Priming Th1 Immunity to Viral Core Particles Is Facilitated by Trace Amounts of RNA Bound to Its Arginine-Rich Domain

Riedl, Petra; Stober, Detlef; C, Oehninger; Melber, Karl; Reimann, Jörg; Schirmbeck, Reinhold

doi:10.4049/jimmunol.168.10.4951

Cited by 93 publications

(73 citation statements)

References 51 publications

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“…On the other hand, mRNA stabilized by association to a cationic component like the natural peptide protamine can mature DC. Similar results were recently described by Riedl et al [33], who showed that minute amounts of prokaryotic or eukaryotic RNA molecules associated with the argininerich tail of the self-assembling hepatitis core protein have an adjuvant effect mediated through IL-12 release by DC and resulting in the skewing of the immune response against the hepatitis B core antigen (HBcAg) toward a Th1 type. In this report, we show that RNA molecules protected against RNase-mediated degradation either by association with a cationic peptide (trans-protection) or through a phosphorothioate backbone (cis-protection) are very potent immunostimulating molecules.…”

Section: Introductionsupporting

confidence: 87%

“…Surprisingly, the anti-g -Gal humoral immune response triggered by phosphorothioate RNA is weak and reveals a Th2 type of immunity (production of IgG1 antibodies). On the contrary, as reported previously, CpG DNA, transstabilized RNA (not shown, and Riedl et al [33]) and poly I:C (double-stranded RNA) trigger a Th1 type of response (IgG2a antibodies are dominant).…”

Section: Immunostimulating Capacities Of Rna In Vivosupporting

confidence: 72%

“…The immunostimulating capacity of mRNA associated with a cationic peptide was recently addressed by Riedl et al [33]. In that work, the authors show that nanogram amounts of bacterial or eukaryotic RNA, bound to native HBcAg particles through the C-terminal arginine-rich domain, facilitate priming of Th1 immunity.…”

Section: Discussionmentioning

confidence: 99%

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Immunostimulating capacities of stabilized RNA molecules

Scheel

Braedel²,

Probst³

et al. 2004

Eur J Immunol

125

110

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Since direct injection of naked mRNA induces an immune response, we tested the capacity of RNA to signal danger. We show here that mRNA molecules that are protected from immediate degradation either through interaction with cationic proteins (trans protection) or through chemical modification of the phosphodiester backbone (phosphorothioate RNA; cis protection) act as sequence-independent danger signals on mouse DC. As opposed to CpG DNA, the cis-stabilized RNA is degraded in a few minutes, does not activate B cells and, in contrast to double-stranded RNA, requires MyD88 for activation of the DC. We postulate that phosphorothioate RNA, which mimics trans-stabilized RNA, is a new PAMP.

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Section: Introductionsupporting

confidence: 87%

Section: Immunostimulating Capacities Of Rna In Vivosupporting

confidence: 72%

See 1 more Smart Citation

Immunostimulating capacities of stabilized RNA molecules

Scheel

Braedel²,

Probst³

et al. 2004

Eur J Immunol

125

110

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“…Furthermore, particle-incorporated RNA has 1000-fold higher potency as a Th1-inducing adjuvant than free RNA mixed to a protein antigen. 30 The HBV has been detected in many different tissues apart from hepatocytes. 1 Therefore, we considered that the nasal route would be a very efficient route to induce immunity against the 183 amino acid HBcAg nucleoprotein.…”

Section: Introductionmentioning

confidence: 99%

Development of a nasal vaccine for chronic hepatitis B infection that uses the ability of hepatitis B core antigen to stimulate a strong Th1 response against hepatitis B surface antigen

et al. 2004

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SummaryThere are estimated to be 350 million chronic carriers of hepatitis B infection worldwide. Patients with chronic hepatitis B are at risk of liver cirrhosis with associated mortality because of hepatocellular carcinoma and other complications. An important goal, therefore, is the development of an effective therapeutic vaccine against chronic hepatitis B virus (HBV). A major barrier to the development of such a vaccine is the impaired immune response to HBV antigens observed in the T cells of affected patients. One strategy to overcome these barriers is to activate mucosal T cells through the use of nasal vaccination because this may overcome the systemic immune downregulation that results from HBV infection. In addition, it may be beneficial to present additional HBV epitopes beyond those contained in the traditional hepatitis B surface antigen (HbsAg) vaccine, for example, by using the hepatitis B core antigen (HBcAg). This is advantageous because HBcAg has a unique ability to act as a potent Th1 adjuvant to HbsAg, while also serving as an immunogenic target. In this study we describe the effect of coadministration of HBsAg and HBcAg as part of a strategy to develop a more potent and effective HBV therapeutic vaccine.

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“…Elimination of the C terminus of the HBc in the HBc⌬ particles drastically reduced the Th1-biased immunogenicity of the HBc (32). This finding can be explained by the presence of CpG-like sequences in the bacterial RNA, which is packaged within the full-length HBc-derived particles.…”

Section: Discussionmentioning

confidence: 93%

Construction and Immunological Evaluation of Multivalent Hepatitis B Virus (HBV) Core Virus-Like Particles Carrying HBV and HCV Epitopes

Sominskaya

Skrastiņa

Dislers

et al. 2010

Clin Vaccine Immunol

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A multivalent vaccine candidate against hepatitis B virus (HBV) and hepatitis C virus (HCV) infections was constructed on the basis of HBV core (HBc) virus-like particles (VLPs) as carriers. Chimeric VLPs that carried a virus-neutralizing HBV pre-S1 epitope corresponding to amino acids (aa) 20 to 47 in the major immunodominant region (MIR) and a highly conserved N-terminal HCV core epitope corresponding to aa 1 to 60 at the C terminus of the truncated HBc⌬ protein (N-terminal aa 1 to 144 of full-length HBc) were produced in Escherichia coli cells and examined for their antigenicity and immunogenicity. The presence of two different foreign epitopes within the HBc molecule did not interfere with its VLP-forming ability, with the HBV pre-S1 epitope exposed on the surface and the HCV core epitope buried within the VLPs. After immunization of BALB/c mice, specific T-cell activation by both foreign epitopes and a high-titer antibody response against the pre-S1 epitope were found, whereas an antibody response against the HBc carrier was notably suppressed. Both inserted epitopes also induced a specific cytotoxic-T-lymphocyte (CTL) response, as shown by the gamma interferon (IFN-␥) production profile.Genetically engineered virus-like particle (VLP)-based vaccines are one of the most promising tools in modern vaccinology. VLPs from almost all classes of viruses are being evaluated now or have just been adopted to use as carriers for presentation of foreign immunological epitopes (for a review, see references 29 and 31). VLP technologies possess obvious advantages for the generation of safe and efficacious vaccines. First, the repetitive antigenic structure of VLPs makes them highly immunogenic. Second, VLPs lack viral genomes or genes and are noninfectious, although they mimic infectious viruses in their structural and immunological features. Third, VLPs are generated by highly efficient heterologous expression of the cloned viral structural genes with subsequent quantitative in vivo or in vitro self-assembly of their products. Fourth, VLPs can be obtained by simple and efficient purification procedures. VLPs can be used for a broad range of applications, but the generation of vaccines against hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is of special interest.The HBV core (HBc) protein was first reported as a promising VLP carrier in 1986 and was published in 1987 (6, 10, 24). In many ways, HBc occupies a unique position among the VLP carriers because of its high-level synthesis and efficient selfassembly in virtually all known homologous and heterologous expression systems, including bacteria (for a review, see references 29 to 31). The major HBc B-cell epitopes (c and e1) are localized within the major immunodominant region (MIR), whereas the next important epitope, e2, is localized around amino acid position 130, close to the C-terminal histone-like region (for a review, see reference 30).The high-resolution spatial structure of HBc icosahedrons (11,43) shows that the MIR is located on the tip of th...

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Priming Th1 Immunity to Viral Core Particles Is Facilitated by Trace Amounts of RNA Bound to Its Arginine-Rich Domain

Cited by 93 publications

References 51 publications

Immunostimulating capacities of stabilized RNA molecules

Immunostimulating capacities of stabilized RNA molecules

Development of a nasal vaccine for chronic hepatitis B infection that uses the ability of hepatitis B core antigen to stimulate a strong Th1 response against hepatitis B surface antigen

Construction and Immunological Evaluation of Multivalent Hepatitis B Virus (HBV) Core Virus-Like Particles Carrying HBV and HCV Epitopes

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