddases MMP-1 and MMP-9 production in PBMCs of healthy persons exposed in vitro to the bacterium; that the single nucleotide polymorphisms (SNPs) in MMP-7 and MMP-9 were more frequent in patients with persistent Q fever; and, that the circulating MMP-7 serum levels were higher in patients with persistent Q fever.…”

Section: Introductionmentioning

confidence: 99%

High Concentrations of Serum Soluble E-Cadherin in Patients With Q Fever

Mezouar

¹

,

Osman

²

,

Melenotte

³

et al. 2019

Front. Cell. Infect. Microbiol.

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Cadherins switching is a hallmark of neoplasic processes. The E-cadherin (E-cad) subtype is one of the surface molecules regulating cell-to-cell adhesion. After its cleavage by sheddases, a soluble fragment (sE-cad) is released that has been identified as a pro-carcinogenic inflammatory signal in several bacteria-induced cancers. Recently we reported that Q fever, a disease due to Coxiella burnetii infection, can be complicated by occurrence of non-Hodgkin lymphoma (NHL). Therefore, we studied E-cad switching in Q fever. The sE-cad levels were found increased in the sera of acute and persistent Q fever patients, whereas they remained at the baseline in controls groups of healthy donors, people cured of Q fever, patients suffering from unrelated inflammatory diseases, and past Q fever patients who developed NHL. These results indicate that sE-cad can be considered as a new biomarker of C. burnetii infection rather than a marker of NHL-associated to Q fever. We wondered if changes in sE-cad reflected variations in the CDH1 gene transcription. The expression of E-cad mRNA and its intracellular ligand β-catenin was down-regulated in peripheral blood mononuclear cells (PBMCs) of patients with either acute or persistent forms of Q fever. Indeed, a lower cell-surface expression of E-cad was measured in a minority (<5%) subpopulation of HLADR + /CD16 + monocytes from patients with acute Q fever. However, a very strong increase in E-cad expression was observed on more than 30% of the HLADR + /CD16 + monocytes of persistent Q fever patients, a cell subpopulation known to be a target for C. burnetii in humans. An experimental in vitro infection of healthy donors' PBMCs with C. burnetii , was performed to directly evaluate the link between C. burnetii interaction with PBMCs and their E-cad expression. A significant increase in the percentage of HLADR + /CD16 + monocytes expressing E-cad was measured after PBMCs had been incubated for 8 h with C. burnetii Nine Mile strain. Altogether, these data demonstrate that C. burnetii severely impairs the E-cad expression in circulating cells of Q fever patients.

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Involvement of matrix metalloproteinases in chronic Q fever

Abstract: Coxiella burnetii-induced MMP production may contribute to the development of chronic Q fever.

Cited by 11 publications

References 46 publications

TLR3 Deficiency Leads to a Dysregulation in the Global Gene-Expression Profile in Murine Oviduct Epithelial Cells Infected with Chlamydia muridarum

TLR3 Deficiency Leads to a Dysregulation in the Global Gene-Expression Profile in Murine Oviduct Epithelial Cells Infected with Chlamydia muridarum

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High Concentrations of Serum Soluble E-Cadherin in Patients With Q Fever

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