Virus-mediated Immune Response Research Articles

India's Pink-Eye Mystery: Decoding the 2023 Conjunctivitis Outbreak.

The pink eye outbreak in 2023 was caused due to humid weather conditions in most regions of India. The most affected states include Delhi, Gujrat (21% cases), Maharashtra (30%), Himachal Pradesh (4%) and Karnataka (4%). The epidemiological data indicates that males have a high prevalence rate as compared to females; urban areas were most affected, and professionals as well as students were the population group that had the highest prevalence rate. The most common clinical manifestations were the presence of red eye, eye discharge, grittiness, and eyelashes being stuck together. One of the hallmarks of histopathology is a cobblestone formation of flattened nodules with central vascular centers. Conjunctivitis is a virusmediated immune response accompanied by inflammation, which proceeds the immune reaction, giving rise to vasodilation, pseudo membrane formation, and conjunctivital discharge. The gold standard for the diagnosis of Conjunctivitis is the Adenoplus kit using PCR technology; apart from this slit lamp biomicroscope can be used for the evaluation. It is the need of the hour to spread awareness about the Pink Eye disease and the measures to prevent it.

COVID-19 and sudden-onset ocular neurogenic palsy in prior healthy patients: a systematic review

ABSTRACT Background The aim of this systematic review is to identify cases of neurogenic ocular palsy in the presence of COVID-19 and to document patient characteristics, type of palsy and possible aetiologies. Methods A systematic search of PubMed, Medline and CINAHL databases was conducted on the 6th of January 2023 to identify cases of neurogenic ocular palsy in patients with current or previous COVID-19 infection. Data were pooled to summarise the neurogenic palsy, patient clinical characteristics and proposed palsy mechanisms. Results The combined database search yielded 1197 articles. Of these, 23 publications consisting of 25 patients met the inclusion criteria. Most patients were male (68%) and ranged in age from 2 to 71 years (median=32.7, SD=21.4). Seven patients (28%) were children aged 2 to 10 years old. Abducens palsies were most common (68%) and the most common ocular presentation was diplopia (76%) with an average time of onset 15 days from testing positive to COVID-19 or having symptoms of the virus. Proposed mechanism of development of a neurogenic palsy secondary to COVID-19 infection was classified into one of three categories: vascular/thrombotic, a viral neuro-invasive or inflammatory virus-mediated immune response. Discussion This study suggests that COVID-19 infection may be linked to oculomotor, trochlear and abducens nerve palsies and the underlying mechanisms may vary but are difficult to definitively establish. Further studies investigating the onset of neurogenic palsy secondary to COVID-19 infection is required.

Exploring the therapeutic nature of limonoids and triterpenoids against SARS-CoV-2 by targeting nsp13, nsp14, and nsp15 through molecular docking and dynamics simulations

Background and aimThe ongoing global pandemic due to SARS-CoV-2 caused a medical emergency. Since December 2019, the COVID-19 disease is spread across the globe through physical contact and respiratory droplets. Coronavirus caused a severe effect on the human immune system where some of the non-structural proteins (nsp) are involved in virus-mediated immune response and pathogenesis. To suppress the viral RNA replication mechanism and immune-mediated responses, we aimed to identify limonoids and triterpenoids as antagonists by targeting helicases (nsp13), exonuclease (nsp14), and endoribonuclease (nsp15) of SARS-CoV-2 as therapeutic proteins. Experimental procedureIn silico molecular docking and drug-likeness of a library of 369 phytochemicals from limonoids and triterpenoids were performed to screen the potential hits that binds effectively at the active site of the proteins target. In addition, the molecular dynamics simulations of the proteins and their complexes with the potential hits were performed for 100 ns by using GROMACS. Results and conclusionThe potential compounds 26-deoxyactein and 25-O-anhydrocimigenol 3-O-beta-d-xylopyranoside posing strong interactions with a minimum binding energy of −10.1 and −9.5 kcal/mol, respectively and sustained close contact with nsp13 for 100 ns. The nsp14 replication fork activity was hindered by the tomentosolic acid, timosaponin A-I, and shizukaol A with the binding affinity score of −9.2, −9.2, and −9.0 kcal/mol, respectively. The nsp15 endoribonuclease catalytic residues were inhibited potentially by limonin, 25-O-anhydrocimigenol 3-O-alpha-l-arabinopyranoside, and asperagenin posing strong binding affinity scores of −9.0, −8.8, and −8.7 kcal/mol, respectively. Computationally predicted potential phytochemicals for SARS-CoV-2 are known to possess various medicinal properties.

An immune-competent, replication-permissive Syrian Hamster glioma model for evaluating Delta-24-RGD oncolytic adenovirus.

Oncolytic adenoviruses are promising new treatments against solid tumors, particularly for glioblastoma (GBM), and preclinical models are required to evaluate the mechanisms of efficacy. However, due to the species selectivity of adenovirus, there is currently no single animal model that supports viral replication, tumor oncolysis, and a virus-mediated immune response. To address this gap, we took advantage of the Syrian hamster to develop the first intracranial glioma model that is both adenovirus replication-permissive and immunocompetent. We generated hamster glioma stem-like cells (hamGSCs) by transforming hamster neural stem cells with hTERT, simian virus 40 large T antigen, and h-RasV12. Using a guide-screw system, we generated an intracranial tumor model in the hamster. The efficacy of the oncolytic adenovirus Delta-24-RGD was assessed by survival studies, and tumor-infiltrating lymphocytes (TILs) were evaluated by flow cytometry. In vitro, hamGSCs supported viral replication and were susceptible to Delta-24-RGD mediated cell death. In vivo, hamGSCs consistently developed into highly proliferative tumors resembling high-grade glioma. Flow cytometric analysis of hamster gliomas revealed significantly increased T-cell infiltration in Delta-24-RGD infected tumors, indicative of immune activation. Treating tumor-bearing hamsters with Delta-24-RGD led to significantly increased survival compared to hamsters treated with phosphate buffered saline (PBS). This adenovirus-permissive, immunocompetent hamster glioma model overcomes the limitations of previous model systems and provides a novel platform to study the interactions between tumor cells, the host immune system, and oncolytic adenoviral therapy; understanding of which will be critical to implementing oncolytic adenovirus in the clinic.

Generation of a Novel Oncolytic Vaccinia Virus Using the IHD-W Strain.

Oncolytic viruses are promising cancer therapies due to their selective killing of tumor cells and ability to stimulate the host immune system. As an oncolytic virus platform, vaccinia virus has unique advantages, including rapid replication, a broad range of host targets, and a large capacity for transgene incorporation. In this study, we developed a novel oncolytic vaccinia virus with high potency and a favorable safety profile. We began with the International Health Department-White (IHD-W) strain, which had the strongest cytotoxicity against tumor cells among the four vaccinia virus strains tested. Next, several candidate viruses were constructed by deleting three viral genes (C11R, K3L, and J2R) in various combinations, and their efficacy and safety were compared. The virus ultimately selected, named KLS-3010, exhibited strong antitumor activity against broad targets in vitro and in vivo. Furthermore, KLS-3010 showed a favorable safety profile in mice, as determined by the biodistribution and body weight change. More promisingly, KLS-3010 was able to shift the tumor microenvironment to a proinflammatory state, as evidenced by an increase in activated lymphocytes after KLS-3010 administration, suggesting that this strain may elicit an oncolytic virus-mediated immune response. The KLS-3010 strain thus represents a promising platform for the further development of oncolytic virus-based cancer therapies.

Comparative analysis of MicroRNA expression in dog lungs infected with the H3N2 and H5N1 canine influenza viruses

MicroRNAs, a class of noncoding RNAs 18 to 23 nucleotides (nt) in length, play critical roles in a wide variety of biological processes. The objective of this study was to examine differences in microRNA expression profiles derived from the lungs of beagle dogs infected with the avian-origin H3N2 canine influenza virus (CIV) or the highly pathogenic avian influenza (HPAI) H5N1 virus (canine-origin isolation strain). After dogs were infected with H3N2 or H5N1, microRNA expression in the lungs was assessed using a deep-sequencing approach. To identify the roles of microRNAs in viral pathogenicity and the host immune response, microRNA target genes were predicted, and their functions were analyzed using bioinformatics software. A total of 229 microRNAs were upregulated in the H5N1 infection group compared with those in the H3N2 infection group, and 166 microRNAs were downregulated. MicroRNA target genes in the H5N1 group were more significantly involved in metabolic pathways, such as glycerolipid metabolism and glycerophospholipid metabolism, than those in the H3N2 group. The inhibition of metabolic pathways may lead to appetite loss, weight loss and weakened immunity. Moreover, miR-485, miR-144, miR-133b, miR-4859-5p, miR-6902-3p, miR-7638, miR-1307-3p and miR-1346 were significantly altered microRNAs that potentially led to the inhibition of innate immune pathways and the heightened pathogenicity of H5N1 compared with that of H3N2 in dogs. This study deepens our understanding of the complex relationships among microRNAs, the influenza virus-mediated immune response and immune injury in dogs.

Pure mechanistic analysis of additive neuroprotective effects between baicalin and jasminoidin in ischemic stroke mice.

Both baicalin (BA) and jasminoidin (JA) are active ingredients in Chinese herb medicine Scutellaria baicalensis and Fructus gardeniae, respectively. They have been shown to exert additive neuroprotective action in ischemic stroke models. In this study we used transcriptome analysis to explore the pure therapeutic mechanisms of BA, JA and their combination (BJ) contributing to phenotype variation and reversal of pathological processes. Mice with middle cerebral artery obstruction were treated with BA, JA, their combination (BJ), or concha margaritifera (CM). Cerebral infarct volume was examined to determine the effect of these compounds on phenotype. Using the hippocampus microarray and ingenuity pathway analysis (IPA) software, we exacted the differentially expressed genes, networks, pathways, and functions in positive-phenotype groups (BA, JA and BJ) by comparing with the negative-phenotype group (CM). In the BA, JA, and BJ groups, a total of 7, 4, and 11 specific target molecules, 1, 1, and 4 networks, 51, 59, and 18 canonical pathways and 70, 53, and 64 biological functions, respectively, were identified. Pure therapeutic mechanisms of BA and JA were mainly overlapped in specific target molecules, functions and pathways, which were related to the nervous system, inflammation and immune response. The specific mechanisms of BA and JA were associated with apoptosis and cancer-related signaling and endocrine and hormone regulation, respectively. In the BJ group, novel target profiles distinct from mono-therapies were revealed, including 11 specific target molecules, 10 functions, and 10 pathways, the majority of which were related to a virus-mediated immune response. The pure additive effects between BA and JA were based on enhanced action in virus-mediated immune response. This pure mechanistic analysis may provide a clearer outline of the target profiles of multi-target compounds and combination therapies.

Protective Role of LGP2 in Influenza Virus Pathogenesis

Influenza A virus triggers a contagious respiratory disease that can cause considerable morbidity and mortality. Using an in vitro approach, we previously demonstrated that the pattern recognition receptor retinoic acid-inducible gene I (RIG-I) plays a key role in influenza A virus-mediated immune response. However, the importance of RIG-I signaling in vivo has not been thoroughly examined, because of the lack of an appropriate mouse models. To circumvent this issue, we generated a new transgenic mouse overexpressing LGP2 (hereafter, "LGP2 TG mice"), a major regulator of the RIG-I signaling pathway. The time course of several parameters was compared in infected wild-type and LGP2 TG mice. We found that LGP2 TG mice displayed significantly reduced inflammatory mediators and a lower leukocyte infiltration into the bronchoalveolar airspace. More importantly, LGP2 TG mice had a significant survival advantage. Hence, our in vivo study reveals that LGP2 is a major downregulator of the influenza A virus-triggered detrimental inflammatory response.

Cellular Immunity in Human Herpes Viruses 6 and 7 Infected Gastrointestinal Cancer Patients

Cellular Immunity in Human Herpes Viruses 6 and 7 Infected Gastrointestinal Cancer Patients CD4+ T lymphocytes appear to be the preferential target for replication of HHV-6 (human herpes virus) as well as HHV-7 viruses in vivo. In addition, CD8+ T cells, monocytes/macrophages, natural killer cells, epithelial, endothelial, neural cells and fibroblasts may be infected. By definition, however, even a tumour designated by pathologists to be early stage may be late stage when considered by the immune system. Certainly, even early stage tumours have evaded immune control, suggesting that they have acquired many immunosuppressive characteristics. The aim of the study was to clarify the influence of beta-herpes viruses on cellular immune response. In 95 gastrointestinal cancer patients we determined the immunocompetent cell level CD3, CD4, CD8, CD19, CD38, CD95, CD25 using laser flow cytofluorimeter and B- herpes viruses HHV-6, HHV-7 presence using a nested polymerase chain reaction method. Our data showed no statistically significant difference in immunocompetent cell level between negative, latent and active HHV-6, HHV-7 infection. Patients with immunocompromised immune status (lymphopenia) had a tendency to decreased CD4+, CD19+ absolute count. It may be suggested that virus-mediated immune response inhibition seems to be similar to cancer mediated, but differences in immune response among the same group of individuals had no influence on the average number of the immunocompetent cells in the group. Therefore, to characterise host-virus-tumour interactions, individual interpretation of each case is needed.

Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling

A monoclonal antibody (mAb) against human Toll-like receptor (TLR) 3 was established and its effect on TLR3-mediated responses was tested using human fibroblast cell lines expressing TLR3 on the cell surface. Fibroblasts are known to produce IFN-β upon viral infection or treatment with double-stranded RNA (dsRNA) through distinct signaling pathways. Here, we show the mAb to TLR3 suppressed poly(I):poly(C)-mediated IFN-β production by human fibroblasts naturally expressing TLR3 on their surface. By reporter gene assay using HEK293 cells transfected with a human TLR3 expression vector, TLR3 recognized dsRNA to activate NF-κB and the IFN-β promoter. TLR3 signaling was not elicited by either single-stranded RNA (ssRNA) or dsDNA. Thus, specific recognition of dsRNA by extracellular TLR3 is essential for induction of type I IFN: the interassociation between dsRNA and TLR3, regardless of direct or indirect binding, should be disrupted by mAb being attached to TLR3. The mAb against TLR3 reported herein may serve as a regulator for virus-mediated immune response via an alternative pathway involving the dsRNA–TLR3 recognition which might occur on host cells.