Update on Viral Infections Involving the Central Nervous System in Pediatric Patients.

Infections of the central nervous system (CNS) are mainly caused by viruses, and these infections can be life-threatening in pediatric patients. Although the prognosis of CNS infections is often favorable, mortality and long-term sequelae can occur. The aims of this narrative review were to describe the specific microbiological and clinical features of the most frequent pathogens and to provide an update on the diagnostic approaches and treatment strategies for viral CNS infections in children. A literature analysis showed that the most common pathogens worldwide are enteroviruses, arboviruses, parechoviruses, and herpesviruses, with variable prevalence rates in different countries. Lumbar puncture (LP) should be performed as soon as possible when CNS infection is suspected, and cerebrospinal fluid (CSF) samples should always be sent for polymerase chain reaction (PCR) analysis. Due to the lack of specific therapies, the management of viral CNS infections is mainly based on supportive care, and empiric treatment against herpes simplex virus (HSV) infection should be started as soon as possible. Some researchers have questioned the role of acyclovir as an empiric antiviral in older children due to the low incidence of HSV infection in this population and observed that HSV encephalitis may be clinically recognizable beyond neonatal age. However, the real benefit-risk ratio of selective approaches is unclear, and further studies are needed to define appropriate indications for empiric acyclovir. Research is needed to find specific therapies for emerging pathogens. Moreover, the appropriate timing of monitoring neurological development, performing neuroimaging evaluations and investigating the effectiveness of rehabilitation during follow-up should be evaluated with long-term studies.

Effective Nasal Disinfection as an Overlooked Strategy in Our Fight against COVID-19.

Although the recent advent of a vaccine and other therapeutic aids in our fight against COVID-19 has brought us a step closer to controlling the pandemic, our fight is far from over. Handwashing, masks, and social distancing practices are considered reasonable measures to control the spread of the disease have been well accepted by government officials and public health officials despite scarce and conflicting scientific evidence. Taking into consideration the aforementioned measures, there is an additional perhaps overlooked practice that warrants our attention-nasal disinfection and hygiene.

Corrigendum: Differential association of viral dynamics with disease severity depending on patients' age group in COVID-19.

[This corrects the article DOI: 10.3389/fmicb.2021.712260.].

Mixed Warm and Cold Autoimmune Hemolytic Anemia With Concomitant Immune Thrombocytopenia Following Recent SARS-CoV-2 Infection and Ongoing Rhinovirus Infection.

Mixed-type autoimmune hemolytic anemia (AIHA) is a term used to describe hemolysis occurring in the context of both warm and cold reactive autoantibodies to red blood cells. Immune thrombocytopenia (ITP) is an acquired form of thrombocytopenia potentially complicated by hemorrhage due to autoantibodies reactive with platelets and megakaryocytes. Diagnosis of ITP requires exclusion of other known causes of thrombocytopenia. AIHA and ITP may be primary disorders or associated with lymphoproliferative, autoimmune, or viral infections. Here, we report a rare case of simultaneous mixed-type autoimmune hemolytic anemia with immune thrombocytopenia following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection treated with Paxlovid followed by Rhinovirus infection.

The Role of Spermidine and Its Key Metabolites in Important, Pathogenic Human Viruses and in Parasitic Infections Caused by Plasmodium falciparum and Trypanosoma brucei.

The triamine spermidine is a key metabolite of the polyamine pathway. It plays a crucial role in many infectious diseases caused by viral or parasitic infections. Spermidine and its metabolizing enzymes, i.e., spermidine/spermine-N1-acetyltransferase, spermine oxidase, acetyl polyamine oxidase, and deoxyhypusine synthase, fulfill common functions during infection in parasitic protozoa and viruses which are obligate, intracellular parasites. The competition for this important polyamine between the infected host cell and the pathogen determines the severity of infection in disabling human parasites and pathogenic viruses. Here, we review the impact of spermidine and its metabolites in disease development of the most important, pathogenic human viruses such as SARS-CoV-2, HIV, Ebola, and in the human parasites Plasmodium and Trypanosomes. Moreover, state-of-the-art translational approaches to manipulate spermidine metabolism in the host and the pathogen are discussed to accelerate drug development against these threatful, infectious human diseases.

Immune Responses and Pathogenesis following Experimental SARS-CoV-2 Infection in Domestic Cats.

Several reports demonstrated the susceptibility of domestic cats to SARS-CoV-2 infection. Here, we describe a thorough investigation of the immune responses in cats after experimental SARS-CoV-2 inoculation, along with the characterization of infection kinetics and pathological lesions. Specific pathogen-free domestic cats (n = 12) were intranasally inoculated with SARS-CoV-2 and subsequently sacrificed on DPI (days post-inoculation) 2, 4, 7 and 14. None of the infected cats developed clinical signs. Only mild histopathologic lung changes associated with virus antigen expression were observed mainly on DPI 4 and 7. Viral RNA was present until DPI 7, predominantly in nasal and throat swabs. The infectious virus could be isolated from the nose, trachea and lungs until DPI 7. In the swab samples, no biologically relevant SARS-CoV-2 mutations were observed over time. From DPI 7 onwards, all cats developed a humoral immune response. The cellular immune responses were limited to DPI 7. Cats showed an increase in CD8+ cells, and the subsequent RNA sequence analysis of CD4+ and CD8+ subsets revealed a prominent upregulation of antiviral and inflammatory genes on DPI 2. In conclusion, infected domestic cats developed a strong antiviral response and cleared the virus within the first week after infection without overt clinical signs and relevant virus mutations.

Identification and Profiling of a Novel Bombyx mori latent virus Variant Acutely Infecting Helicoverpa armigera and Trichoplusia ni.

Insect cell expression systems are increasingly being used in the medical industry to develop vaccines against diseases such as COVID-19. However, viral infections are common in these systems, making it necessary to thoroughly characterize the viruses present. One such virus is Bombyx mori latent virus (BmLV), which is known to be specific to Bombyx mori and to have low pathogenicity. However, there has been little research on the tropism and virulence of BmLV. In this study, we examined the genomic diversity of BmLV and identified a variant that persistently infects Trichoplusia ni-derived High Five cells. We also assessed the pathogenicity of this variant and its effects on host responses using both in vivo and in vitro systems. Our results showed that this BmLV variant causes acute infections with strong cytopathic effects in both systems. Furthermore, we characterized the RNAi-based immune response in the T. ni cell line and in Helicoverpa armigera animals by assessing the regulation of RNAi-related genes and profiling the generated viral small RNAs. Overall, our findings shed light on the prevalence and infectious properties of BmLV. We also discuss the potential impact of virus genomic diversity on experimental outcomes, which can help interpret past and future research results.

Breakthrough SARS-CoV-2 Infections in the PROVENT Prevention Trial Were Not Associated with AZD7442 (Tixagevimab/Cilgavimab) Resistant Variants.

BACKGROUND: We report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of SARS-CoV-2 variants identified from breakthrough infections in the PROVENT pre-exposure prophylaxis trial (NCT04625725). METHODS: Variants identified from PROVENT participants with reverse-transcription polymerase chain reaction-positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility of variant-specific pseudotyped virus-like particles. RESULTS: At completion of 6 months' follow-up, no AZD7442-resistant variants were observed in breakthrough COVID-19 cases. SARS-CoV-2 neutralizing antibody titers were similar in breakthrough and non-breakthrough cases. CONCLUSION: Symptomatic COVID-19 breakthrough cases in PROVENT were not due to resistance-associated substitutions in AZD7442 binding sites or lack of AZD7442 exposure.

Wastewater early warning system for SARS-CoV-2 outbreaks and variants in a Coruña, Spain.

Wastewater-based epidemiology has been widely used as a cost-effective method for tracking the COVID-19 pandemic at the community level. Here we describe COVIDBENS, a wastewater surveillance program running from June 2020 to March 2022 in the wastewater treatment plant of Bens in A Coruña (Spain). The main goal of this work was to provide an effective early warning tool based in wastewater epidemiology to help in decision-making at both the social and public health levels. RT-qPCR procedures and Illumina sequencing were used to weekly monitor the viral load and to detect SARS-CoV-2 mutations in wastewater, respectively. In addition, own statistical models were applied to estimate the real number of infected people and the frequency of each emerging variant circulating in the community, which considerable improved the surveillance strategy. Our analysis detected 6 viral load waves in A Coruña with concentrations between 103 and 106 SARS-CoV-2 RNA copies/L. Our system was able to anticipate community outbreaks during the pandemic with 8-36 days in advance with respect to clinical reports and, to detect the emergence of new SARS-CoV-2 variants in A Coruña such as Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (B.1.1.529 and BA.2) in wastewater with 42, 30, and 27 days, respectively, before the health system did. Data generated here helped local authorities and health managers to give a faster and more efficient response to the pandemic situation, and also allowed important industrial companies to adapt their production to each situation. The wastewater-based epidemiology program developed in our metropolitan area of A Coruña (Spain) during the SARS-CoV-2 pandemic served as a powerful early warning system combining statistical models with mutations and viral load monitoring in wastewater over time.

Reprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses.

Type I interferons (IFNs-α/ß) are antiviral cytokines that constitute the innate immunity of hosts to fight against viral infections. Recent studies, however, have revealed the pleiotropic functions of IFNs, in addition to their antiviral activities, for the priming of activation and maturation of adaptive immunity. In turn, many viruses have developed various strategies to counteract the IFN response and to evade the host immune system for their benefits. The inefficient innate immunity and delayed adaptive response fail to clear of invading viruses and negatively affect the efficacy of vaccines. A better understanding of evasion strategies will provide opportunities to revert the viral IFN antagonism. Furthermore, IFN antagonism-deficient viruses can be generated by reverse genetics technology. Such viruses can potentially serve as next-generation vaccines that can induce effective and broad-spectrum responses for both innate and adaptive immunities for various pathogens. This review describes the recent advances in developing IFN antagonism-deficient viruses, their immune evasion and attenuated phenotypes in natural host animal species, and future potential as veterinary vaccines.

SARS-CoV-2 Omicron Specific Mutations Affecting Infectivity, Fusogenicity, and Partial TMPRSS2-Independency.

The COVID-19 pandemic resulted from the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since its first appearance in 2019, new SARS-CoV-2 variants of concern (VOCs) have emerged frequently, changing the infection's dynamic. SARS-CoV-2 infects cells via two distinct entry routes; receptor-mediated endocytosis or membrane fusion, depending on the absence or presence of transmembrane serine protease 2 (TMPRSS2), respectively. In laboratory conditions, the Omicron SARS-CoV-2 strain inefficiently infects cells predominantly via endocytosis and is phenotypically characterized by decreased syncytia formation compared to the earlier Delta variant. Thus, it is important to characterize Omicron's unique mutations and their phenotypic manifestations. Here, by utilizing SARS-CoV-2 pseudovirions, we report that the specific Omicron Spike F375 residue decreases infectivity, and its conversion to the Delta S375 sequence significantly increases Omicron infectivity. Further, we identified that residue Y655 decreases Omicron's TMPRSS2 dependency and entry via membrane fusion. The Y655H, K764N, K856N and K969N Omicron revertant mutations, bearing the Delta variant sequence, increased the cytopathic effect of cell-cell fusion, suggesting these Omicron-specific residues reduced the severity of SARS-CoV-2. This study of the correlation of the mutational profile with the phenotypic outcome should sensitize our alertness towards emerging VOCs.

The Pivotal Role of Galectin-3 in Viral Infection: A Multifaceted Player in Host-Pathogen Interactions.

Galectin-3 (Gal-3), a beta-galactoside-binding lectin, plays a pivotal role in various cellular processes, including immune responses, inflammation, and cancer progression. This comprehensive review aims to elucidate the multifaceted functions of Gal-3, starting with its crucial involvement in viral entry through facilitating viral attachment and catalyzing internalization. Furthermore, Gal-3 assumes significant roles in modulating immune responses, encompassing the activation and recruitment of immune cells, regulation of immune signaling pathways, and orchestration of cellular processes such as apoptosis and autophagy. The impact of Gal-3 extends to the viral life cycle, encompassing critical phases such as replication, assembly, and release. Notably, Gal-3 also contributes to viral pathogenesis, demonstrating involvement in tissue damage, inflammation, and viral persistence and latency elements. A detailed examination of specific viral diseases, including SARS-CoV-2, HIV, and influenza A, underscores the intricate role of Gal-3 in modulating immune responses and facilitating viral adherence and entry. Moreover, the potential of Gal-3 as a biomarker for disease severity, particularly in COVID-19, is considered. Gaining further insight into the mechanisms and roles of Gal-3 in these infections could pave the way for the development of innovative treatment and prevention options for a wide range of viral diseases.

Nasal spray of an IgM-like ACE2 fusion protein HH-120 accelerates SARS-CoV-2 clearance: A single-center propensity score-matched cohort study.

HH-120, a recently developed IgM-like ACE2 fusion protein with broad-spectrum neutralizing activity against all ACE2-utilizing coronaviruses, has been developed as a nasal spray for use as an early treatment agent to reduce disease progression and airborne transmission. The objective of this study was to evaluate the safety and efficacy of the HH-120 nasal spray in SARS-CoV-2-infected subjects. Eligible symptomatic or asymptomatic SARS-CoV-2-infected participants were enrolled in a single-arm trial to receive the HH-120 nasal spray for no longer than 6 days or until viral clearance at a single hospital between August 3 and October 7, 2022. An external control was built from real-world data of SARS-CoV-2-infected subjects contemporaneously hospitalized in the same hospital using a propensity score matching (PSM) method. After PSM, 65 participants in the HH-120 group and 103 subjects with comparable baseline characteristics in the external control group were identified. The viral clearance time was significantly shorter in participants receiving the HH-120 nasal spray than that in subjects of the control group (median 8 days vs. 10 days, p < 0.001); the difference was more prominent in those subgroup subjects with higher baseline viral load (median 7.5 days vs. 10.5 days, p < 0.001). The incidence of treatment-emergent adverse events and treatment-related adverse events of HH-120 group were 35.1% (27/77) and 3.9% (3/77), respectively. All the adverse events observed were mild, being of CTCAE grade 1 or 2, and transient. The HH-120 nasal spray showed a favorable safety profile and promising antiviral efficacy in SARS-CoV-2-infected subjects. The results from this study warrant further assessment of the efficacy and safety of the HH-120 nasal spray in large-scale randomized controlled clinical trials.

Low-dose radiation therapy suppresses viral pneumonia by enhancing broad-spectrum anti-inflammatory responses via transforming growth factor-ß production.

Low-dose radiation therapy (LDRT) can suppress intractable inflammation, such as that in rheumatoid arthritis, and is used for treating more than 10,000 rheumatoid arthritis patients annually in Europe. Several recent clinical trials have reported that LDRT can effectively reduce the severity of coronavirus disease (COVID-19) and other cases of viral pneumonia. However, the therapeutic mechanism of LDRT remains unelucidated. Therefore, in the current study, we aimed to investigate the molecular mechanism underlying immunological alterations in influenza pneumonia after LDRT. Mice were irradiated to the whole lung 1 day post-infection. The changes in levels of inflammatory mediators (cytokines and chemokines) and immune cell populations in the bronchoalveolar lavage (BALF), lungs, and serum were examined. LDRT-treated mice displayed markedly increased survival rates and reduced lung edema and airway and vascular inflammation in the lung; however, the viral titers in the lungs were unaffected. Levels of primary inflammatory cytokines were reduced after LDRT, and transforming growth factor-ß (TGF-ß) levels increased significantly on day 1 following LDRT. Levels of chemokines increased from day 3 following LDRT. Additionally, M2 macrophage polarization or recruitment was increased following LDRT. We found that LDRT-induced TGF-ß reduced the levels of cytokines and polarized M2 cells and blocked immune cell infiltration, including neutrophils, in BALF. LDRT-induced early TGF-ß production was shown to be a key regulator involved in broad-spectrum anti-inflammatory activity in virus-infected lungs. Therefore, LDRT or TGF-ß may be an alternative therapy for viral pneumonia.

SARS-CoV2 infection induce miR-155 expression and skewed Th17/Treg balance by changing SOCS1 level: A clinical study.

BACKGROUND: One of the regulators in severe acute respiratory syndrome coronavirus2 (SARS-CoV2) infection is miRNAs. In COVID-19 patients, immunological responses to SARS-CoV2 infection may be impacted by miR-155, a miRNA associated to inflammation. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) of 50 confirmed COVID-19 patients /Healthy Controls (HCs) was isolated by Ficoll. The frequency of T helper 17 and regulatory T cells was analyzed by flowcytometry. The RNA was extracted from each sample and after synthesis of c-DNA, the relative expression of miR-155, suppressor of cytokine signaling (SOCS-1), Signal transducer and activator of transcription 3(STAT3), and Fork Head Box Protein 3 (FoxP3) was evaluated by real-time PCR. The protein level of STAT3, FoxP3 and RORγT in the isolated PBMCs measured by western blotting. The serum level of IL-10, TGF-ß, IL-17 and IL21 was assessed by ELISA method. RESULTS: The population of Th17 cells showed a significant rise, whereas Treg cells reduced in COVID-19 cases. The master transcription factor of Treg (FoxP3) and Th17 (RORγT) relative expression showed the same pattern as flowcytometry. STAT3 level of expression at RNA and protein level increased in COVID-19 cases. FOXP3 and SOCS-1 proteins were down-regulated. The relative expression of miR-155, up-regulated in PBMC of COVID-19 patients and revealed a negative correlation with SOCS-1. The serum cytokine profile showed a reduction in TGF-ß, on the other hand an increase was seen in IL-17, IL-21 and IL-10 in COVID-19 cases toward control group. CONCLUSION: Based on the studies conducted in this field, it can be suggested that Th17/Treg in covid-19 patients can be affected by miR-155 and it can be considered a valuable diagnostic and prognostic factor in this disease.

[Clinic and functional features of chronic obstructive pulmonary disease after virus-induced acute exacerbations.]

AIM: To establish symptoms, lung function and to evaluate subsequent exacerbations of chronic obstructive pulmonary disease (COPD) during a year after virus-induced COPD exacerbations. MATERIALS AND METHODS: Patients hospitalized with viral (n=60), bacterial (n=60) and viral-bacterial (n=60) COPD exacerbations were enrolled to single-center prospective observational study. COPD was diagnosed according spirography criteria. Viral infection was established in bronchoalveolar lavage fluid or sputum by real-time reverse transcription-polymerase chain reaction for RNA of influenza A and B virus, rhinovirus, respiratory syncytial virus and SARS-CoV-2. Symptoms, lung function, COPD exacerbations were assessed. Patients were investigated at the hospitalization onset and then 4 and 52 weeks following the discharge from the hospital. RESULTS: After 52 weeks in viral and viral-bacterial COPD exacerbations groups the rate of forced expiratory volume in one second (FEV1) decline were maximal - 71 (68; 73) ml/year and 69 (67; 72) ml/year versus 59 (55; 62) ml/year after bacterial exacerbations. Low levels of diffusion lung capacity for carbon monoxide (DLco/Va) - 52.5% (45.1%; 55.8%), 50.2% (44.9%; 56.0%) and 75.3% (72.2%; 80.1%) respectively, of 6-minute walk distance; p<0.001 in relation to bacterial exacerbations. In Cox proportional hazards regression analyses viral and viral-bacterial exacerbations were associated with increased risk of subsequent COPD exacerbations by 2.4 times independent of exacerbations rate before index event and FEV1. In linear regression models the relationships between airflow limitation and respiratory syncytial virus, rhinovirus and influenza virus infection, between low DLco/Va and rhinovirus, influenza virus and SARS-CoV-2 infection. CONCLUSION: COPD after virus-induced exacerbations were characterized by progression of airflow limitation, low DLco/Va, low 6-minute walking test distance, subsequent COPD exacerbations risk.

Innate and adaptive immunity to SARS-CoV-2 and predisposing factors.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has affected all countries worldwide. Although some symptoms are relatively mild, others are still associated with severe and even fatal clinical outcomes. Innate and adaptive immunity are important for the control of SARS-CoV-2 infections, whereas a comprehensive characterization of the innate and adaptive immune response to COVID-19 is still lacking and the mechanisms underlying immune pathogenesis and host predisposing factors are still a matter of scientific debate. Here, the specific functions and kinetics of innate and adaptive immunity involved in SARS-CoV-2 recognition and resultant pathogenesis are discussed, as well as their immune memory for vaccinations, viral-mediated immune evasion, and the current and future immunotherapeutic agents. We also highlight host factors that contribute to infection, which may deepen the understanding of viral pathogenesis and help identify targeted therapies that attenuate severe disease and infection.

CoVEffect: interactive system for mining the effects of SARS-CoV-2 mutations and variants based on deep learning.

BACKGROUND: Literature about SARS-CoV-2 widely discusses the effects of variations that have spread in the past 3 years. Such information is dispersed in the texts of several research articles, hindering the possibility of practically integrating it with related datasets (e.g., millions of SARS-CoV-2 sequences available to the community). We aim to fill this gap, by mining literature abstracts to extract-for each variant/mutation-its related effects (in epidemiological, immunological, clinical, or viral kinetics terms) with labeled higher/lower levels in relation to the nonmutated virus. RESULTS: The proposed framework comprises (i) the provisioning of abstracts from a COVID-19-related big data corpus (CORD-19) and (ii) the identification of mutation/variant effects in abstracts using a GPT2-based prediction model. The above techniques enable the prediction of mutations/variants with their effects and levels in 2 distinct scenarios: (i) the batch annotation of the most relevant CORD-19 abstracts and (ii) the on-demand annotation of any user-selected CORD-19 abstract through the CoVEffect web application (http://gmql.eu/coveffect), which assists expert users with semiautomated data labeling. On the interface, users can inspect the predictions and correct them; user inputs can then extend the training dataset used by the prediction model. Our prototype model was trained through a carefully designed process, using a minimal and highly diversified pool of samples. CONCLUSIONS: The CoVEffect interface serves for the assisted annotation of abstracts, allowing the download of curated datasets for further use in data integration or analysis pipelines. The overall framework can be adapted to resolve similar unstructured-to-structured text translation tasks, which are typical of biomedical domains.

COVID-19-Induced Myopathy and Diaphragmatic Weakness: A Case Report.

Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that can induce myopathy, which can evolve into potentially life-threatening muscle weakness, including diaphragmatic paralysis. We present a case report of a 57-year-old female treated in the medical ICU for acute respiratory distress syndrome (ARDS) triggered by active COVID-19 infection, who subsequently developed worsening respiratory weakness from underlying COVID-19 myopathy manifesting as respiratory muscle weakness. Our patient's muscle biopsy highlights the development of muscle atrophy without evidence of inflammatory myopathy, making the presence of pre-existing autoimmune myopathy unlikely. While literature cites different biochemical etiologies for the development of myopathy, the exact mechanism behind this phenomenon is not yet defined.