Toll-Like Receptor 2 (TLR2) Plays a Major Role in Innate Resistance in the Lung against Murine Mycoplasma

Love, Wees; Dobbs, Nicole; Tabor, Leslie; Simecka, Jerry W.

doi:10.1371/journal.pone.0010739

Cited by 37 publications

(29 citation statements)

References 46 publications

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“…In addition other triacylated lipoproteins signal through TLR 1 and 2 but are independent of TLR6 [145]. As expected by these data, an in vivo model of pulmonary mycoplasma infection is heavily reliant on TLR2 [146].…”

Section: Cell Wall Free Bacteriasupporting

confidence: 65%

Pathogen Associated Molecular Patterns, Pattern Recognition Receptors and Pediatric Sepsis

Doughty¹

2011

TOINFJ

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Abstract:The mortality of septic shock in the pediatric population has improved over the last 2 decades with better supportive care however it still remains unacceptably high. Exaggerated inflammatory responses early in septic shock have been associated with poor outcomes. Regulation of the magnitude of the early inflammatory response is not well understood. The earliest aspect of the inflammatory response to pathogens is the innate immune response which is important to pathogen containment. Elements of the innate immune system activate the adaptive immune system in an antigen-specific way which leads to pathogen-specific protection and lasting immunologic memory to prevent subsequent infection. Pattern recognition receptors (PRRs) are evolutionarily conserved receptors on multiple types of innate immune cells and are capable of responding to highly conserved components of pathogens called pathogen associated molecular patterns (PAMPs). Numerous PRRs have been defined and are present on the cell surface as well as in the cytosol. These receptors fall into several classes called Toll-like receptors which are expressed on the cell surface or on the endosomal plasma membrane, C type lectin receptors and scavenger receptors which are only present on the cell surface. Other PRRs are present in the cytosol and including NOD-like receptors which can aggregate to form inflammasomes and RIG1 like receptors. Pathogenic microorganisms are extremely diverse however there are some common patterns repeated in components of structures such as the cell wall. PRRs can respond to PAMPs comprised of proteins, lipids, and carbohydrates, DNA and RNA. Numerous PAMPs have been described for many classes of pathogenic microorganisms such as Gram negative bacteria, Gram positive bacteria, viruses, fungi, and protozoa. The interactions between PRRs and PAMPs comprise the earliest immune responses to foreign substances and are critical for pathogen containment and amplification of the full repertoire of the immune response. There are developmental differences in the immune systems of infants and children compared to adults. The innate immune system matures much earlier than the adaptive immune response and as a result infants and young children may be more reliant on their innate immune system. For this reason it important to fully understand the key elements of the innate immune response including the many categories of PRRs and their cognate PAMPs. As these interactions are very early in the immune response, they are particularly relevant targets for therapeutic intervention. Below is a discussion of the major classes of PRRs, their expression, ligands, and signaling pathways as well as the major classes of PAMPs that activate them.

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Section: Cell Wall Free Bacteriasupporting

confidence: 65%

Pathogen Associated Molecular Patterns, Pattern Recognition Receptors and Pediatric Sepsis

Doughty¹

2011

TOINFJ

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“…However, the antagonistic relationship between M. or C. pneumoniae and influenza virus infection (and the lack of association of B. pertussis with influenza virus infection) could be explained by the innate immune pathways activated by the detection of each of these pathogens, in particular those triggered by Toll-like receptor (TLR)-mediated recognition. Specifically, while the innate immune response to B. pertussis is primarily TLR-4-mediated [16], the responses to both M. pneumoniae [17, 18] and C. pneumoniae [19] are driven in large part by TLR-2-mediated pathways. This distinction is important in the context of our analysis, as proper clearance of influenza is also known to rely heavily on TLR-2 recognition [20, 21].…”

Section: Discussionmentioning

confidence: 99%

Estimating the prevalence of coinfection with influenza virus and the atypical bacteria Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae

Mina

Burke

Klugman

2014

Eur J Clin Microbiol Infect Dis

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Coinfections with common bacterial respiratory pathogens and influenza viruses are well-known causes of disease, often via synergistic interactions between the influenza virus, the bacteria, and the human host. However, relatively little is known about interactions between atypical bacteria and influenza viruses. A recent report by Reinton et al. explored this issue by analyzing data from 3,661 patients seeking medical assistance for the presence of Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Bordetella pertussis, as well as influenza A or B virus in nasal swab specimens. The report, however, did not accurately assess the epidemiologic interactions of these pathogens. We aimed to describe the interactions between these bacterial species and influenza infections. Strong and highly statistically significant antagonistic interspecies interactions were detected between C. pneumoniae and influenza virus [odds ratio (OR): 0.09; p<0.0001) and M. pneumoniae and influenza virus infections (OR: 0.29; p=0.003). No association was detected between B. pertussis and influenza infection (p=0.34), contrary to the initial report, and coinfection was not detected at a higher-than-by-chance frequency within the population. Further support of these results is supplied by the analysis of two earlier investigations reporting data on influenza virus and these atypical bacteria. Our results supplement the large body of literature regarding interactions between influenza virus and typical respiratory pathogens, providing a fuller picture of the spectrum of interactions between influenza viruses and respiratory bacteria. Further, we demonstrate the importance of choosing the most appropriate reference populations for the analysis being performed and describe the pitfalls that may occur when care is not taken in this regard.

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“…Furthermore, while both TLR4 and TLR7 can be coupled to Myd88, the inability of other TLR agonists to induce histamine that are also coupled via this pathway might suggest histamine production is mediated via non-classical pathways. We were surprised to observe that the TLR2 agonists FSL-1 and PGN did not induce histamine, since is has been recently shown that TLR2 is critical for protection against Mycoplasma pulmonis in mice [28] and this organism was used in the study connecting neutrophils to histamine production [14]. Furthermore, systemic injection with lipid A, a TLR4 agonist, or FSL-1, a TLR2/6 agonist, has been shown to elevate the relative HDC activity in the lungs of mice [29], although the specific cell sources were not identified in that study.…”

Section: Discussionmentioning

confidence: 99%

TLR-induced activation of neutrophils promotes histamine production via a PI3 kinase dependent mechanism

2011

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Histamine is a bioactive amine that exerts immunomodulatory functions, including many allergic symptoms. It is preformed and stored in mast cells and basophils but recent evidence suggests that other cell types produce histamine in an inducible fashion. During infection, it has been suggested that neutrophils may produce histamine. We also observed that histamine is released in a neutrophil-mediated LPS-induced model of acute lung injury. Therefore, we sought to examine whether innate signals promote histamine production by neutrophils. Bone marrow-derived neutrophils stimulated with a range of TLR agonists secreted histamine in response to LPS or R837, suggesting TLR4 or TLR7 are important. LPS-driven histamine was enhanced by coculture with GM-CSF and led to a transient release of histamine that peaked at 8 hours post stimulation. This was dependent upon de novo synthesis of histamine, since cells derived from histidine decarboxylase (HDC) deficient mice were unable to produce histamine but did generate reactive oxygen species upon stimulation. Using pharmacological inhibitors, we show that histamine production requires PI3 kinase, which has been shown to regulate other neutrophil functions, including activation and selective granule release. However, unlike mast cells, HDC deficiency did not alter the granule structure of neutrophils, suggesting that histamine does not participate in granule integrity in these cells. Consequently, our findings establish that neutrophils generate histamine in response to a select panel of innate immune triggers and that this might contribute to acute lung injury responses.

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Toll-Like Receptor 2 (TLR2) Plays a Major Role in Innate Resistance in the Lung against Murine Mycoplasma

Cited by 37 publications

References 46 publications

Pathogen Associated Molecular Patterns, Pattern Recognition Receptors and Pediatric Sepsis

Pathogen Associated Molecular Patterns, Pattern Recognition Receptors and Pediatric Sepsis

Estimating the prevalence of coinfection with influenza virus and the atypical bacteria Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae

TLR-induced activation of neutrophils promotes histamine production via a PI3 kinase dependent mechanism

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