Pathogenesis Of Virus Infection Research Articles

Chicken GSDME, a major pore-forming molecule responsible for RNA virus-induced pyroptosis in chicken.

Pyroptosis is an inflammatory type of programmed cell death that mainly depends on the formation of plasma membrane pores by Gasdermin D (GSDMD) in mammals. However, the genetic deficiency of GSDMD in chicken renders avian pyroptosis elusive. Here, we show that infection of DF-1 cells (a chicken cell line) with infectious bursal disease virus (IBDV) induced cell death associated with chicken GSDME (chGSDME) cleavage, and so did cells with other RNA virus (VSV, AIV, or NDV) infections, indicating a broad role of chGSDME in RNA virus-induced pyroptosis in chicken. Furthermore, infection of DF-1 cells by IBDV or treatment of cells with Poly(I:C) initiated MDA5-mediated signaling pathway, followed by the activation of chCaspase-3/7 cleaving chGSDME at a specific site 270DAVD273. Moreover, knockdown or knockout of chGSDME expression in cells markedly reduced IBDV-induced pyroptosis and viral release. These results unravel the mechanisms of pyroptosis in chickens with RNA virus infection, providing important clues to uncover the role of GSDM proteins of different species in host response against pathogenic infection.IMPORTANCEPyroptosis is an inflammatory type of programmed cell death that mainly depends on the function of GSDMD in mammals and plays a crucial role in the pathogenesis of viral infection, whereas the mechanism of pyroptosis in chicken remains elusive. Herein, we show that IBDV and other RNA virus induced pyroptosis through the chMDA5-CASP8/9-CASP3/7-chGSDME pathway. The finding advances our understanding of GSDM proteins of different species in host response against pathogenic infection.

A complex remodeling of cellular homeostasis distinguishes RSV/SARS-CoV-2 co-infected A549-hACE2 expressing cell lines.

Concurrent infections with two or more pathogens with analogous tropism, such as RSV and SARS-CoV-2, may antagonize or facilitate each other, modulating disease outcome. Clinically, discrepancies in the severity of symptoms have been reported in children with RSV/SARS-CoV-2 co-infection. Herein, we propose an in vitro co-infection model to assess how RSV/SARS-CoV-2 co-infection alters cellular homeostasis. To this end, A549-hACE2 expressing cells were either infected with RSV or SARS-CoV-2 alone or co-infected with both viruses. Viral replication was assessed at 72 hours post infection by droplet digital PCR, immunofluorescence, and transmission electron microscopy. Anti-viral/receptor/autophagy gene expression was evaluated by RT-qPCR and confirmed by secretome analyses and intracellular protein production. RSV/SARS-CoV-2 co-infection in A549-hACE2 cells was characterized by: 1) an increase in the replication rate of RSV compared to single infection; 2) an increase in one of the RSV host receptors, ICAM1; 3) an upregulation in the expression/secretion of pro-inflammatory genes; 4) a rise in the number and length of cellular conduits; and 5) augmented autophagosomes formation and/or alteration of the autophagy pathway. These findings suggest that RSV/SARS-CoV-2 co-infection model displays a unique and specific viral and molecular fingerprint and shed light on the viral dynamics during viral infection pathogenesis. This in vitro co-infection model may represent a potential attractive cost-effective approach to mimic both viral dynamics and host cellular responses, providing in future readily measurable targets predictive of co-infection progression.

Biochemical implication of acetylcholine, histamine, IL-18, and interferon-alpha as diagnostic biomarkers in hepatitis C virus, coronavirus disease 2019, and dual hepatitis C virus-coronavirus disease 2019 patients.

Globally, hepatitis C virus (HCV) andcoronavirus disease 2019(COVID-19) are the most common causes of death due to the lack of early predictive and diagnostic tools. Therefore, research for a new biomarker is crucial. Inflammatory biomarkers are critical central players in the pathogenesis of viral infections. IL-18, produced by macrophages in early viral infections, triggers inflammatory biomarkers and interferon production, crucial for viral host defense. Finding out IL-18 function can help understand COVID-19 pathophysiology and predict disease prognosis. Histamine and its receptors regulate allergic lung responses, with H1 receptor inhibition potentially reducing inflammation insevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. angiotensin-converting enzyme 2 (ACE-2) receptors on cholangiocytes suggest liver involvement in SARS-CoV-2 infection. The current study presents the potential impact of circulating acetylcholine, histamine, IL-18, and interferon-Alpha as diagnostic tools in HCV, COVID-19, and dual HCV-COVID-19 pathogenesis. The current study was a prospective cross-section conducted on 188 participants classified into the following four groups: Group 1 COVID-19 (n = 47), Group 2 HCV (n = 47), and Group 3 HCV-COVID-19 patients (n = 47), besides the healthy control Group 4 (n = 47). The levels of acetylcholine, histamine, IL-18, and interferon-alpha were assayed using the ELISA method. Liver and kidney functions within all groups showed a marked alteration compared to the healthy control group. Our statistical analysis found that individuals with dual infection with HCV-COVID-19 had high ferritin levels compared to other biomarkers while those with COVID-19 infection had high levels of D-Dimer. The histamine, acetylcholine, and IL-18 biomarkers in both COVID-19 and dual HCV-COVID-19 groups have shown discriminatory power, making them potential diagnostic tests for infection. These three biomarkers showed satisfactory performance in identifying HCV infection. The IFN-Alpha test performed well in the HCV-COVID-19 group and was fair in the COVID-19 group, but it had little discriminative value in the HCV group. Moreover, our findings highlighted the pivotal role of acetylcholine, histamine, IL-18, and interferon-Alpha in HCV, COVID-19, and dual HCV-COVID-19 infection. Circulating levels of acetylcholine, histamine, IL-18, and interferon-Alpha can be potential early indicators for HCV, COVID-19, and dual HCV-COVID-19 infection. We acknowledge that further large multicenter experimental studies are needed to further investigate the role biomarkers play in influencing the likelihood of infection to confirm and extend our observations and to better understand and ultimately prevent or treat these diseases.

Hepatocyte Intrinsic Innate Antiviral Immunity against Hepatitis Delta Virus Infection: The Voices of Bona Fide Human Hepatocytes.

The pathogenesis of viral infection is attributed to two folds: intrinsic cell death pathway activation due to the viral cytopathic effect, and immune-mediated extrinsic cellular injuries. The immune system, encompassing both innate and adaptive immunity, therefore acts as a double-edged sword in viral infection. Insufficient potency permits pathogens to establish lifelong persistent infection and its consequences, while excessive activation leads to organ damage beyond its mission to control viral pathogens. The innate immune response serves as the front line of defense against viral infection, which is triggered through the recognition of viral products, referred to as pathogen-associated molecular patterns (PAMPs), by host cell pattern recognition receptors (PRRs). The PRRs-PAMPs interaction results in the induction of interferon-stimulated genes (ISGs) in infected cells, as well as the secretion of interferons (IFNs), to establish a tissue-wide antiviral state in an autocrine and paracrine manner. Cumulative evidence suggests significant variability in the expression patterns of PRRs, the induction potency of ISGs and IFNs, and the IFN response across different cell types and species. Hence, in our understanding of viral hepatitis pathogenesis, insights gained through hepatoma cell lines or murine-based experimental systems are uncertain in precisely recapitulating the innate antiviral response of genuine human hepatocytes. Accordingly, this review article aims to extract and summarize evidence made possible with bona fide human hepatocytes-based study tools, along with their clinical relevance and implications, as well as to identify the remaining gaps in knowledge for future investigations.

Pathogenesis of viral infections during pregnancy.

SUMMARYViral infections during pregnancy are associated with significant adverse perinatal and fetal outcomes. Pregnancy is a unique immunologic and physiologic state, which can influence control of virus replication, severity of disease, and vertical transmission. The placenta is the organ of the maternal-fetal interface and provides defense against microbial infection while supporting the semi-allogeneic fetus via tolerogenic immune responses. Some viruses, such as cytomegalovirus, Zika virus, and rubella virus, can breach these defenses, directly infecting the fetus and having long-lasting consequences. Even without direct placental infection, other viruses, including respiratory viruses like influenza viruses and severe acute respiratory syndrome coronavirus 2, still cause placental damage and inflammation. Concentrations of progesterone and estrogens rise during pregnancy and contribute to immunological adaptations, placentation, and placental development and play a pivotal role in creating a tolerogenic environment at the maternal-fetal interface. Animal models, including mice, nonhuman primates, rabbits, and guinea pigs, are instrumental for mechanistic insights into the pathogenesis of viral infections during pregnancy and identification of targetable treatments to improve health outcomes of pregnant individuals and offspring.

Molecular Mechanisms of Ferroptosis and Its Role in Viral Pathogenesis.

Ferroptosis is a novelty form of regulated cell death, and it is mainly characterized by iron accumulation and lipid peroxidation in the cells. Its underlying mechanism is related to the amino acid, iron, and lipid metabolisms. During viral infection, pathogenic microorganisms have evolved to interfere with ferroptosis, and ferroptosis is often manipulated by viruses to regulate host cell servicing for viral reproduction. Therefore, this review provides a comprehensive overview of the mechanisms underlying ferroptosis, elucidates the intricate signaling pathways involved, and explores the pivotal role of ferroptosis in the pathogenesis of viral infections. By enhancing our understanding of ferroptosis, novel therapeutic strategies can be devised to effectively prevent and treat diseases associated with this process. Furthermore, unraveling the developmental mechanisms through which viral infections exploit ferroptosis will facilitate development of innovative antiviral agents.

Increased IL-6 Levels and the Upregulation of Iron Regulatory Biomarkers Contribute to the Progression of Japanese Encephalitis Virus Infection's Pathogenesis.

Integrated analysis of iron regulatory biomarkers and inflammatory response could be an important strategy for Japanese encephalitis viral (JEV) infection disease management. In the present study, the inflammatory response was assessed by measuring serum Interleukin-6 (IL-6) levels using ELISA, and the transcription levels of iron homeostasis regulators were analyzed via RT-PCR. Furthermore, inter-individual variation in the transferrin gene was analyzed by PCR-RFLP and their association with clinical symptoms, susceptibility, severity, and outcomes was assessed through binary logistic regression and classification and regression tree (CART) analysis. Our findings revealed elevated levels of IL-6 in serum as well as increased expression of hepcidin (HAMP), transferrin (TF), and transferrin receptor-1 (TFR1) mRNA in JEV infection cases. Moreover, we found a genetic variation in TF (rs4481157) associated with clinical symptoms of meningoencephalitis. CART analysis indicates that individuals with the wild-type TF genotype are more susceptible to moderate JEV infection, while those with the homozygous type are in the high-risk group to develop a severe JEV condition. In summary, the study highlights that JEV infection induces alteration in both IL-6 levels and iron regulatory processes, which play pivotal roles in the development of JEV disease pathologies.

THU401 Impact Of Hypercalcemia On Outcomes Among Patients Admitted With COVID-19

Abstract Disclosure: E. Krishnaraju: None. V. Deenadayalan: None. E. Martinez Trevino: None. K.N. Patolia: None. A.G. Olafimihan: None. Background Calcium plays a pivotal role in the pathogenesis of viral infections by contributing to virus development, gene expression, maturation, and release. Alterations in intracellular calcium can lead to an inflammatory signaling cascade that may result in cell injury. Previous studies have shown hypocalcemia was associated with higher mortality and worse outcomes in hospitalized and critically ill patients (PMID: 32533508). This study aims to compare the outcomes of patients admitted with COVID-19 with and without a secondary diagnosis of hypercalcemia. Methods This was a retrospective study of the 2020 National Inpatient Sample (NIS) database, utilizing ICD-10 codes to identify patients admitted for COVID-19 with and without hypercalcemia. The groups were compared based on socio-demographics, medical comorbidities, inpatient mortality, length of stay (LOS), and total hospitalization charges (THC). Secondary outcomes included a diagnosis of acute kidney injury, acute respiratory failure, pneumonia, sepsis, shock, myocardial infarction, deep venous thrombosis, pulmonary embolism, cerebrovascular accident, blood transfusions, pressor use, and need for intubation. Statistical analyses were done using t-test, univariate and multinomial logistic regression models. Results Approximately 1,058,815 patients with COVID-19 were identified and 0.3% (N=4060) were hypercalcemic on presentation. Those with hypercalcemia were more likely to be white (44.83%, p<0.001), have a Charlson comorbidity index score >5 (48.89%, p<0.001) and have Medicare insurance (68.45%, p<0.001). Among the secondary outcomes, the COVID-hypercalcemia group had significantly higher odds of having an AKI (AOR:2.47, p<.001), sepsis (AOR:2.33, p<0.001), shock (AOR:2.06,p<.001), DVT (AOR:1.47, P:.068), CVA(AOR:2.33, p:.001), blood transfusion (AOR:1.63, p<.001), intubation(AOR:2.40, p<.001), and pressor use(AOR:2.03, p<.001). The in-hospital mortality for patients with COVID-19 and hypercalcemia was 1.5-fold higher compared to those without hypercalcemia (aOR: 1.55, 95%CI: 1.27-1.88, P<0.001) when adjusted for patient demographics, comorbidities, and hospital characteristics. It is also notable that the COVID-hypercalcemia group had an increased LOS by approximately 5 days compared to patients without hypercalcemia (aOR: 4.91, 95% CI: 3.93 - 5.89, P=0.00). Conclusion Based on the results of this large-caliber retrospective analysis, COVID-19-related mortality, length of hospital stay, and secondary clinical outcomes such as AKI, sepsis, shock, intubation, and pressor use were higher in patients with hypercalcemia and COVID compared to those without hypercalcemia. It is evident that serum calcium is yet another useful factor in determining the severity of the disease and should be considered on initial presentation of COVID-19 patients for prognostication. Presentation Date: Thursday, June 15, 2023

Identification of endoplasmic reticulum stress response genes in homologous vs. heterologous asf infections in vitro

Abstract The endoplasmic reticulum (ER) is crucial for the production, processing and transport of proteins. Infection with pathogens activates Unfolded Protein Response (UPR), which can lead to their survival/replication or elimination from the body. Although little is known about the role of the ER stress response in the pathogenesis of viral infections, the regulation of ER stress may be important in intractable infectious diseases. We conducted a comparative analysis of the expression of genes involved in ER stress response in peripheral blood mononuclear cells (PBMCs) from animals immunized with an attenuated strain of ASFV strain Congo-a (KK262) and then stimulated in vitro by two serologically different virulent strains Congo-v (K49) or Mozambique-v (M78), to expand our understanding of the early determinants of response to homologous and heterologous infection. We found up-regulation of genes of all three sensory molecules (PERK, ATF6 and IRE1) of UPR pathway in cells infected with only a homologous strain. For the first time, a number of up-regulated genes of the ER-associated degradation pathway (ERAD), which destroys misfolded proteins, were also detected. By understanding how viruses modify elements of cellular response to stress, we learn more about the pathogenesis, as well as how we can use it to prevent viral diseases.

Anti-Inflammatory Effects of Olive Leaf Extract and Its Bioactive Compounds Oleacin and Oleuropein-Aglycone on Senescent Endothelial and Small Airway Epithelial Cells.

Olive tree by-products have been deeply studied as an invaluable source of bioactive compounds. Several in vitro and in vivo studies showed that olive leaf extract (OLE) has anti-inflammatory and antioxidant properties. Here, we wanted to assess the valuable benefits of two less-studied OLE components-3,4-DHPEA-EDA (Oleacin, OC) and 3,4-DHPEA-EA (Oleuropein-Aglycone, OA)-directly purified from OLE using a cost-effective and environmentally sustainable method, in line with the principles of circular economy. OLE, OC and OA were then tested in human cellular models involved in acute and chronic inflammation and in the pathogenesis of viral infections, i.e., lipopolysaccharide (LPS)-treated monocyte/macrophages (THP-1) and endothelial cells (HUVECs), senescent HUVECs and Poly(I:C)-treated small airway epithelial cells (hSAECs). Results showed that OC and OA are efficient in ameliorating almost all of the pro-inflammatory readouts (IL-1β, TNF-α, IL-8, ICAM, VCAM) and reducing the release of IL-6 in all the cellular models. In hSAECs, they also modulate the expression of SOD2, NF-kB and also ACE2 and TMPRSS2, whose expression is required for SARS-CoV-2 virus entry. Overall, these data suggest the usefulness of OLE, OC and OA in controlling or preventing inflammatory responses, in particular those associated with viral respiratory infections and aging.

Extracellular vesicles: A promising therapy against SARS-CoV-2 infection

Extracellular vesicles: A promising therapy against SARS-CoV-2 infection

Canonical fibroblast growth factors in viral infection.

Fibroblast growth factors (FGFs) are a family of proteins that play a crucial role in the development and maintenance of various tissues in the body. There are three function-al groups of FGFs: canonical FGFs (cFGFs), intracellularly retained FGFs, and metabolic (also called endocrine) FGFs. cFGFs are secreted and act in an autocrine/paracrine fashion to regulate differentiation during foetal development, as well as tissue repair in adults. Recent studies have also begun to unravel the role of cFGFs during viral infections, suggesting that FGF-2 and other canonical FGFs may have an important virus-specific role, also by the regulation of the immune response. Because dysregulation in the FGF pathways is pivotal in cancer development, FGFs are the target of many anticancer drugs. These drugs may be repurposed to treat viral infection, since dysregulation of FGF signalling has been implicated in the pathogenesis of viral infections, such as hepatitis C. Overall, the role of cFGFs during viral infection is an underrepresented area of current research. This review focuses on overviewing the effects of canonical FGFs during infection by different viruses. Many studies highlight that the effects of FGFs during viral infection may be complex and context-dependent. While there is evidence to suggest that FGFs may have a beneficial impact on the immune response and tissue repair during viral infection, further studies are needed to fully understand the mechanisms underlying these effects and to determine in what cases FGFs could be targeted as a therapeutic approach for viral infection.

Baculovirus Actin Rearrangement-Inducing Factor 1 Can Remodel the Mammalian Actin Cytoskeleton.

The actin rearrangement-inducing factor 1 (Arif-1) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is an early viral protein that manipulates the actin cytoskeleton of host insect cells. Arif-1 is conserved among alphabaculoviruses and is responsible for the accumulation of F-actin at the plasma membrane during the early phase of infection. However, the molecular mechanism underlying Arif-1-induced cortical actin accumulation is still open. Recent studies have demonstrated the formation of invadosome-like structures induced by Arif-1, suggesting a function in systemic virus spread. Here, we addressed whether Arif-1 is able to manipulate the actin cytoskeleton of mammalian cells comparably to insect cells. Strikingly, transient overexpression of Arif-1 in B16-F1 mouse melanoma cells revealed pronounced F-actin remodeling. Actin assembly was increased, and intense membrane ruffling occurred at the expense of substrate-associated lamellipodia. Deletion mutagenesis studies of Arif-1 confirmed that the C-terminal cytoplasmic region was not sufficient to induce F-actin remodeling, supporting that the transmembrane region for Arif-1 function is also required in mammalian cells. The similarities between Arif-1-induced actin remodeling in insect and mammalian cells indicate that Arif-1 function relies on conserved cellular interaction partners and signal transduction pathways, thus providing an experimental tool to elucidate the underlying mechanism. IMPORTANCE Virus-induced changes of the host cell cytoskeleton play a pivotal role in the pathogenesis of viral infections. The baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is known for intervening with the regulation of the host actin cytoskeleton in a wide manner throughout the infection cycle. The actin rearrangement-inducing factor 1 (Arif-1) is a viral protein that causes actin rearrangement during the early phase of AcMNPV infection. Here, we performed overexpression studies of Arif-1 in mammalian cells to establish an experimental tool that allows elucidation of the mechanism underlying the Arif-1-induced remodeling of actin dynamics in a well-characterized and genetically accessible system.

The microbiota as a modulator of mucosal inflammation and HIV/HPV pathogenesis: From association to causation.

Although the microbiota has largely been associated with the pathogenesis of viral infections, most studies using omics techniques are correlational and hypothesis-generating. The mechanisms affecting the immune responses to viral infections are still being fully understood. Here we focus on the two most important sexually transmitted persistent viruses, HPV and HIV. Sophisticated omics techniques are boosting our ability to understand microbiota-pathogen-host interactions from a functional perspective by surveying the host and bacterial protein and metabolite production using systems biology approaches. However, while these strategies have allowed describing interaction networks to identify potential novel microbiota-associated biomarkers or therapeutic targets to prevent or treat infectious diseases, the analyses are typically based on highly dimensional datasets -thousands of features in small cohorts of patients-. As a result, we are far from getting to their clinical use. Here we provide a broad overview of how the microbiota influences the immune responses to HIV and HPV disease. Furthermore, we highlight experimental approaches to understand better the microbiota-host-virus interactions that might increase our potential to identify biomarkers and therapeutic agents with clinical applications.

Analysis of Subcellular Localization and Pathogenicity of Plum Bark Necrosis Stem-Pitting Associated Virus Protein P6

Infection of <i>plum bark necrosis stem pitting associated virus</i> (PBNSPaV) has been reported in many <i>Prunus</i> species in several countries, causing significant economic losses. The very small proteins encoded by plant viruses are often overlooked due to their short sequences and uncertain significance. However, numerous studies have indicated that they might play important roles in the pathogenesis of virus infection. The role of small hydrophobic protein P6, encoded by the open reading frame 2 of PBNSPaV, has not been well explored. In this study, we amplified the P6 fragment from a PBNSPaV isolate by RT-PCR using specific primers and found that it is 174 bp long and encodes a protein of approximately 6.3 kD with a transmembrane domain. Subcellular localization analysis of P6 proteins in tobacco leaves showed that P6 localizes to the cytomembrane and nuclear membrane. To further clarify the pathogenicity of P6 proteins, we constructed a PVX-P6 expression vector by inserting the p6 fragment into a <i>potato virus X</i> (PVX)-based vector and transformed it into <i>Agrobacterium tumefaciens GV3101</i>. Infiltration of <i>Nicotiana benthamiana</i> (<i>N. benthamiana)</i> with the PVX vector-transformed <i>A. tumefaciens</i> led to slight mosaic symptoms at 14 days of post-inoculation. Meanwhile, infiltration with the PVX-P6 vector-transformed <i>A. tumefaciens</i> resulted in no significant symptoms. These results demonstrated that heterologous expression of P6 in <i>N. benthamiana</i> could not enhance the pathogenicity of PVX. Our study indicates that P6 may not be a potential pathogenic factor associate with the causing of symptoms, and the mode of action of PBNSPaV-P6 protein remains to be further studied.

Study of serum level of kisspeptin and interferon-beta in genital wart patients.

Researchers are interested in genital wart (GW) studies due to their increased incidence. In a single experimental research, virally infected mouse models showed elevated kisspeptin levels and low interferon levels. The objective of the study was to evaluate the serum levels of kisspeptin and interferon (INF)-beta in GW patients. Forty patients with GWs and forty healthy participants of comparable age and sex as a control group were included in this case-control study. Serum levels of kisspeptin and IFN-beta were measured using ELISA during the period from December 2021 to April 2022. Kisspeptin was significantly higher among cases than controls, whereas IFN-beta level was lower among cases than controls (P < 0.001). There were no significant relations between kisspeptin and IFN-beta levels and the clinical data for the studied participants, and there was no significant correlation between both (P > 0.05). The reported increased kisspeptin level which was associated with decreased interferon-beta level in patients with GWs might indicate a new insight into viral infection pathogenesis. Further research including all steps in kisspeptin/G protein-coupled receptor 54 pathway is required. Targeted therapy for this pathway may be of value for those patients.

Male guanine-rich RNA sequence binding factor 1 knockout mice (Grsf1-/-) gain less body weight during adolescence and adulthood.

The guanine-rich RNA sequence binding factor 1 (GRSF1) is an RNA-binding protein of the heterogenous nuclear ribonucleoprotein H/F (hnRNP H/F) family that binds to guanine-rich RNA sequences forming G-quadruplex structures. In mice and humans there are single copy GRSF1 genes, but multiple transcripts have been reported. GRSF1 has been implicated in a number of physiological processes (e.g. embryogenesis, erythropoiesis, redox homeostasis, RNA metabolism) but also in the pathogenesis of viral infections and hyperproliferative diseases. These postulated biological functions of GRSF1 originate from in vitro studies rather than complex in vivo systems. To assess the in vivo relevance of these findings, we created systemic Grsf1-/- knockout mice lacking exons 4 and 5 of the Grsf1 gene and compared the basic functional characteristics of these animals with those of wildtype controls. We found that Grsf1-deficient mice are viable, reproduce normally and have fully functional hematopoietic systems. Up to an age of 15weeks they develop normally but when male individuals grow older, they gain significantly less body weight than wildtype controls in a gender-specific manner. Profiling Grsf1 mRNA expression in different mouse tissues we observed high concentrations in testis. Comparison of the testicular transcriptomes of Grsf1-/- mice and wildtype controls confirmed near complete knock-out of Grsf1 but otherwise subtle differences in transcript regulations. Comparative testicular proteome analyses suggested perturbed mitochondrial respiration in Grsf1-/- mice which may be related to compromised expression of complex I proteins. Here we present, for the first time, an in vivo complete Grsf1 knock-out mouse with comprehensive physiological, transcriptomic and proteomic characterization to improve our understanding of the GRSF1 beyond in vitro cell culture models.

Elevated ubiquitination contributes to protective immunity against severe SARS-CoV-2 infection.

The crosstalk between the ubiquitin-proteasome and the immune system plays an important role in the health and pathogenesis of viral infection. However, there have been few studies of ubiquitin activation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated the effect of ubiquitination on SARS-CoV-2 infection and patient prognosis by integrating published coronavirus disease 2019 (COVID-19) multi-transcriptome data and bioinformatics methods. The differential expression of COVID-19 samples revealed changed ubiquitination in most solid and hollow organs, and it was activated in lymphatic and other immune tissues. In addition, in the respiratory system of COVID-19 patients, the immune response was mainly focused on the alveoli, and the expression of ubiquitination reflected increasing immune infiltration. Ubiquitination stratification could significantly differentiate patients' prognosis and inflammation levels through the general transcriptional analysis of the peripheral blood of patients with COVID-19. Moreover, high ubiquitination levels were associated with a favourable prognosis, low inflammatory response, and reduced mechanical ventilation and intensive care unit. Moreover, high ubiquitination promoted a beneficial immune response while inhibiting immune damage. Finally, prognostic stratification and biomarker screening based on ubiquitination traits played an important role in clinical management and drug development. Ubiquitination characteristics provides new ideas for clinical intervention and prognostic guidance for COVID-19 patients.

Myeloid CD169/Siglec1: An immunoregulatory biomarker in viral disease.

CD169, also known as Siglec1 or Sialoadhesin (Sn), is a surface adhesion molecule on human myeloid cells. Being part of the Siglec family, it acts as a receptor for sialylated molecular structures, which are found among various pathogenic and non-pathogenic ligands. Recent data suggest that CD169 may represent a promising new biomarker in acute respiratory and non-respiratory viral infections, such as SARS-CoV-2, Respiratory syncytial virus (RSV) and Human immunodeficiency virus (HIV). Therein lies a great potential to sufficiently differentiate viral from bacterial infection, which has been an incessant challenge in the clinical management of infectious disease. CD169 equips myeloid cells with functions, reaching far beyond pathogen elimination. In fact, CD169 seems to crosslink innate and adaptive immunity by antigen presentation and consecutive pathogen elimination, embodying a substantial pillar of immunoregulation. Yet, our knowledge about the kinetics, mechanisms of induction, signaling pathways and its precise role in host-pathogen interaction remains largely obscure. In this review, we describe the role of CD169 as a potentially novel diagnostic biomarker for respiratory viral infection by evaluating its strengths and weaknesses and considering host factors that are involved in pathogenesis of virus infection. Finally, this brief review aims to point out shortcomings of available evidence, thus, guiding future work revolving the topic.

Respiratory viral infections, SARS-СoV-2 and chronic obstructive pulmonary disease

Further study of the distribution, pathogenesis of viral infection, the role of respiratory viruses in the formation and exacerbation of chronic lung diseases will allow the development of new methods of protection, the creation of modern pharmaceutical approaches for the treatment and prevention of COVID-19.The aim. The article presents an analytical review of the scientific literature in PubMed, Google Scholar, medRxiv, bioRxiv which was conducted to study and evaluate the mechanisms, pathogenesis, and clinical picture of respiratory viral infections, including Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-СoV-2).Conclusion. Understanding the specific mechanisms of the development of the host’s immune response to respiratory viruses allows a better understanding of the course of a new coronavirus infection, including in patients with COPD, since respiratory tract infections are closely associated with the formation and exacerbation of COPD. Respiratory viruses activate immune responses and exacerbate underlying inflammation in COPD. SARS-СoV-2 leads to a dysregulated immune response and, in severe cases, an overactive immune response, causing the development of a cytokine storm and acute respiratory distress syndrome (ARDS). Unlike seasonal respiratory viruses, SARS-СoV-2 circulates throughout the year and can be a source of frequent and severe exacerbations in patients with COPD which require further monitoring and research.