A Lipopolysaccharide‐Deficient Mutant of<i>Neisseria meningitidis</i>Elicits Attenuated Cytokine Release by Human Macrophages and Signals via Toll‐like Receptor (TLR) 2 but Not via TLR4/MD2

Chronic infections are caused by microorganisms that display effective immune evasion mechanisms. Dendritic cell (DC)-dependent T cell-mediated adaptive immunity is one of the mechanisms that have evolved to prevent the occurrence of chronic bacterial infections. In turn, bacterial pathogens have developed strategies to evade immune recognition. In this study, we show that Gram-negative and Gram-positive bacteria differ in their ability to activate DCs and that Gram-negative bacteria are far more effective inducers of DC maturation. Moreover, we observed that only Gram-negative bacteria can induce loss of adhesive podosome structures in DCs, a response necessary for the induction of effective DC migration. We demonstrate that the ability of Gram-negative bacteria to trigger podosome turnover and induce DC migration reflects their capacity to selectively activate TLR4. Examining mice defective in TLR4 signaling, we show that this DC maturation and migration are mainly Toll/IL-1 receptor domain-containing adaptor-inducing IFNβ-dependent. Furthermore, we show that these processes depend on the production of PGs by these DCs, suggesting a direct link between TLR4-mediated signaling and arachidonic metabolism. These findings demonstrate that Gram-positive and Gram-negative bacteria profoundly differ in their capacity to activate DCs. We propose that this inability of Gram-positive bacteria to induce DC maturation and migration is part of the armamentarium necessary for avoiding the induction of an effective cellular immune response and may explain the frequent involvement of these pathogens in chronic infections.

Section: Discussionsupporting

confidence: 72%

TLR4-Mediated Podosome Loss Discriminates Gram-Negative from Gram-Positive Bacteria in Their Capacity to Induce Dendritic Cell Migration and Maturation

Helden

Dries

Oud

et al. 2009

“…Previous work from our group and others has shown that PorB interacts with HeLa cells (26,27). Although HeLa cells do not express endogenous TLR2 (28) or TLR1 (10) on their surface, a recent report describes weak levels of most TLRs mRNA (34). In agreement with these reports, TLR1 mRNA was detected by RT-PCR (P. Massari, unpublished observation), but anti-TLR2 or anti-TLR1 Abs failed to detect surface expression of these receptors in the HeLa cells used in this work.…”

Section: Discussionmentioning

confidence: 88%

Meningococcal Porin PorB Binds to TLR2 and Requires TLR1 for Signaling

Massi

Visintin

Gunawardana

et al. 2006

144

166

TLR2 plays a key role in the initiation of the cellular innate immune responses by a wide range of bacterial products. TLRs signaling, including TLR2 and its coreceptors TLR1 and TLR6, is mediated by a number of specific ligands. Although many of the TLR-mediated cell signaling pathways have been elucidated in the past few years, the molecular mechanisms that lead to cell activation are still poorly understood. In this study, we investigate the interaction of PorB from Neisseria meningitidis with TLR2 and describe the direct binding of a bacterial protein to TLR2 for the first time. Using labeled PorB, we demonstrate its binding to TLR2 both in its soluble form in vitro, and when it is over-expressed on the surface of human embryonic kidney 293 cells. We also show that TLR2-mediated binding of PorB is directly related to cellular activation. In addition, using 293 cells expressing the chimeric TLR2/TLR1 and TLR2/TLR6 complexes, we report the selectivity of PorB binding to the TLR2/TLR1 heterodimer, which is required for initiating signaling in transfected 293 cells and in murine B cells. Together, these data provide new evidence that TLR2 recognizes PorB through direct binding, and that PorB-induced cell activation is mediated by a TLR2/TLR1 complex.

“…Thus, the involvement of other TLRs in the cellular response to neisserial porins was investigated. Recent reports regarding the participation of TLR2 in response to Neisseria meningitidis (32,33) suggested that outer membrane components of meningococcus can activate immune cells by engaging TLR2. However, the specific role of porins was not determined.…”

mentioning

confidence: 99%

Cutting Edge: Immune Stimulation by Neisserial Porins Is Toll-Like Receptor 2 and MyD88 Dependent

Massi

Henneke

et al. 2002

269

212

The immunopotentiating activity of neisserial porins, the major outer membrane protein of the pathogenic Neisseria, is mediated by its ability to stimulate B cells and up-regulate the surface expression of B7-2. This ability is dependent on MyD88 and Toll-like receptor (TLR)2 expression, as demonstrated by a lack of a response by B cells from MyD88 or TLR2 knockout mice to the porins. Using previously described TLR2-dependent reporter constructs, these results were confirmed and were shown to be due to induction of NF-κB nuclear translocation. This is the first demonstration of known vaccine adjuvant to stimulate immune cells via TLR2.