Association of TLR4 Polymorphisms with Symptomatic Respiratory Syncytial Virus Infection in High-Risk Infants and Young Children

Awomoyi, Agnes A.; Rallabhandi, Prasad; Pollin, Toni I.; Lorenz, Eva; Sztein, Marcelo B.; Boukhvalova, Marina S.; Hemming, Val G.; Blanco, Jorge C. G.; Vogel, Stefanie N.

doi:10.4049/jimmunol.179.5.3171

Cited by 166 publications

(153 citation statements)

References 56 publications

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“…[5][6][7] Because we could not demonstrate such a difference for dengue, the correlation between the TLR4 polymorphism and RSV infection is likely to be virus specific. Interestingly, our screening of TLR4 polymorphisms showed that the distribution of the TLR4 polymorphism has a high frequency of cosegregated 299/399 in all analyzed groups.…”

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confidence: 86%

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Toll-Like Receptor 4 Polymorphisms in Dengue Virus–Infected Children

Djamiatun

Ferwerda²,

Netea³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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Abstract. Differential viral recognition by cells bearing Toll-like receptor 4 (TLR4) polymorphisms Asp299Gly and Thr399Ile may influence susceptibility and severity of dengue virus infection. In central Java, Indonesia, we investigated 201 children with dengue hemorrhagic fever (DHF) and 179 healthy controls. Patients and controls were mostly ethnic Javanese. A nearly complete cosegregation of the two mutations was observed. The TLR4 299/399 genotype was found in five patients and four controls. Prevalence of the TLR4 299/399 genotype did not differ significantly between controls and DHF patients or between patients with different severities of DHF. Also, vascular leakage in patients with different TLR4 genotypes did not differ. Thus, the 299/399 TLR4 haplotype has only minor influence on susceptibility and severity of complicated dengue virus infection.

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confidence: 86%

“…3 , 4 Children who have the Toll-like receptor 4 (TLR4) polymorphisms Asp299Gly and Thr399Ile were more susceptible to respiratory syncytial virus (RSV), a flavivirus similar to dengue virus. [5][6][7] Therefore, we assessed in children with DHF to see whether these TLR4 polymorphisms influenced susceptibility to and severity of dengue virus infections.…”

mentioning

confidence: 99%

Toll-Like Receptor 4 Polymorphisms in Dengue Virus–Infected Children

Djamiatun

Ferwerda²,

Netea³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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“…Charge variation at a single residue can alter the response to lipid IV A stimulation. Single nucleotide polymorphisms at TLR4 residues 299 and 399 reportedly decrease the proinflammatory response to LPS stimulation (20). Because these residues do not directly affect recep-tor dimerization (supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

MD-2 Residues Tyrosine 42, Arginine 69, Aspartic Acid 122, and Leucine 125 Provide Species Specificity for Lipid IVA

Meng

Drolet

Monks

et al. 2010

Journal of Biological Chemistry

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Lipopolysaccharide (LPS) activates the innate immune response through the Toll-like receptor 4 (TLR4)⅐MD-2 complex. A synthetic lipid A precursor, lipid IV A , induces an innate immune response in mice but not in humans. Both TLR4 and MD-2 are required for the agonist activity of lipid IV A in mice, with TLR4 interacting through specific surface charges at the dimerization interface. In this study, we used site-directed mutagenesis to identify the MD-2 residues that determine lipid IV A species specificity. A single mutation of murine MD-2 at the hydrophobic pocket entrance, E122K, substantially reduced the response to lipid IV A . Combining the murine MD-2 E122K with the murine TLR4 K367E/S386K/R434Q mutations completely abolished the response to lipid IV A , effectively converting the murine cellular response to a human-like response. In human cells, however, simultaneous mutations of K122E, K125L, Y41F, and R69G on human MD-2 were required to promote a response to lipid IV A . Combining the human MD-2 quadruple mutations with the human TLR4 E369K/Q436R mutations completely converted the human MD-2/human TLR4 receptor to a murinelike receptor. Because MD-2 residues 122 and 125 reside at the dimerization interface near the pocket entrance, surface charge differences here directly affect receptor dimerization. In comparison, residues 42 and 69 reside at the MD-2/TLR4 interaction surface opposite the dimerization interface. Surface charge differences there likely affect the binding angle and/or rigidity between MD-2 and TLR4, exerting an indirect influence on receptor dimerization and activation. Thus, surface charge differences at the two MD-2/TLR4 interfaces determine the species-specific activation of lipid IV A .Lipopolysaccharide (LPS), also known as endotoxin, activates the innate immune response during Gram-negative bacterial infection. Lipid A, the active component of LPS, anchors LPS to the outer leaflet of the outer membrane of Gram-negative bacteria. When bacteria divide or die, LPS released into local tissue or the circulation can trigger innate immune recognition (1). Lipid A from most species is highly proinflammatory, although certain lipid A molecules and precursors lack stimulatory power. The synthetic precursor of Escherichia coli lipid A, tetraacylated lipid IV A (2) (compound 406), is an agonist in murine cells and a partial agonist in equine cells but is an antagonist in human cells (3).The Toll-like receptor 4 (TLR4) 2 and MD-2 complex constitute the essential components of a receptor system for LPS (4, 5). CD14, initially believed to be the LPS receptor, is an enhancing component of the LPS receptor (6). The lack of a transmembrane or an intracellular signaling domain led to speculation about an additional LPS receptor component that actually transduces the LPS signal. TLR4 was identified as the signaling component of the LPS receptor, based on positional cloning in mice that fail to respond to LPS (4, 7) and on the finding that TLR4 knock-out cells did not respond to LPS (8). The co-recept...

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“…Previous genetic studies have demonstrated a significant association between the inherited polymorphisms in several immunological and surfactant protein genes and the incidence of severe viral infection and level of infection-related morbidity among preterm infants [50,51]. Also, pre-existing impairments in lung function have also been attributed to increased susceptibility to severe viral infection and infection-related morbidity among preterm infants, particularly during early life [52–54].…”

Section: Viral Infection Requiring Readmission In Early Lifementioning

confidence: 99%

The impact of respiratory viruses on lung health after preterm birth

Townsi

Laing

Hall

et al. 2018

European Clinical Respiratory Journal

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Children born preterm, less than 37 weeks’ gestation, are at increased risk of viral respiratory infections and associated complications both during their initial birth hospitalisation and in their first years following discharge. This increased burden of viral respiratory infections is likely to have long term implications for lung health and function in individuals born preterm, particularly those with bronchopulmonary dysplasia. Several hypotheses have been put forward to explain the association between early life viral respiratory infection and development of suboptimal lung health and function later in life following preterm birth. Although preterm infants with diminished lung function, particularly small airways, might be particularly susceptible to asthma and wheezing disorders following viral infection, there is evidence that respiratory viruses can activate number of inflammatory and airway re-modelling pathways. Therefore, the aim of this review is to highlight the perinatal and early life risk factors that may contribute to increased susceptibility to viral respiratory infections among preterm infants during early life and to understand how respiratory viral infection may influence the development of abnormal lung health and function later in life.

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Association of TLR4 Polymorphisms with Symptomatic Respiratory Syncytial Virus Infection in High-Risk Infants and Young Children

Cited by 166 publications

References 56 publications

Toll-Like Receptor 4 Polymorphisms in Dengue Virus–Infected Children

Toll-Like Receptor 4 Polymorphisms in Dengue Virus–Infected Children

MD-2 Residues Tyrosine 42, Arginine 69, Aspartic Acid 122, and Leucine 125 Provide Species Specificity for Lipid IVA

The impact of respiratory viruses on lung health after preterm birth

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