scholarly journals Integrative Analysis of HTNV Glycoprotein Derived MHC II Epitopes by In Silico Prediction and Experimental Validation

2021 ◽  
Vol 11 ◽  
Author(s):  
Hao Sun ◽  
Zhenhua Lu ◽  
Guoyun Xuan ◽  
Ning Liu ◽  
Tianhu Wang ◽  
...  
Keyword(s):  
In Silico ◽  
Rna Virus ◽  
Large Population ◽  
Hemorrhagic Fever ◽  
Hantaan Virus ◽  
Class I Mhc ◽  
Mhc I ◽  
Mhc Ii ◽  
Host Virus Interactions ◽  
Virus Interactions

Hantaan virus (HTNV), the causative pathogen of hemorrhagic fever with renal syndrome (HFRS), is a negative RNA virus belonging to the Orthohantaviridae family. HTNV envelope glycoprotein (GP), encoded by the genomic medium segment, is immunogenic and is therefore a promising vaccine candidate. Major histocompatibility complex class I (MHC-I) epitopes derived from HTNV has been extensively studied, but little is known of MHC-II epitopes. In silico predictions based on four databases indicated that the full-length HTNV GP has 1121 15-mer epitopes, of which 289 had a high score for binding to the human and murine MHC-II superfamily. It found that epitope ILTVLKFIANIFHTS could potentially bind most MHC-II molecules covering human and murine haplotypes. Dominant epitopes were validated by enzyme-linked immunospot assay of splenocytes from immunized mice; 6 of 10 epitopes supported the predictions including TATYSIVGPANAKVP, TKTLVIGQCIYTITS, FSLLPGVAHSIAVEL, CETYKELKAHGVSCP, CGLYLDRLKPVGSAY, and NLGENPCKIGLQTSS. Conservation analysis of dominant epitopes revealed host–virus interactions without geographic stratification, thus meeting the requirements of candidate vaccines for large-population prophylaxis. These findings provide insight into hantavirus antigenicity and suggest that vaccines targeting MHC-II could provide immune protection in large population to complement symptomatic therapies for the treatment of HFRS.

scholarly journals 5,6-Dichloro-2-Phenyl-Benzotriazoles: New Potent Inhibitors of Orthohantavirus

Viruses ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 122 ◽  
Author(s):  
Giuseppina Sanna ◽  
Sandra Piras ◽  
Silvia Madeddu ◽  
Bernardetta Busonera ◽  
Boris Klempa ◽  
...  
Keyword(s):  
Rna Virus ◽  
Hemorrhagic Fever ◽  
Hantaan Virus ◽  
Reduction Assay ◽  
Antiviral Activities ◽  
Syncytial Virus ◽  
Focus Reduction ◽  
Approved Drugs ◽  
Reservoir Hosts ◽  
Fda Approved Drugs

Orthohantaviruses, previously known as hantaviruses (family Hantaviridae, order Bunyavirales), are emerging zoonoses hosted by different rodent and insectivore species. Orthohantaviruses are transmitted by aerosolized excreta (urine, saliva and feces) of their reservoir hosts. When transmitted to humans, they cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus (cardio) pulmonary syndrome (HPS) in the Americas. Clinical studies have shown that early treatments of HFRS patients with ribavirin (RBV) improve prognosis. Nevertheless, there is the need for urgent development of specific antiviral drugs. In the search for new RNA virus inhibitors, we recently identified a series of variously substituted 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives active against the human respiratory syncytial virus (HRSV). Interestingly, several 2-phenyl-benzotriazoles resulted in fairly potent inhibitors of the Hantaan virus in a chemiluminescence focus reduction assay (C-FRA) showing an EC50 = 4–5 µM, ten-fold more active than ribavirin. Currently, there are no FDA approved drugs for the treatment of orthohantavirus infections. Antiviral activities and cytotoxicity profiles suggest that 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazoles could be promising candidates for further investigation as a potential treatment of hantaviral diseases.

scholarly journals Pathways and microRNAs bioinformatics analyses identifying possible existing therapeutics for COVID-19 treatment

2020 ◽  
Author(s):  
Laura Teodori ◽  
Piero Sestili ◽  
Valeria Madiai ◽  
Sofia Coppari ◽  
Daniele Fraternale ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Hdac Inhibitors ◽  
Converting Enzyme ◽  
Bioinformatics Analyses ◽  
Off Label ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Ranked List

Abstract Over 180.000 SARS-COV-2 positive cases have been confirmed in Italy as April 20, with the number of deaths exceeding 23 thousand, making Italy the second Country for world COVID-19 deaths. Such enormous occurrence of infected and dead people raises the urgent demand of effective fast available treatments to control and diminish this pandemic. Discovering the cellular/molecular mechanisms of SARS-COV-2 pathogenicity is of paramount importance to understand how the infection becomes a disease and for therapeutically approaching it. From literature data, through a bioinformatics approach, an in silico analysis was performed, to predict the putative virus targets and evidence the already available therapeutics. Literature experimental results identified angiotensin-converting enzyme ACE and Spike proteins particularly involved in COVID-19. We thus investigate on the signaling pathways modulated by the two proteins through query miRNet, the platform linking miRNAs, targets and functions. We predicted microRNAs (miRs), miR-335-5p and miR-26b-5p, as being modulated by Spike and ACE together with deacetylate histones pathway HDAC. Our results matched with the available clinical data. We hypothesize the current and EMA-approved, SARS-COV-2 off-label, HDAC inhibitors (HDACis) drugs may be repurposed to limit or block host-virus interactions. A ranked list of compounds is given that can be tested.

scholarly journals Activation of Human Dendritic Cells by Ascophyllan Purified from Ascophyllum nodosum

Marine Drugs ◽  
2019 ◽  
Vol 17 (1) ◽  
pp. 66 ◽  
Author(s):  
Wei Zhang ◽  
Minseok Kwak ◽  
Hae-Bin Park ◽  
Takasi Okimura ◽  
Tatsuya Oda ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Human Peripheral Blood ◽  
Human Monocyte ◽  
Ascophyllum Nodosum ◽  
Class I Mhc ◽  
Mhc I ◽  
Mhc Ii ◽  
Cytokine Levels ◽  
Human Dendritic Cells

In our previous study, we showed that ascophyllan purified from Ascophyllum nodosum treatment promotes mouse dendritic cell (DC) activation in vivo, further induces an antigen-specific immune response and has anticancer effects in mice. However, the effect of ascophyllan has not been studied in human immune cells, specifically in terms of activation of human monocyte-derived DCs (MDDCs) and human peripheral blood DCs (PBDCs). We found that the treatment with ascophyllan induced morphological changes in MDDCs and upregulated co-stimulatory molecules and major histocompatibility complex class I (MHC I) and MHC II expression. In addition, pro-inflammatory cytokine levels in culture medium was also dramatically increased following ascophyllan treatment of MDDCs. Moreover, ascophyllan promoted phosphorylation of ERK, p38 and JNK signaling pathways, and inhibition of p38 almost completely suppressed the ascophyllan-induced activation of MDDCs. Finally, treatment with ascophyllan induced activation of BDCA1 and BDCA3 PBDCs. Thus, these data suggest that ascophyllan could be used as an immune stimulator in humans.

scholarly journals Activation of NKT Cells Protects Mice from Tuberculosis

2002 ◽  
Vol 70 (11) ◽  
pp. 6302-6309 ◽  
Author(s):  
Alissa Chackerian ◽  
Jen Alt ◽  
Vaji Perera ◽  
Samuel M. Behar
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tissue Injury ◽  
Adaptive Immune Response ◽  
Nkt Cells ◽  
Cell Immune Response ◽  
Class I Mhc ◽  
Mhc I ◽  
Mhc Ii

ABSTRACT The T-cell immune response to Mycobacterium tuberculosis is critical in preventing clinical disease. While it is generally accepted that both major histocompatibility complex class I (MHC-I)-restricted CD8+ and MHC-II-restricted CD4+ T cells are important for the immune response to M. tuberculosis, the role of non-MHC-restricted T cells is still not clearly delineated. We have previously reported that CD1d−/− mice do not differ from CD1d+/+ mice in their survival following infection with M. tuberculosis. We now show that, although CD1d-restricted NKT cells are not required for optimum immunity to M. tuberculosis, specific activation of NKT cells by the CD1d ligand α-galactosylceramide protects susceptible mice from tuberculosis. Treatment with α-galactosylceramide reduced the bacterial burden in the lungs, diminished tissue injury, and prolonged survival of mice following inoculation with virulent M. tuberculosis. The capacity of activated NKT cells to stimulate innate immunity and modulate the adaptive immune response to promote a potent antimicrobial immune response suggests that α-galactosylceramide administration could have a role in new strategies for the therapy of infectious diseases.

scholarly journals Adrenal Steroids Modulate the Immune Response during Brucella abortus Infection by a Mechanism That Depends on the Regulation of Cytokine Production

2015 ◽  
Vol 83 (5) ◽  
pp. 1973-1982 ◽  
Author(s):  
María Virginia Gentilini ◽  
Lis Noelia Velásquez ◽  
Paula Barrionuevo ◽  
Paula Constanza Arriola Benitez ◽  
Guillermo Hernán Giambartolomei ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Signs ◽  
Human Brucellosis ◽  
Adrenal Steroids ◽  
Class I Mhc ◽  
Mhc I ◽  
Content Type ◽  
Mhc Ii ◽  
Ifn Γ ◽  
Dhea Treatment

Human brucellosis is a protean disease with a diversity of clinical signs and symptoms resulting from infection withBrucellaspecies. Recent reports suggest a cross-regulation between adrenal steroids (cortisol and dehydroepiandrosterone [DHEA]) and the immune system. Monocytes and macrophages are the main replication niche forBrucella. Therefore, we investigated the role of adrenal hormones on the modulation of the immune response mediated by macrophages inB. abortusinfection. Cortisol treatment duringB. abortusinfection significantly inhibits cytokine, chemokine, and MMP-9 secretion. In contrast, DHEA treatment had no effect. However, DHEA treatment increases the expression of costimulatory molecules (CD40, CD86), the adhesion molecule CD54, and major histocompatibility complex class I (MHC-I) and MHC-II expression on the surface ofB. abortus-infected monocytes. It is known thatB. abortusinfection inhibits MHC-I and MHC-II expression induced by gamma interferon (IFN-γ) treatment. DHEA reversesB. abortusdownmodulation of the MHC-I and -II expression induced by IFN-γ. Taken together, our data indicate that DHEA immune intervention may positively affect monocyte activity duringB. abortusinfection.

scholarly journals Pathways and microRNAs bioinformatics analyses identifying possible existing therapeutics for COVID-19 treatment

2020 ◽  
Author(s):  
Laura Teodori ◽  
Piero Sestili ◽  
Valeria Madiai ◽  
Sofia Coppari ◽  
Daniele Fraternale ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Hdac Inhibitors ◽  
Converting Enzyme ◽  
Bioinformatics Analyses ◽  
Off Label ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Ranked List

Abstract Over 180.000 SARS-COV-2 positive cases have been confirmed in Italy as April 20, with the number of deaths exceeding 23 thousand, making Italy the second Country for world COVID-19 deaths. Such enormous occurrence of infected and dead people raises the urgent demand of effective fast available treatments to control and diminish this pandemic. Discovering the cellular/molecular mechanisms of SARS-COV-2 pathogenicity is of paramount importance to understand how the infection becomes a disease and for therapeutically approaching it. From literature data, through a bioinformatics approach, an in silico analysis was performed, to predict the putative virus targets and evidence the already available therapeutics. Literature experimental results identified angiotensin-converting enzyme ACE and Spike proteins particularly involved in COVID-19. We thus investigate on the signaling pathways modulated by the two proteins through query miRNet, the platform linking miRNAs, targets and functions. We predicted microRNAs (miRs), miR-335-5p and miR-26b-5p, as being modulated by Spike and ACE together with deacetylate histones pathway HDAC. Our results matched with the available clinical data. We hypothesize the current and EMA-approved, SARS-COV-2 off-label, HDAC inhibitors (HDACis) drugs may be repurposed to limit or block host-virus interactions. A ranked list of compounds is given that can be tested.

scholarly journals Bovine tongue epithelium-derived cells: A new source of bovine mesenchymal stem cells

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Jienny Lee ◽  
Jeong Su Byeon ◽  
Na-Yeon Gu ◽  
Siu Lee ◽  
Se-A Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Culture Conditions ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Lineages ◽  
Mhc Ii ◽  
Multiple Cell ◽  
Low Glucose

Abstract Mesenchymal stem cells (MSCs) possess the ability to differentiate into multiple cell lineages, and thus, confer great potential for use in regenerative medicine and biotechnology. In the present study, we attempted to isolate and characterize bovine tongue tissue epithelium-derived MSCs (boT-MSCs) and investigate the culture conditions required for long-term culturing of boT-MSCs. boT-MSCs were successfully isolated by the collagenase digestion method and their proliferative capacity was maintained for up to 20 or more passages. We observed a significant increase in the proliferation of boT-MSCs during the 20 consecutive passages under low-glucose Dulbecco’s modified Eagle’s medium culture condition among the three culture conditions. These boT-MSCs presented pluripotency markers (octamer-binding transcription factor 3/4 (Oct3/4) and sex determining region Y-box2 (Sox2)) and cell surface markers, which included CD13, CD29, CD44, CD73, CD90, CD105, CD166, and major histocompatibility complex (MHC) class I (MHC-I) but not CD11b, CD14, CD31, CD34, CD45, CD80, CD86, CD106, CD117, and MHC-II at third passage. Moreover, these boT-MSCs could differentiate into mesodermal (adipocyte, osteocyte, and chondrocyte) cell lineages. Thus, the present study suggests that the tongue of bovines could be used as a source of bovine MSCs.

scholarly journals An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination

2018 ◽  
Vol 15 (140) ◽  
pp. 20180041 ◽  
Author(s):  
Liam V. Brown ◽  
Eamonn A. Gaffney ◽  
Jonathan Wagg ◽  
Mark C. Coles
Keyword(s):  
Lymph Node ◽  
In Silico ◽  
Cytotoxic T Lymphocyte ◽  
Lymphocyte Activation ◽  
Vaccination Strategy ◽  
Peptide Vaccination ◽  
Class I Mhc ◽  
Vaccination Site ◽  
Mhc I ◽  
Short Peptide

Tumour immunotherapy is dependent upon activation and expansion of tumour-targetting immune cells, known as cytotoxic T-lymphocytes (CTLs). Cancer vaccines developed in the past have had limited success and the mechanisms resulting in failure are not well characterized. To elucidate these mechanisms, we developed a human-parametrized, in silico , agent-based model of vaccination-driven CTL activation within a clinical short-peptide vaccination context. The simulations predict a sharp transition in the probability of CTL activation, which occurs with variation in the separation rate (or off-rate) of tumour-specific immune response-inducing peptides (cognate antigen) from the major histocompatibility class I (MHC-I) receptors of dendritic cells (DCs) originally at the vaccination site. For peptides with MHC-I off-rates beyond this transition, it is predicted that no vaccination strategy will lead to successful expansion of CTLs. For slower off-rates, below the transition, the probability of CTL activation becomes sensitive to the numbers of DCs and T cells that interact subsequent to DC migration to the draining lymph node of the vaccination site. Thus, the off-rate is a key determinant of vaccine design.

scholarly journals HLA-class II specificity assessed by high-density peptide microarray interactions

2020 ◽  
Author(s):  
Thomas Osterbye ◽  
Morten Nielsen ◽  
Nadine L. Dudek ◽  
Sri H. Ramarathinam ◽  
Anthony W. Purcell ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Cell Epitope ◽  
Class Ii ◽  
High Density ◽  
Class I Mhc ◽  
Mhc I ◽  
Peptide Epitopes ◽  
Mhc Ii ◽  
Prediction Tools ◽  
Binding Data

AbstractThe ability to predict and/or identify MHC binding peptides is an essential component of T cell epitope discovery; something that ultimately should benefit the development of vaccines and immunotherapies. In particular, MHC class I (MHC-I) prediction tools have matured to a point where accurate selection of optimal peptide epitopes is possible for virtually all MHC-I allotypes; in comparison, current MHC class II (MHC-II) predictors are less mature. Since MHC-II restricted CD4+ T cells control and orchestrate most immune responses, this shortcoming severely hampers the development of effective immunotherapies. The ability to generate large panels of peptides and subsequently large bodies of peptide-MHC-II interaction data is key to the solution of this problem; a solution that also will support the improvement of bioinformatics predictors, which critically relies on the availability of large amounts of accurate, diverse and representative data. Here, we have used recombinant HLA-DRB1*01:01 and HLA-DRB1*03:01 molecules to interrogate high-density peptide arrays, in casu containing 70,000 random peptides in triplicates. We demonstrate that the binding data acquired contains systematic and interpretable information reflecting the specificity of the HLA-DR molecules investigated. Collectively, with a cost per peptide reduced to a few cents combined with the flexibility of recombinant HLA technology, this poses an attractive strategy to generate vast bodies of MHC-II binding data at an unprecedented speed and for the benefit of generating peptide-MHC-II binding data as well as improving MHC-II prediction tools.

scholarly journals Genetic Diversity in RNA Virus Quasispecies Is Controlled by Host-Virus Interactions

2001 ◽  
Vol 75 (14) ◽  
pp. 6566-6571 ◽  
Author(s):  
William L. Schneider ◽  
Marilyn J. Roossinck
Keyword(s):  
Mosaic Virus ◽  
Rna Virus ◽  
Viral Diseases ◽  
Diverse Populations ◽  
New Host ◽  
Prediction And Prevention ◽  
Emerging Viral Diseases ◽  
Host Virus Interactions ◽  
Virus Interactions ◽  
Different Levels

ABSTRACT Many RNA viruses have genetically diverse populations known as quasispecies. Important biological characteristics may be related to the levels of diversity in the quasispecies (quasispecies cloud size), including adaptability and host range. Previous work usingTobacco mosaic virus and Cucumber mosaic virusindicated that evolutionarily related viruses have very different levels of diversity in a common host. The quasispecies cloud size for these viruses remained constant throughout serial passages. Inoculation of these viruses on a number of hosts demonstrated that quasispecies cloud size is not constant for these viruses but appears to be dependent on the host. The quasispecies cloud size remained constant as long as the viruses were maintained on a given host. Shifting the virus between hosts resulted in a change in cloud size to levels associated with the new host. Quasispecies cloud size for these viruses is related to host-virus interactions, and understanding these interactions may facilitate the prediction and prevention of emerging viral diseases.

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