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Neisseriae internalization by epithelial cells is enhanced by TLR2 stimulation.

ABSTRACT: Neisseria meningitidis (NM) is an opportunistic gram-negative human pathogen that colonizes the human nasopharyngeal epithelium. Asymptomatic carriage is common, but some meningococcal strains can invade nasopharyngeal epithelial cells and proceed to cause severe and often fatal infections. Invasion is predominantly driven by expression of bacterial virulence factors and host cell cognate receptors for bacterial recognition. Porins are among the Neisserial components involved in host cell activation and bacterial internalization processes. Similar to other virulence factors, porins present antigenic and structure variability among strains. Such sequence variability in the surface-exposed loop regions has been correlated to bacterial invasiveness and to variability in host cell responses via Toll-like receptor 2 (TLR2). Here, we examined whether TLR2 signaling by porins influences recovery of intracellular Neisseriae from epithelial cells in vitro. Our results show that TLR2 stimulation, either by the organism or exogenously, generally enhances Neisseriae internalization by epithelial cells. TLR2-driven intracellular signaling via ERK1/2, JNK and particularly NF-?B plays a role in this process. Based on these results, it is possible that expression of porin sequence variants that strongly induce TLR2 activation may be a mechanism to enhance the invasive features of pathogenic Neisseriae strains.

SUBMITTER: Toussi DN

PROVIDER: S-EPMC5050100 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Neisseriae internalization by epithelial cells is enhanced by TLR2 stimulation.

Toussi Deana N DN Wetzler Lee M LM Liu Xiuping X Massari Paola P

Microbes and infection 20160701 10

Neisseria meningitidis (NM) is an opportunistic gram-negative human pathogen that colonizes the human nasopharyngeal epithelium. Asymptomatic carriage is common, but some meningococcal strains can invade nasopharyngeal epithelial cells and proceed to cause severe and often fatal infections. Invasion is predominantly driven by expression of bacterial virulence factors and host cell cognate receptors for bacterial recognition. Porins are among the Neisserial components involved in host cell activa ...[more]

PMID: 27373686

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Project description:Bovine mammary epithelial cells (bMECs) contribute to mammary gland defense against invading pathogens, such as Staphylococcus aureus (intracellular facultative), which is recognized by TLR2. In a previous report, we showed that sodium octanoate [NaO, a medium chain fatty acid (C8)] induces (0.25 mM) or inhibits (1 mM) S. aureus internalization into bMECs and differentially regulates the innate immune response (IIR). However, the molecular mechanisms have not been described, which was the aim of this study. The results showed that α5β1 integrin membrane abundance (MA) was increased in 0.25 mM NaO-treated cells, but TLR2 or CD36 MA was not modified. When these receptors were blocked individually, 0.25 mM NaO-increased S. aureus internalization was notably reduced. Interestingly, in this condition, the IIR of the bMECs was impaired because MAPK (p38, JNK, and ERK1/2) phosphorylation and the activation of transcription factors related to these pathways were decreased. In addition, the 1 mM NaO treatment induced TLR2 MA, but neither the integrin nor CD36 MA was modified. The reduction in S. aureus internalization induced by 1 mM NaO was increased further when TLR2 was blocked. In addition, the phosphorylation levels of the MAPKs increased, and 13 transcriptional factors related to the IIR were slightly activated (CBF, CDP, c-Myb, AP-1, Ets-1/Pea-3, FAST-1, GAS/ISRE, AP-2, NFAT-1, OCT-1, RAR/DR-5, RXR/DR-1, and Stat-3). Moreover, the 1 mM NaO treatment up-regulated gene expression of IL-8 and RANTES and secretion of IL-1β. Notably, when 1 mM NaO-treated bMECs were challenged with S. aureus, the gene expression of IL-8 and IL-10 increased, while IL-1β secretion was reduced. In conclusion, our results showed that α5β1 integrin, TLR2 and CD36 are involved in 0.25 mM NaO-increased S. aureus internalization in bMECs. In addition, 1 mM NaO activates bMECs via the TLR2 signaling pathways (p38, JNK, and ERK1/2), which improves IIR before S. aureus invasion. Additionally, NaO (1 mM) might exert anti-inflammatory effects after bacterial internalization.

Project description:Background and Objectives: Chronic valvular inflammation associated with monocyte infiltration promotes calcific aortic valve disease (CAVD) progression. Further, innate immunity in aortic valve interstitial cells (AVICs), mediated by Toll-like receptors (TLRs), up-regulates cellular inflammatory, fibrogenic and osteogenic activities. Currently, the pro-inflammatory communication between monocytes and AVICs and the underlying mechanism are unclear. We hypothesized that monocytes up-regulate AVIC inflammatory activity. This study sought to characterize the interaction between monocytes and AVICs and to elucidate the mechanism underlying cell-to-cell communication. Methods and Results: AVICs, monocytes and co-cultures were exposed to a low concentration of TLR2 activator Pam3CSK4 (0.03 µg/ml). The TLR2 activator at this dose induced a marked increase in AVIC production of ICAM-1 and VCAM-1 only when co-cultured with monocytes. Adding conditioned medium from Pam3CSK4-treated monocytes (Pam3 CM, containing 0.1 µg/ml of Pam3CSK4) to AVIC culture (30% vol/vol; diluting Pam3CSK4 to 0.03 µg/ml) greatly increased the expression of adhesion molecules while adding conditioned medium from untreated monocytes (control CM) had no effect. Inhibition or knockdown of TLR2 in AVICs markedly reduced ICAM-1 and VCAM-1 expression induced by Pam3 CM. Further, Pam3 CM increased TLR2 levels in AVICs. Multiplex-ELISA analysis of Pam3 CM identified greater levels of TNF-α. Neutralization of TNF-α abolished the effect of Pam3 CM on AVIC TLR2 levels, resulting in marked attenuation of its potency in the induction of adhesion molecule expression. Conclusions: This study demonstrates that activated monocytes use paracrine signaling to sensitize AVICs for inflammatory responses to a low level of TLR2 activator. The mechanism of sensitization involves up-regulation of AVIC TLR2 levels by TNF-α from monocytes. Infiltrated monocytes in aortic valve tissue may exacerbate valvular inflammation by rendering AVICs hypersensitive to TLR2 activators.

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Neisseriae internalization by epithelial cells is enhanced by TLR2 stimulation.

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Neisseriae internalization by epithelial cells is enhanced by TLR2 stimulation.

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