scholarly journals mRNA Vaccines against Flaviviruses

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 148
Author(s):  
Clayton J. Wollner ◽  
Justin M. Richner
Keyword(s):  
Immune Responses ◽  
Protein Expression ◽  
Viral Antigen ◽  
Viral Infections ◽  
Coding Region ◽  
Exogenous Protein ◽  
The Face

Numerous vaccines have now been developed using the mRNA platform. In this approach, mRNA coding for a viral antigen is in vitro synthesized and injected into the host leading to exogenous protein expression and robust immune responses. Vaccines can be rapidly developed utilizing the mRNA platform in the face of emerging pandemics. Additionally, the mRNA coding region can be easily manipulated to test novel hypotheses in order to combat viral infections which have remained refractory to traditional vaccine approaches. Flaviviruses are a diverse family of viruses that cause widespread disease and have pandemic potential. In this review, we discuss the mRNA vaccines which have been developed against diverse flaviviruses.

scholarly journals Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC

2008 ◽  
Vol 205 (13) ◽  
pp. 3187-3199 ◽  
Author(s):  
Lee-Hwa Tai ◽  
Marie-Line Goulet ◽  
Simon Belanger ◽  
Noriko Toyama-Sorimachi ◽  
Nassima Fodil-Cornu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Function ◽  
Viral Infections ◽  
Plasmacytoid Dendritic Cell ◽  
Class I ◽  
Type I ◽  
Class I Mhc ◽  
Mhc Molecules

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2Kb. Conversely, CpG-ODN–dependent IFN-α production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2Kb ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo.

scholarly journals Escaping High Viral Load Exhaustion

2002 ◽  
Vol 195 (9) ◽  
pp. 1089-1101 ◽  
Author(s):  
Stephanie Reignat ◽  
George J.M. Webster ◽  
David Brown ◽  
Graham S. Ogg ◽  
Abigail King ◽  
...  
Keyword(s):  
Viral Infections ◽  
Low Frequency ◽  
High Viral Load ◽  
Functional Impairments ◽  
Cd8 Cells ◽  
Cell Dysfunction ◽  
Chronic Hepatitis B Virus ◽  
The Face

Deletion, anergy, and a spectrum of functional impairments can affect virus-specific CD8 cells in chronic viral infections. Here we characterize a low frequency population of CD8 cells present in chronic hepatitis B virus (HBV) infection which survive in the face of a high quantity of viral antigen. Although they do not appear to exert immunological pressure in vivo, these CD8 cells are not classically “tolerant” since they proliferate, lyse, and produce antiviral cytokines in vitro. They are characterized by altered HLA/peptide tetramer reactivity, which is not explained by TCR down-regulation or reduced functional avidity and which can be reversed with repetitive stimulation. CD8 cells with altered tetramer binding appear to have a specificity restricted to envelope antigen and not to other HBV antigens, suggesting that mechanisms of CD8 cell dysfunction are differentially regulated according to the antigenic form and presentation of individual viral antigens.

scholarly journals Dose-dependent phorbol 12-myristate-13-acetate-mediated monocyte-to-macrophage differentiation induces unique proteomic signatures in THP-1 cells

2020 ◽  
Author(s):  
Sneha M. Pinto ◽  
Hera Kim ◽  
Yashwanth Subbannayya ◽  
Miriam Giambelluca ◽  
Korbinian Bösl ◽  
...  
Keyword(s):  
Immune Responses ◽  
Protein Expression ◽  
Macrophage Differentiation ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Cellular Processes ◽  
Human Monocytic Cell Line ◽  
Human Monocytic Cell ◽  
Altered Gene

AbstractMacrophages are sentinels of the innate immune system, and the human monocytic cell line THP-1 is one of the widely used in vitro models to study immune responses. Several monocyte-to-macrophage differentiation protocols exist, with phorbol 12-myristate-13-acetate (PMA) being the widely used and accepted method. However, the concentrations and duration of PMA treatment vary widely in the published literature and their effect on protein expression is not fully deciphered. In this study, we employed a dimethyl labeling-based quantitative proteomics approach to determine the changes in the protein repertoire of macrophage-like cells differentiated from THP-1 monocytes by three commonly used PMA-based differentiation protocols. Our analysis shows that variations in PMA concentration and duration of rest post-stimulation result in downstream differences in the protein expression and cellular processes. We demonstrate that these differences result in altered gene expression of cytokines upon stimulation with various TLR agonists. Together, these findings provide a valuable resource that significantly expands the knowledge of protein expression dynamics with one of the most common in vitro models for macrophages, which in turn has a profound impact on the immune responses being studied.

scholarly journals Positive and Negative Regulation of Cellular Immune Responses in Physiologic Conditions and Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
S. Viganò ◽  
M. Perreau ◽  
G. Pantaleo ◽  
A. Harari
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Viral Infections ◽  
Therapeutic Interventions ◽  
Cellular Immune

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences bothin vitroandin vivosuggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer.

scholarly journals Singapore grouper iridovirus-encoded semaphorin homologue (SGIV-sema) contributes to viral replication, cytoskeleton reorganization and inhibition of cellular immune responses

2014 ◽  
Vol 95 (5) ◽  
pp. 1144-1155 ◽  
Author(s):  
Yang Yan ◽  
Huachun Cui ◽  
Chuanyu Guo ◽  
Jingguang Wei ◽  
Youhua Huang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Viral Replication ◽  
Host Cells ◽  
Early Gene ◽  
Coding Region ◽  
Cytoskeletal Structure ◽  
Wide Range ◽  
Fish Cells ◽  
Cellular Immune

Semaphorins are a large, phylogenetically conserved family of proteins that are involved in a wide range of biological processes including axonal steering, organogenesis, neoplastic transformation, as well as immune responses. In this study, a novel semaphorin homologue gene belonging to the Singapore grouper iridovirus (SGIV), ORF155R (termed SGIV-sema), was cloned and characterized. The coding region of SGIV-sema is 1728 bp in length, encoding a predicted protein with 575 aa. SGIV-sema contains a ~370 aa N-terminal Sema domain, a conserved plexin-semaphorin-integrin (PSI) domain, and an immunoglobulin (Ig)-like domain near the C terminus. SGIV-sema is an early gene product during viral infection and predominantly distributed in the cytoplasm with a speckled and clubbed pattern of appearance. Functionally, SGIV-sema could promote viral replication during SGIV infection in vitro, with no effect on the proliferation of host cells. Intriguingly, ectopically expressed SGIV-sema could alter the cytoskeletal structure of fish cells, characterized by a circumferential ring of microtubules near the nucleus and a disrupted microfilament organization. Furthermore, SGIV-sema was able to attenuate the cellular immune response, as demonstrated by decreased expression of inflammation/immune-related genes such as IL-8, IL-15, TNF-α and mediator of IRF3 activation (MITA), in SGIV-sema-expressing cells before and after SGIV infection. Ultimately, our study identified a novel, functional SGIV gene that could regulate cytoskeletal structure, immune responses and facilitate viral replication.

scholarly journals Comparative Proteomic Analysis Reveals Varying Impact on Immune Responses in Phorbol 12-Myristate-13-Acetate-Mediated THP-1 Monocyte-to-Macrophage Differentiation

2021 ◽  
Vol 12 ◽  
Author(s):  
Sneha M. Pinto ◽  
Hera Kim ◽  
Yashwanth Subbannayya ◽  
Miriam S. Giambelluca ◽  
Korbinian Bösl ◽  
...  
Keyword(s):  
Immune Responses ◽  
Protein Expression ◽  
Inflammatory Responses ◽  
Macrophage Differentiation ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Integrated Network ◽  
Human Monocytic Cell Line ◽  
Human Monocytic Cell

Macrophages are sentinels of the innate immune system, and the human monocytic cell line THP-1 is one of the widely used in vitro models to study inflammatory processes and immune responses. Several monocyte-to-macrophage differentiation protocols exist, with phorbol 12-myristate-13-acetate (PMA) being the most commonly used and accepted method. However, the concentrations and duration of PMA treatment vary widely in the published literature and could affect the probed phenotype, however their effect on protein expression is not fully deciphered. In this study, we employed a dimethyl labeling-based quantitative proteomics approach to determine the changes in the protein repertoire of macrophage-like cells differentiated from THP-1 monocytes by three commonly used PMA-based differentiation protocols. Employing an integrated network analysis, we show that variations in PMA concentration and duration of rest post-stimulation result in downstream differences in the protein expression and cellular signaling processes. We demonstrate that these differences result in altered inflammatory responses, including variation in the expression of cytokines upon stimulation with various Toll-like receptor (TLR) agonists. Together, these findings provide a valuable resource that significantly expands the knowledge of protein expression dynamics with one of the most common in vitro models for macrophages, which in turn has a profound impact on the immune as well as inflammatory responses being studied.

scholarly journals Increased Cell-Free DNA Plasma Concentration Following Liver Transplantation Is Linked to Portal Hepatitis and Inferior Survival

2020 ◽  
Vol 9 (5) ◽  
pp. 1543 ◽  
Author(s):  
Felix Krenzien ◽  
Shadi Katou ◽  
Alba Papa ◽  
Bruno Sinn ◽  
Christian Benzing ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Immune Responses ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Term Survival ◽  
Cell Free Dna ◽  
Reactive Protein ◽  
Free Dna

Donor organ quality is crucial for transplant survival and long-term survival of patients after liver transplantation. Besides bacterial and viral infections, endogenous damage-associated molecular patterns (DAMPs) can stimulate immune responses. Cell-free DNA (cfDNA) is one such DAMP that exhibits highly proinflammatory effects via DNA sensors. Herein, we measured cfDNA after liver transplantation and found elevated levels when organs from resuscitated donors were transplanted. High levels of cfDNA were associated with high C-reactive protein, leukocytosis as well as granulocytosis in the recipient. In addition to increased systemic immune responses, portal hepatitis was observed, which was associated with increased interface activity and a higher numbers of infiltrating neutrophils and eosinophils in the graft. In fact, the cfDNA was an independent significant factor in multivariate analysis and increased concentration of cfDNA was associated with inferior 1-year survival. Moreover, cfDNA levels were found to be decreased significantly during the postoperative course when patients underwent continuous veno-venous haemofiltration. In conclusion, patients receiving livers from resuscitated donors were characterised by high postoperative cfDNA levels. Those patients showed pronounced portal hepatitis and systemic inflammatory responses in the short term leading to a high mortality. Further studies are needed to evaluate the clinical relevance of cfDNA clearance by haemoadsorption and haemofiltration in vitro and in vivo.

scholarly journals MiR-202-5p Inhibits RIG-I-Dependent Innate Immune Responses to RGNNV Infection by Targeting TRIM25 to Mediate RIG-I Ubiquitination

Viruses ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 261
Author(s):  
Wei Liu ◽  
Yilin Jin ◽  
Wanwan Zhang ◽  
Yangxi Xiang ◽  
Peng Jia ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathway ◽  
Viral Infections ◽  
Ectopic Expression ◽  
Innate Immune ◽  
Negative Regulator ◽  
Nervous Necrosis Virus ◽  
Type I ◽  
Antiviral Genes

The RIG-I-like receptors (RLRs) signaling pathway is essential for inducing type I interferon (IFN) responses to viral infections. Meanwhile, it is also tightly regulated to prevent uncontrolled immune responses. Numerous studies have shown that microRNAs (miRNAs) are essential for the regulation of immune processes, however, the detailed molecular mechanism of miRNA regulating the RLRs signaling pathway remains to be elucidated. Here, our results showed that miR-202-5p was induced by red spotted grouper nervous necrosis virus (RGNNV) infection in zebrafish. Overexpression of miR-202-5p led to reduced expression of IFN 1 and its downstream antiviral genes, thus facilitating viral replication in vitro. In comparison, significantly enhanced levels of IFN 1 and antiviral genes and significantly low viral burden were observed in the miR-202-5p-/- zebrafish compared to wild type zebrafish. Subsequently, zebrafish tripartite motif-containing protein 25 (zbTRIM25) was identified as a target of miR-202-5p in both zebrafish and humans. Ectopic expression of miR-202-5p suppressed zbTRIM25-mediated RLRs signaling pathway. Furthermore, we showed that miR-202-5p inhibited zbTRIM25-mediated zbRIG-I ubiquitination and activation of IFN production. In conclusion, we demonstrate that RGNNV-inducible miR-202-5p acts as a negative regulator of zbRIG-I-triggered antiviral innate response by targeting zbTRIM25. Our study reveals a novel mechanism for the evasion of the innate immune response controlled by RGNNV.

scholarly journals Sharing the burden: antigen transport and firebreaks in immune responses

2008 ◽  
Vol 6 (34) ◽  
pp. 447-454 ◽  
Author(s):  
Andreas Handel ◽  
Andrew Yates ◽  
Sergei S Pilyugin ◽  
Rustom Antia
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Viral Antigen ◽  
Viral Infections ◽  
Virus Production ◽  
Uninfected Cell ◽  
Mixed System ◽  
Target Cells ◽  
Spatial Effects ◽  
Antigen Transport

Communication between cells is crucial for immune responses. An important means of communication during viral infections is the presentation of viral antigen on the surface of an infected cell. Recently, it has been shown that antigen can be shared between infected and uninfected cells through gap junctions, connexin-based channels, that allow the transport of small molecules. The uninfected cell receiving antigen can present it on its surface. Cells presenting viral antigen are detected and killed by cytotoxic T lymphocytes. The killing of uninfected cells can lead to increased immunopathology. However, the immune response might also profit from killing those uninfected bystander cells. One benefit might be the removal of future ‘virus factories’. Another benefit might be through the creation of ‘firebreaks’, areas void of target cells, which increase the diffusion time of free virions, making their clearance more likely. Here, we use theoretical models and simulations to explore how the mechanism of gap junction-mediated antigen transport (GMAT) affects the dynamics of the virus and immune response. We show that under the assumption of a well-mixed system, GMAT leads to increased immunopathology, which always outweighs the benefit of reduced virus production due to the removal of future virus factories. By contrast, a spatially explicit model leads to quite different results. Here we find that the firebreak mechanism reduces both viral load and immunopathology. Our study thus shows the potential benefits of GMAT and illustrates how spatial effects may be crucial for the quantitative understanding of infection dynamics and immune responses.

Molecular and Biological Characterization of a Cervidpoxvirus Isolated From Moose with Necrotizing Dermatitis

2020 ◽  
Vol 57 (2) ◽  
pp. 296-310
Author(s):  
Anibal G. Armién ◽  
Tiffany M. Wolf ◽  
Sunil Kumar Mor ◽  
Terry Fei Fan Ng ◽  
Alexa J. Bracht ◽  
...  
Keyword(s):  
Amino Acid ◽  
Sequence Length ◽  
Whole Genome ◽  
Biological Characterization ◽  
Coding Region ◽  
The North ◽  
The Face

Cervidpoxvirus is one of the more recently designated genera within the subfamily Chordopoxvirinae, with Deerpox virus (DPV) as the only recognized species to date. In this study, the authors describe spontaneous disease and infection in the North American moose ( Alces americanus) by a novel Cervidpoxvirus, here named Moosepox virus (MPV). Three 4-month-old moose calves developed a multifocal subacute-to-chronic, necrotizing, suppurative-to-granulomatous dermatitis that affected the face and the extremities. Ultrastructurally, all stages of MPV morphogenesis—that is, crescents, spherical immature particles, mature particles, and enveloped mature virus—were observed in skin tissue. In vitro infection with MPV confirmed that its morphogenesis was similar to that of the prototype vaccinia virus. The entire coding region, including 170 putative genes of this MPV, was sequenced and annotated. The sequence length was 164,258 bp with 98.5% nucleotide identity with DPV (strain W-1170-84) based on the whole genome. The genome of the study virus was distinct from that of the reference strain (W-1170-84) in certain genes, including the CD30-like protein (83.9% nucleotide, 81.6% amino acid), the endothelin precursor (73.2% nucleotide including some indels, 51.4% amino acid), and major histocompatibility class (MHC) class I–like protein (81.0% nucleotide, 68.2% amino acid). This study provides biological characterization of a new Cervidpoxvirus attained through in vivo and in vitro ultrastructural analyses. It also demonstrates the importance of whole-genome sequencing in the molecular characterization of poxviruses identified in taxonomically related hosts.

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