Increased Toll-like receptor 4 expression in infants with respiratory syncytial virus bronchiolitis

Gagro, Alenka; Tominac, Mirna; Kršulović-Hrešić, Vilka; Baće, Ana; Matić, M; Draženović, Vladimir; Mlinarić‐Galinović, Gordana; Kosor, Ela; Gotovac, Katja; Bolanča, Ivan; Batinica, Stipe; Rabatić, Sabina

doi:10.1111/j.1365-2249.2004.02364.x

Cited by 71 publications

(53 citation statements)

References 27 publications

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“…In contrast, TLR4 expression is increased (Gagro et al, 2004;Kajikawa et al, 2005;Chang et al, 2006;Awasthi et al, 2008). The reduction in the amounts of SP-A and simultaneous increase in TLR4 expression corroborates well with the clinical condition of patients having fulminant infection and inflammation, respectively.…”

Section: Introductionsupporting

confidence: 76%

A Toll-Like Receptor-4-Interacting Surfactant Protein-A-Derived Peptide Suppresses Tumor Necrosis Factor-α Release from Mouse JAWS II Dendritic Cells

Awasthi¹,

Brown²,

King³

et al. 2010

J Pharmacol Exp Ther

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Surfactant protein-A (SP-A) and Toll-like receptor-4 (TLR4) proteins are recognized as pathogen-recognition receptors. An exaggerated activation of TLR4 induces inflammatory response, whereas SP-A protein down-regulates inflammation. We hypothesized that SP-A-TLR4 interaction may lead to inhibition of inflammation. In this study, we investigated interaction between native baboon lung SP-A and baboon and human TLR4-MD2 proteins by coimmunoprecipitation/immunoblotting and microwell-based methods. The interaction between SP-A and TLR4-MD2 proteins was then analyzed using a bioinformatics approach. In the in silico model of SP-A-TLR4 -MD2 complex, we identified potential binding regions and amino acids at the interface of SP-A-TLR4. Using this information, we synthesized a library of human SP-A-derived peptides that contained interacting amino acids. Next, we tested whether the TLR4-interacting SP-A peptides would suppress inflammatory cytokines. The peptides were screened for any changes in the tumor necrosis factor-␣ (TNF-␣) response against lipopolysaccharide (LPS) stimuli in the mouse JAWS II dendritic cell line. Different approaches used in this study suggested binding between SP-A and TLR4-MD2 proteins. In cells pretreated with peptides, three of seven peptides increased TNF-␣ production against LPS. However, two of these peptides (SPA4: GDFRYSDGTPVNYTNWYRGE and SPA5: YVGLTEGPSPGDFRYSDFTP) decreased the TNF-␣ production in LPS-challenged JAWS II dendritic cells; SPA4 peptide showed more pronounced inhibitory effect than SPA5 peptide. In conclusion, we identify a human SP-A-derived peptide (SPA4 peptide) that interacts with TLR4-MD2 protein and inhibits the LPS-stimulated release of TNF-␣ in JAWS II dendritic cells.

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Section: Introductionsupporting

confidence: 76%

A Toll-Like Receptor-4-Interacting Surfactant Protein-A-Derived Peptide Suppresses Tumor Necrosis Factor-α Release from Mouse JAWS II Dendritic Cells

Awasthi¹,

Brown²,

King³

et al. 2010

J Pharmacol Exp Ther

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“…Recently, RSV was shown to upregulate TLR4 and the responsiveness to lipopolysaccharide in human epithelial cells (34). Elevated levels of TLR4 expression were also detected in monocytes from infants with respiratory syncytial virus bronchiolitis (12). While it is likely that both A549 and MRC-5 cells express a repertoire of various TLRs and adapters, expression of TLR4 has only been detected in A549 cells (32,34).…”

Section: Discussionmentioning

confidence: 99%

Differential Role for TLR3 in Respiratory Syncytial Virus-Induced Chemokine Expression

Rudd

Burstein

Duckett

et al. 2005

J Virol

247

203

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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in young infantsworldwide. Previous studies have reported that the induction of interleukin-8/CXCL8 and RANTES/CCL5 correlates with disease severity in humans. The production of these chemokines is elicited by viral replication and is NF-B dependent. RSV, a negative-sense single-stranded RNA virus, requires full-length positive-sense RNA for synthesis of new viral RNA. The aim of our studies was to investigate whether active viral replication by RSV could evoke chemokine production through TLR3-mediated signaling pathways. In TLR3-transfected HEK 293 cells, live RSV preferentially activated chemokines in both a time-and dose-dependent manner compared to vector controls. RSV was also shown to upregulate TLR3 in human lung fibroblasts and epithelial cells (MRC-5 and A549). Targeting the expression of TLR3 with small interfering RNA decreased synthesis of IP-10/CXCL10 and CCL5 but did not significantly reduce levels of CXCL8. Blocking the expression of the adapter protein MyD88 established a role for MyD88 in CXCL8 production, whereas CCL5 synthesis was found to be MyD88 independent. Production of CCL5 by RSV was induced directly through TLR3 signaling pathways and did not require interferon (IFN) signaling through the IFN-␣/␤ receptor. TLR3 did not affect viral replication, since equivalent viral loads were recovered from RSV-infected cells despite altered TLR3 expression. Taken together, our studies indicate that TLR3 mediates inflammatory cytokine and chemokine production in RSV-infected epithelial cells.

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“…The fusion (F) protein binds TLR4 (89), upregulating its surface expression and sensitizing airway epithelial cells to endotoxin (109). The frequency of TLR4 ϩ monocytes is increased in the peripheral blood of some infants with RSV bronchiolitis (46), but the role of TLR4 in vivo is unclear (41).…”

Section: Viral Interactions Affecting Disease Pathogenesis: the Innatmentioning

confidence: 99%

Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

2005

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Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease typically coincides with the development of specific T- and B-cell responses, which seem, in large part, to be responsible for disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. Under different circumstances, specific mediators and T-cell subsets and antibody-antigen immune complex deposition are incriminated as major factors in disease. Animal models of immune enhancement permit a deep understanding of the role of specific immune responses in RSV disease, assist in vaccine design, and indicate which immunomodulatory therapy might be beneficial to children with bronchiolitis

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Increased Toll-like receptor 4 expression in infants with respiratory syncytial virus bronchiolitis

Cited by 71 publications

References 27 publications

A Toll-Like Receptor-4-Interacting Surfactant Protein-A-Derived Peptide Suppresses Tumor Necrosis Factor-α Release from Mouse JAWS II Dendritic Cells

A Toll-Like Receptor-4-Interacting Surfactant Protein-A-Derived Peptide Suppresses Tumor Necrosis Factor-α Release from Mouse JAWS II Dendritic Cells

Differential Role for TLR3 in Respiratory Syncytial Virus-Induced Chemokine Expression

Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

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