Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus

Hepatitis B virus (HBV) infection can cause chronic liver disease, which is associated with increased risk of liver cirrhosis, liver failure, and liver cancer. Clearance of HBV infection requires effective HBV-specific immunity; however, the immunological mechanisms that determine the development of effective HBV-specific immunity are poorly understood. Dendritic cells (DC) play a pivotal role in the regulation of antiviral immunity. Here, we investigated the interaction between HBV surface antigen (HBsAg), the main envelope glycoprotein of HBV, and BDCA1؉ myeloid dendritic cells (mDC). Exposure of peripheral bloodderived BDCA1؉ mDC to HBsAg resulted in strong DC maturation, cytokine production, and enhanced capacity to activate antigen-specific cytotoxic T cells (CTLs). By using neutralizing antibodies, crucial roles for CD14 and Toll-like receptor 4 (TLR4) in HBsAg-mediated BDCA1 ؉ mDC maturation were identified. Concordantly, HBsAg-mediated DC maturation required fetal calf serum (FCS) or human plasma, naturally containing soluble CD14 (sCD14). Intriguingly, HBsAg-induced DC maturation was significantly reduced in umbilical cord blood plasma, which contained less sCD14 than adult plasma, indicating that sCD14 is an important host factor for recognition of HBsAg by DC and subsequent DC activation. A direct interaction between sCD14 and HBsAg was demonstrated by using enzyme-linked immunosorbent assay (ELISA). Moreover, sCD14-HBsAg complexes were detected both in vitro and in sera of HBV-infected patients. The abundance of sCD14-HBsAg complexes varied between chronic HBV disease stages and correlated with activation of BDCA1 ؉ mDC in vivo. We conclude that HBsAg activates BDCA1 ؉ DC via an sCD14-dependent mechanism. These findings provide important novel insights into the initiation of HBV-specific immunity and facilitate development of effective immunotherapeutic interventions for HBV. Hepatitis B virus (HBV) is a double-stranded DNA (dsDNA) virus that is transmitted via blood and specifically infects hepatocytes. It can cause chronic liver disease and progressive liver injury leading to increased risk of liver cirrhosis, liver failure, and liver cancer (1). The current estimated prevalence of HBV infection is 248 million individuals globally (2). Although the initiation of an effective antiviral immune response is paramount for resolving HBV infection (3), the early steps in the recognition of the virus by immune cells and the functional consequences of this interaction remain to be resolved.A pivotal role for dendritic cells (DC) is anticipated, because these cells play a central role in the orchestration of antiviral immunity due to the expression of a wide variety of different pathogen recognition receptors (PRR) and their unique capacity to initiate virus-specific cytotoxic T cell (CTL) responses (4, 5). Among the different DC subsets, BDCA1 ϩ myeloid DC (mDC) are of particular interest for HBV-specific immunity, since hepatitis B surface antigen (HBsAg)-positive mDC were detected in liver (6) an...

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Surface Antigen Activates Myeloid Dendritic Cells via a Soluble CD14-Dependent Mechanism

Montfoort

Bosch

et al. 2016

“…Upon RSV infection, the signal initiated from TLR3 and TLR4 activates the adaptor protein TRIF (7,27,30). Specifically, the RSV fusion protein can bind to TLR4, which induces the production of interleukin-1␤ (IL-1␤), IL-6, IL-8, and tumor necrosis factor alpha (TNF-␣) (38). RSV is a negative-strand, nonsegmented RNA pneumovirus.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Inhibits the TRIF-Dependent Pathway by Upregulating Sterile Alpha and Armadillo Motif Protein, Contributing to Anti-Inflammatory Effects after Respiratory Syncytial Virus Infection

Liu

Zang

Zhou

et al. 2014

Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in young children ELISA). SARM expression was reduced and TRIF expression was increased after infection with RSV. Resveratrol increased SARM expression and decreased TRIF expression after RSV infection. SARM knockdown in resveratrol-treated mice enhanced gamma interferon production, RSV-induced airway inflammation, and airway hyperresponsiveness (AHR). Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression. Resveratrol-mediated inhibition of the TRIF-dependent pathway may be dependent on SARM expression. IMPORTANCEOur study provides insights into the regulation of innate immunity in response to RSV infection. The results suggest that resveratrol-mediated alterations in SARM have therapeutic potential against RSV immunopathology caused by deregulation of the TLR-mediated immune response. Ultimately, improved insight into the complex interplay between TLR adaptor proteins and the occurrence of severe RSV infection might lead to novel therapeutic treatment strategies, such as TLR adjuvants.

“…Both of these strategies are associated with immune dysregulation and immunosuppression, which are deleterious to the control of viral infection. For example, respiratory syncytial virus, by its F protein (42), and mouse mammary tumor virus (MMTV), by its envelope glycoprotein (43), hijack the TLR4 pathway leading to the production of IL-10, a highly immunosuppressive cytokine which is involved in T-cell exhaustion and the weakening of dendritic cell function, thus contributing to the establishment of persistent viral infections, while HCV inhibits the PRR signaling pathway by blocking MyD88 and catalyzing IRF3 degradation by its proteins NS5A (44) and NS3-4A, respectively (45).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes

Planès

Haij

Leghmari

et al. 2016

In this study, we show that the HIV-1 Tat protein interacts with rapid kinetics to engage the Toll-like receptor 4 (TLR4) pathway, leading to the production of proinflammatory and anti-inflammatory cytokines. The pretreatment of human monocytes with Tat protein for 10 to 30 min suffices to irreversibly engage the activation of the TLR4 pathway, leading to the production of tumor necrosis factor alpha (TNF-␣) and interleukin-10 (IL-10), two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Therefore, this study analyzed whether the HIV-1 Tat protein is able to activate these two pathways separately or simultaneously. Using three complementary approaches, including mice deficient in the MyD88, TIRAP/MAL, or TRIF adaptor, biochemical analysis, and the use of specific small interfering RNAs (siRNAs), we demonstrated (i) that Tat was able to activate both the MyD88 and TRIF pathways, (ii) the capacity of Tat to induce TIRAP/MAL degradation, (iii) the crucial role of the MyD88 pathway in the production of Tat-induced TNF-␣ and IL-10, (iv) a reduction but not abrogation of IL-10 and TNF-␣ by Tat-stimulated macrophages from mice deficient in TIRAP/MAL, and (v) the crucial role of the TRIF pathway in Tat-induced IL-10 production. Further, we showed that downstream of the MyD88 and TRIF pathways, the Tat protein activated the protein kinase C (PKC) ␤II isoform, the mitogen-activated protein (MAP) kinases p38 and extracellular signal-regulated kinase 1/2 (ERK1/2), and NF-B in a TLR4-dependent manner. Collectively, our data show that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC, MAP kinase, and NF-B signaling to induce the production of TNF-␣ and IL-10. IMPORTANCEIn this study, we demonstrate that by recruiting the TLR4 pathway with rapid kinetics, the HIV-1 Tat protein leads to the engagement of both the MyD88 and TRIF pathways and to the activation of PKC-␤II, MAP kinase, and NF-B signaling to induce the production of TNF-␣ and IL-10, two cytokines strongly implicated in the chronic activation and dysregulation of the immune system during HIV-1 infection. Thus, it may be interesting to target Tat as a pathogenic factor early after HIV-1 infection. This could be achieved either by vaccination approaches including Tat as an immunogen in potential candidate vaccines or by developing molecules capable of neutralizing the effect of the Tat protein.