Intracellular fate of <i>Ureaplasma parvum</i> entrapped by host cellular autophagy

Nishiumi, Fumiko; Ogawa, Michinaga; Nakura, Yukiko; Hamada, Yusuke; Nakayama, Masahiro; Mitobe, Jiro; Hiraide, Atsushi; Sakai, Norio; Takeuchi, Makoto; Yoshimori, Tamotsu; Yanagihara, Itaru

doi:10.1002/mbo3.441

Cited by 23 publications

(40 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in view of the potential invasion of host cells by Ureaplasma spp. (Waites et al, 2009 ; Nishiumi et al, 2017 ), our findings of missing IL-12 responses in Uu8 and Up3-stimulated monocytes might be of particular importance, potentially facilitating evasion of adaptive immune responses by the pathogen (Jayakumar et al, 2008 ).…”

Section: Discussionmentioning

confidence: 76%

Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro-Inflammation

Glaser¹,

Silwedel²,

Fehrholz³

et al. 2017

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Background: Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation.Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4.Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-α, IL-1β and IL-8 in term neonatal and adult monocytes (p < 0.01 and p < 0.05). Intracellular protein expression of TNF-α, IL-1β and IL-8 in Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1β in adult monocytes (Uu8: p < 0.05). Remarkably, ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1β/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p < 0.01, vs. LPS). In contrast to LPS, both isolates induced TLR2 mRNA in neonatal and adult cells (p < 0.001 and p < 0.05) and suppressed TLR4 mRNA in adult monocytes (p < 0.05). Upon co-stimulation, Uu8 and Up3 inhibited LPS-induced intracellular IL-1β (p < 0.001 and p < 0.05) and IL-8 in adult monocytes (p < 0.01), while LPS-induced neonatal cytokines were maintained or aggravated (p < 0.05).Conclusion: Our data demonstrate a considerable pro-inflammatory capacity of Ureaplasma isolates in human monocytes. Stimulating pro-inflammatory cytokine responses while hardly inducing immunomodulatory and anti-inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of TLR2 and TLR4 expression may shape host susceptibility to inflammation.

show abstract

Section: Discussionmentioning

confidence: 76%

Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro-Inflammation

Glaser¹,

Silwedel²,

Fehrholz³

et al. 2017

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…U. diversum has been associated with infertility in cows and may result in severe placentitis, fetal alveolitis, abortion and internalization into bovine blastocyst . U. parvum can be internalized into HeLa cells and can escape host cellular autophagosomal degradation by disturbing intracellular organisms through an unknown mechanism …”

Section: Genital Ureaplasma Infection and Preterm Birthmentioning

confidence: 99%

Current understanding and treatment of intra‐amniotic infection with Ureaplasma spp.

Tantengco

Yanagihara

2019

J of Obstet and Gynaecol

Self Cite

View full text Add to dashboard Cite

Considerable evidence has shown that intra-amniotic infection with Ureaplasma spp. increases the risk of chorioamnionitis and preterm labor. Ureaplasma spp. are among the smallest organisms, and their isolation is uncommon in routine clinical practice because of their size and high auxotrophy. Although Ureaplasma spp. have been reported as causative agents of preterm birth, they also have a high incidence in vaginal swabs collected from healthy reproductive-age women; this has led to questions on the virulence of Ureaplasma spp. and to them being considered as harmless commensal bacteria. Therefore, many efforts have been made to clarify the pathogenicity of Ureaplasma spp. at the molecular level. Ureaplasma spp. are surrounded by lipoproteins, including multiple-banded antigen. Both multiple-banded antigen and its derivative, that is, the synthetic lipopeptide, UPM-1, induce an inflammatory response in a preterm mice model, which was adequate to cause preterm birth or stillbirth. In this review, we present an overview of the virulence mechanisms of Ureaplasma spp. and treatment of ureaplasma infection during pregnancy to prevent possible serious sequelae in infants. In addition, relevant mechanisms underlying antibiotic resistance in Ureaplasma spp. are discussed. Ureaplasma spp. are naturally resistant against β-lactam antibiotics because of the lack of a cell wall. Azithromycin is one of the effective agents that can control intrauterine ureaplasma infection. In fact, macrolide-and fluoroquinolone-resistant isolates of Ureaplasma spp. have already been observed in perinatal practice in Japan.

show abstract

“…Galectin-3 is also known to be a diverse regulator of cancer cell activities, including transformation, growth, metastasis and apoptosis (Newlaczyl & Yu, 2011). We previously reported that U. parvum internalised into HeLa cells by clathrin-mediated endocytosis, resulting in the cytosolic accumulation of galectin-3 at the site of bacterial internalisation (Nishiumi et al, 2017). The internalised U. parvum was subsequently entrapped by the autophagy marker LC3.…”

Section: Introductionmentioning

confidence: 99%

Blockade of endoplasmic reticulum stress‐induced cell death by Ureaplasma parvum vacuolating factor

Nishiumi

Kawai

Nakura

et al. 2021

Cellular Microbiology

Self Cite

View full text Add to dashboard Cite

Previously, we found that Ureaplasma parvum internalised into HeLa cells and cytosolic accumulation of galectin-3. U. parvum induced the host cellular membrane damage and survived there. Here, we conducted vesicular trafficking inhibitory screening in yeast to identify U. parvum vacuolating factor (UpVF). U. parvum triggered endoplasmic reticulum (ER) stress and upregulated the unfolded protein response-related factors, including BiP, P-eIF2 and IRE1 in the host cells, but it blocked the induction of the downstream apoptotic factors. MicroRNA library screening of U. parvuminfected cells and UpVF-transfected cells identified miR-211 and miR-214 as the negative regulators of the apoptotic cascade under ER stress. Transient expression of UpVF induced HeLa cell death with intracellular vacuolization; however, some stable UpVF transformant survived. U. parvum-infected cervical cell lines showed resistance to actinomycin D, and UpVF stable transformant cell lines exhibited resistance to Xray irradiation, as well as cisplatin and paclitaxel. UpVF expressing cervical cancer xenografts in nude mice also acquired resistance to cisplatin and paclitaxel. A mycoplasma expression vector based on Mycoplasma mycoides, Syn-MBA (multiple banded antigen)-UpVF, reduced HeLa cell survival compared with that of Syn-MBA after 72 hr of infection. These findings together suggest novel mechanisms for Ureaplasma infection and the possible implications for cervical cancer malignancy. Take Aways• Ureaplasmal novel virulence factor, UpVF, was identified.• UpVF triggered ER stress but suppressed apoptotic cascade via miR-211 and -214.• UpVF conferred resistance to anticancer treatments both in vivo and in vitro.• Dual expression of MBA and UpVF in JCVI-syn3B showed host cell damage.

show abstract

Intracellular fate of Ureaplasma parvum entrapped by host cellular autophagy

Cited by 23 publications

References 67 publications

Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro-Inflammation

Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro-Inflammation

Current understanding and treatment of intra‐amniotic infection with Ureaplasma spp.

Blockade of endoplasmic reticulum stress‐induced cell death by Ureaplasma parvum vacuolating factor

Contact Info

Product

Resources

About