Effects of functional Toll‐like receptor‐4 mutations on the immune response to human and experimental sepsis

Feterowski, Carolin; Emmanuilidis, Klaus; Miethke, Thomas; Gerauer, Klaus; Rump, Martina; Ulm, Kurt; Holzmann, Bernhard; Weighardt, Heike

doi:10.1046/j.1365-2567.2003.01674.x

Cited by 109 publications

(72 citation statements)

References 20 publications

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“…Our genetic findings in heterozygous individuals support a model in which alleles 896G and 1196T act in a dominant fashion with respect to the wild-type alleles in their association with resistance to LD. Similarly, previous genetic studies (19)(20)(21)(22)(23)(32)(33)(34)(35) with these TLR4 SNPs suggest that altered susceptibility to infection is found in heterozygous individuals.…”

Section: Resultssupporting

confidence: 56%

“…Previous association studies (19)(20)(21)(22)(23)(32)(33)(34)(35) with SNPs A896G and C1196T have shown either no effect or an association with increased risk from infection. The conditions that showed an association with increased infectious risk include mortality from systemic inflammatory response syndrome, severe acute infections (e.g., pneumonia, pyelonephritis, peritonitis, diverticulitis, and sepsis), septic shock, Gram-negative bacteremia, and respiratory syncytial virus bronchiolitis (19)(20)(21)(22)(23).…”

Section: Resultsmentioning

confidence: 90%

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Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease

Hawn

Verbon

Janer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

154

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The immunogenetic factors that influence susceptibility to pneumonia are poorly understood. Recent studies suggest an association of toll-like receptor 4 (TLR4) polymorphisms with increased susceptibility to some infections. Here, we examined whether polymorphisms in TLR4 influence susceptibility to Legionnaires' disease (LD) by using a case-control study to compare the allele frequencies of two SNPs (A896G and C1196T). Cases (n ‫؍‬ 108) were obtained from a LD outbreak in The Netherlands in 1999. Controls were exposed at the same outbreak, did not develop pneumonia, and were either unmatched (n ‫؍‬ 421) or matched (n ‫؍‬ 89) to patients for age, sex, and geographic residence. Allele 896G was associated with LD susceptibility with a frequency of 6.5% in the combined control group (matched and unmatched) vs. Although previous studies suggest that these TLR4 SNPs are associated with an increased risk of infection, this study demonstrates an association with resistance. This protective association illustrates that an innate immune receptor can mediate either beneficial or deleterious inflammatory responses and that these outcomes vary with different pathogens.genetic markers ͉ immunity ͉ inflammation A lthough lower respiratory tract infections are the most common cause of death due to infectious disease in the United States, the influence of host immunogenetic factors on human susceptibility to pneumonia is poorly understood (1). Toll-like receptors (TLRs) constitute a family of transmembrane proteins that differentially recognize pathogen-associated molecular patterns through an extracellular domain and initiate inflammatory signaling pathways through an intracellular domain (2-5). Because of their central role in regulation of the immune response to pathogens, TLRs are excellent candidate genes for genetic susceptibility studies (6). Legionella pneumophila, described in 1976 as the agent of Legionnaires' disease (LD), is a flagellated Gram-negative bacterium that causes from 1% to 30% of cases of community-acquired pneumonia (7-11). In vitro studies indicate that Legionella is recognized by several TLRs, including TLR2, TLR4, and TLR5 (12-15). We recently demonstrated (13,16,17) that TLR5 recognizes bacterial flagellin and that a common dominant TLR5 stop codon variant is associated with susceptibility to LD. It is not known whether polymorphisms in other TLRs influence human susceptibility to LD. TLR4, the receptor for lipopolysaccharide (LPS), has two common polymorphisms (A896G and C1196T) that are associated with LPS hyporesponsiveness in heterozygous individuals in response to inhaled endotoxin (18). Although several small genetic studies suggest a possible association of these SNPs in heterozygous individuals with an increased risk of some bacterial infections, the influence of these SNPs on human infections remains poorly understood and controversial (19)(20)(21)(22)(23). Furthermore, inflammatory responses of heterozygous individuals are not uniformly impaired, and the result appears to depend on the mea...

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Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 90%

Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease

Hawn

Verbon

Janer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

154

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“…Because TLR4 primarily recognizes LPS of Gram-negative bacteria (12) and expression levels correlate with LPS susceptibility in mice (36), the entire expression pattern in neonatal sepsis might reflect the fact that Gram-positive microorganisms are responsible for the majority of cases. In experimental endotoxemia and adults with Gram-positive as well as Gram-negative sepsis, TLR4 expression on monocytes did not change and decreased on granulocytes in experimental endotoxemia (16,17).…”

Section: Discussionmentioning

confidence: 99%

Expression of Toll-Like Receptors in Neonatal Sepsis

et al. 2005

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Despite recent identification of specific pattern recognition receptors (PRR) for distinct microbial structures, data indicating their relevance in human infectious diseases are limited. We determined the expression levels of the Toll-like receptor (TLR)2 and TLR4 by flow cytometry on granulocytes and monocytes of healthy neonates compared with healthy adults. The basal expression of TLR2 was only slightly lower in neonatal phagocytes, whereas no differences could be detected for TLR4. Analyzing neonates with sepsis, we found an impressive up-regulation of TLR2 on blood phagocytes already at initial presentation of symptoms. Comparison with C-reactive protein, IL-8, and IL-6 suggested that TLR2 expression on monocytes is comparably valuable as an early sepsis marker. Neonatal sepsis remains a leading cause of neonatal morbidity and mortality despite recent advances in neonatal intensive care (1,2). Although several deficiencies in the neonatal immune system have been revealed, including qualitative and quantitative deficits in phagocytes and humoral components (3-8), they may only partly explain the overwhelming nature of neonatal sepsis. The key for differences in the course of neonatal and adult sepsis might be molecular mechanisms involved in the initiation process of systemic inflammatory response syndromes, i.e. the activation of innate immune cells through invading microbes. In the innate immune system, many types of receptors participate in microbe detection. An exciting discovery was the finding that host organisms have developed a set of specific receptors (PRR) for the recognition of highly conserved and essential molecular structures of microbes [pathogen-associated molecular patterns, PAMP)] (9). TLR2 was identified as a receptor for Gram-positive peptidoglycan and bacterial lipopeptides (10,11), whereas TLR4 is part of a receptor complex recognizing Gram-negative bacterial LPS and is required for LPS signal transduction (12). Both finally trigger inflammatory responses through an IL-1 receptor-like pathway that uses an adapter protein (MyD88), IL-1 receptor associated kinase (IRAK), and tumor necrosis factor receptor-associated factor (TRAF)-6 signaling to activate nuclear factot (NF)B and mitogen-activated protein kinase dependent signaling pathways (13). They initiate distinct genetic programs, including the induction of a subset of chemokines like macrophage inflammatory protein (MIP)-1␣, MIP-1␤, and RANTES (regulated upon activation, normal t-cell expressed and secreted) mediated by TLR2 and TLR4, whereas IP-10 is preferentially induced by TLR4 and IL-8 preferentially by TLR2 (14). The model of microbial recognition has now evolved into one in which immune cells use multiple PRR to detect several features of a microbe simultaneously. The signal pattern transduced by the combination of different innate immune receptors may be the key to the kind of immune response that is elicited (15).Except for in vitro experiments or murine models, data regarding the expression and in vivo relevance of TLR in ...

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“…Therefore, it is tempting to postulate that increased expression of TLRs would have a beneficial effect in trauma patients. Polymorphism of TLRs was one of the factors that increased the susceptibility to infections caused by particular bacteria, but in patients with mixed severe infections did not show any significant effect on their course and outcome [39]. In some experimental studies a lack of TLRs increased the susceptibility to infections in mice [40] and caused disorders in inflammatory mediator secretion as well as disorders in phagocytosis and antigen presentation [41][42][43].…”

Section: Tlr-dependent Anti-bacterial Responsementioning

confidence: 99%

Alterations in innate antibacterial response after immunomodulatory nutrition

Słotwiński¹,

Słotwińska²,

Kędziora³

et al. 2012

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Septic infections in malnourished surgical patients show the highest morbidity and mortality rate. The attempt to correct postoperative immune and nutritional disorders by introducing immune-enhancing nutrition (immunonutrition) is a promising way of improving outcome, but as yet little is known about the mechanisms of correcting an extensive postoperative inflammatory response (systemic inflammatory response syndrome [SIRS]) to a massive infection using this type of nutrition. A significant role in the innate antibacterial and inflammatory response is played by Toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns (PAMPs). The regulatory impact of immunonutrition on TLR expression in surgical septic patients seems to be a new research direction. In this paper special emphasis was put on clinical trials and the research results for the TLR-dependent immune response and anti-bacterial/anti-inflammatory response applying immu nomo dulatory nutrition with increased concentrations of glutamine and unsaturated fatty acids. StreszczenieZakażenia septyczne w grupie niedożywionych pacjentów chirurgicznych obarczone są najwyższym wskaźnikiem chorobowości i śmiertelności. Korekcja pooperacyjnych zaburzeń odporności i niedożywienia poprzez żywienie immunomodulujące jest obiecującą metodą uzyskania lepszych wyników leczenia, ale nadal niewiele wiadomo o mechanizmach regulacji zwiększonej pooperacyjnej odpowiedzi zapalnej (systemic inflammatory response syndrome -SIRS) na masywne zakażenie za pomocą tego typu terapii. Istotne znaczenie w regulacji wrodzonej odpowiedzi przeciwbakteryjnej i przeciwzapalnej mają receptory TLRs (Toll-like receptors), rozpoznające związane z patogenami wzory molekularne (pathogen-associated molecular patterns -PAMPs). Ocena regulacyjnego wpływu żywienia immunomodulacyjnego na ekspresję receptorów TLR u septycznych pacjentów chirurgicznych jest nowym kierunkiem badań naukowych. W przedstawionej pracy szczególną uwagę zwrócono na wyniki badań klinicznych i eksperymentalnych dotyczące regulacji zależnej od TLRs odpowiedzi przeciwbakteryjnej/przeciwzapalnej za pomocą żywienia immunomodulacyjnego, zawierającego zwiększone stężenia glutaminy i nienasyconych kwasów tłuszczowych.

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Effects of functional Toll‐like receptor‐4 mutations on the immune response to human and experimental sepsis

Cited by 109 publications

References 20 publications

Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease

Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires' disease

Expression of Toll-Like Receptors in Neonatal Sepsis

Alterations in innate antibacterial response after immunomodulatory nutrition

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