The lipopeptide Pam3CSK4 inhibits Rift Valley fever virus infection and protects from encephalitis.

Rift Valley fever virus (RVFV) is an encephalitic bunyavirus that can infect neurons in the brain. There are no approved therapeutics that can protect from RVFV encephalitis. Innate immunity, the first line of defense against infection, canonically antagonizes viruses through interferon signaling. We found that interferons did not efficiently protect primary cortical neurons from RVFV, unlike other cell types. To identify alternative neuronal antiviral pathways, we screened innate immune ligands and discovered that the TLR2 ligand Pam3CSK4 inhibited RVFV infection, and other bunyaviruses. Mechanistically, we found that Pam3CSK4 blocks viral fusion, independent of TLR2. In a mouse model of RVFV encephalitis, Pam3CSK4 treatment protected animals from infection and mortality. Overall, Pam3CSK4 is a bunyavirus fusion inhibitor active in primary neurons and the brain, representing a new approach toward the development of treatments for encephalitic bunyavirus infections.

Sequential Infection with Influenza A Virus Followed by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Leads to More Severe Disease and Encephalitis in a Mouse Model of COVID-19.

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence of SARS-CoV-2 with seasonal respiratory viruses, particularly influenza viruses, is a global health concern. To understand this, transgenic mice expressing the human ACE2 receptor (K18-hACE2) were infected with influenza A virus (IAV) followed by SARS-CoV-2 and the host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 alone. The sequentially infected mice showed reduced SARS-CoV-2 RNA synthesis, yet exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to the singly infected or control mice. Sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz Tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis, albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by IAV inhibits SARS-CoV-2. Interestingly, infection with an attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest coinfection ('twinfection') is deleterious and mitigation steps should be instituted as part of the comprehensive public health and management strategy of COVID-19.

[Epidemiological characteristic of viral encephalitis in children and adolescents in Henan Province, 2012-2023].

Objective: To understand the epidemiological characteristics and spatiotemporal distribution of viral encephalitis in children and adolescents in Henan Province from 2012 to 2023. Methods: The information about viral encephalitis cases from October 1, 2012 to July 26, 2023 were collected from Zhengzhou Children's Hospital (National Children's Regional Medical Center),Henan Provincial Children's Hospital for the analyses on temporal distribution the cases, the severe illness rate, age distribution, pathogen type and imaging findings of the cases. Results: A total of 6 276 cases of viral encephalitis were included in this study after excluding cases with incomplete information. The cases mainly originated from Zhengzhou (38.96%), followed by Zhoukou (9.93%), Xuchang (8.68%), Zhumadian (7.90%) and Pingdingshan (7.39%). The cases in boys accounted for 62.13% and the cases in girls accounted for 37.87%. Most cases (72.45%) occurred in age group 7-13 years. The overall rate of severe illness cases was 4.51% from 2012 to 2023. There were significant differences in severe illness cases among different areas and years (χ2=5.33,P=0.021; χ2=48.14,P<0.001). Enteroviruses were mainly detected (31.57%), in which Coxsackie virus was predominant (58.37%). Imaging findings showed that cerebral hemisphere damage was most common in children and adolescents with viral encephalitis (54.93%). Conclusions: From 2012 to 2023, more cases of viral encephalitis occurred in boys in Henan. Children and adolescents aged 7-13 years were the main affected group. The prevention of enteroviruses infection, especially Coxsackie virus, needs to be strengthened. Special attention should be paid to the prevention of cerebral hemisphere damage after viral encephalitis diagnosis.

Phenotypic and transcriptional changes in peripheral blood mononuclear cells during alphavirus encephalitis in mice.

Sindbis virus (SINV) infection of mice provides a model system for studying the pathogenesis of alphaviruses that infect the central nervous system (CNS) to cause encephalomyelitis. While studies of human viral infections typically focus on accessible cells from the blood, this compartment is rarely evaluated in mice. To bridge this gap, single-cell RNA sequencing (scRNAseq) was combined with flow cytometry to characterize the transcriptional and phenotypic changes of peripheral blood mononuclear cells (PBMCs) from SINV-infected mice. Twenty-one clusters were identified by scRNAseq at 7 days after infection, with a unique cluster and overall increase in naive B cells for infected mice. Uninfected mice had fewer immature T cells and CCR9+ CD4 T cells and a unique immature T cell cluster. Gene expression was most altered in the Ki67+ CD8 T cell cluster, with chemotaxis and proliferation-related genes upregulated. Global analysis indicated metabolic changes in myeloid cells and increased expression of Ccl5 by NK cells. Phenotypes of PBMCs and cells infiltrating the CNS were analyzed by flow cytometry over 14 days after infection. In PBMCs, CD8 and Th1 CD4 T cells increased in representation, while B cells showed a transient decrease at day 5 in total, Ly6a+, and naive cells, and an increase in activated B cells. In the brain, CD8 T cells increased for the first 7 days, while Th1 CD4 T cells and naive and Ly6a+ B cells continued to accumulate for 14 days. Therefore, dynamic immune cell changes can be identified in the blood as well as the CNS during viral encephalomyelitis. IMPORTANCE: The outcome of viral encephalomyelitis is dependent on the host immune response, with clearance and resolution of infection mediated by the adaptive immune response. These processes are frequently studied in mouse models of infection, where infected tissues are examined to understand the mechanisms of clearance and recovery. However, studies of human infection typically focus on the analysis of cells from the blood, a compartment rarely examined in mice, rather than inaccessible tissue. To close this gap, we used single-cell RNA sequencing and flow cytometry to profile the transcriptomic and phenotypic changes of peripheral blood mononuclear cells (PBMCs) before and after central nervous system (CNS) infection in mice. Changes to T and B cell gene expression and cell composition occurred in PBMC and during entry into the CNS, with CCL5 being a differentially expressed chemokine. Therefore, dynamic changes occur in the blood as well as the CNS during the response of mice to virus infection, which will inform the analysis of human studies.

Detection of encephalitis-causing viruses reveals predominance of chikungunya virus in the state of Bahia, Brazil.

OBJECTIVES: Encephalitis is a severe neurological syndrome for which herpesvirus and enteroviruses are the most common etiological agents. Arboviruses, a wildly diverse group of pathogens, are also critical epidemiological agents associated with encephalitis. In Brazil, little is known about the causative agents of encephalitis. METHODS: We conducted a hospital surveillance for encephalitis between 2020 and 2022. Molecular (RT-PCR and qPCR) and serological (virus-specific IgM and viral antigens) techniques were performed in cerebrospinal fluid and serum samples obtained from study participants. RESULTS: In the 43 participants evaluated, the etiologic agent or the presence of IgM was detected in 16 (37.2%). Nine (20.9%) cases were positive for chikungunya virus (CHIKV), three (7.0%) for dengue virus, two (4.7%) for human adenovirus, one (2.3%) for varicella-zoster virus, and one (2.3%) for enterovirus. Whole-genome sequencing revealed that the CHIKV identified belongs to the East/Central/South African lineage. CONCLUSION: Herein, CHIKV is a common pathogen identified in encephalitis cases. Our results reinforce previous evidence that chikungunya represents a significant cause of encephalitis during CHIKV outbreaks and epidemics and add to existing information on the epidemiology of encephalitis in Brazil.

First parechovirus reported case in Saudi Arabia in hospitalized immunocompromised adult patient.

Human parechovirus, a member of the Picornaviridae family (PeVs), can lead to severe infections, including severe meningitis, meningoencephalitis, and sepsis-like syndrome. We report a case of human parechovirus-related encephalitis in a 52-year-old woman diagnosed with glioblastoma multiforme. She underwent surgical resection in June 2022. Unfortunately, her disease recurred, and she underwent a second resection in August 2022, followed by radiation therapy and Temozolomide therapy. She presented to the hospital with acute confusion followed by seizures, necessitating intubation for airway support. A cerebrospinal fluid (CSF) sample was obtained and processed using the Biofire FilmArray, which reported the detection of HSV-1. Despite being on Acyclovir, the patient did not show signs of improvement. Consequently, a second CSF sample was obtained and sent for next-generation sequencing (NGS), which returned a positive result for Parechovirus. In this presented case, the patient exhibited symptoms of an unknown infectious cause. The utilization of NGS and metagenomic analysis helped identify Parechovirus as the primary pathogen present, in addition to previously identified HSV. This comprehensive approach facilitated a thorough assessment of the underlying infection and guided targeted treatment. In conclusion, the application of NGS techniques and metagenomic analysis proved instrumental in identifying the root cause of the infection.

Comparative study of virus and lymphocyte distribution with clinical data suggests early high dose immunosuppression as potential key factor for the therapy of patients with BoDV-1 infection.

ABSTRACTBorna disease virus 1 (BoDV-1) was just recently shown to cause predominantly fatal encephalitis in humans. Despite its rarity, bornavirus encephalitis (BVE) can be considered a model disease for encephalitic infections caused by neurotropic viruses and understanding its pathomechanism is of utmost relevance. Aim of this study was to compare the extent and distribution pattern of cerebral inflammation with the clinical course of disease, and individual therapeutic procedures. For this, autoptic brain material from seven patients with fatal BVE was included in this study. Tissue was stained immunohistochemically for pan-lymphocytic marker CD45, the nucleoprotein of BoDV-1, as well as glial marker GFAP and microglial marker Iba1. Sections were digitalized and counted for CD45-positive and BoDV-1-positive cells. For GFAP and Iba1, a semiquantitative score was determined. Furthermore, detailed information about the individual clinical course and therapy were retrieved and summarized in a standardized way. Analysis of the distribution of lymphocytes shows interindividual patterns. In contrast, when looking at the BoDV-1-positive glial cells and neurons, a massive viral involvement in the brain stem was noticeable. Three of the seven patients received early high-dose steroids, which led to a significantly lower lymphocytic infiltration of the central nervous tissue and a longer survival compared to the patients who were treated with steroids later in the course of disease. This study highlights the potential importance of early high-dose immunosuppressive therapy in BVE. Our findings hint at a promising treatment option which should be corroborated in future observational or prospective therapy studies.ABBREVIATIONS: BoDV-1: Borna disease virus 1; BVE: bornavirus encephalitis; Cb: cerebellum; CNS: central nervous system; FL: frontal lobe; GFAP: glial fibrillary acid protein; Hc: hippocampus; Iba1: ionized calcium-binding adapter molecule 1; Iba1act: general activation of microglial cells; Iba1nod: formation of microglial nodules; IL: insula; Me: mesencephalon; Mo: medulla oblongata; OL: occipital lobe; pASS: per average of 10 screenshots; patearly: patients treated with early high dose steroid shot; patlate: patients treated with late or none high dose steroid shot; Po: pons; So: stria olfactoria; Str: striatum.

Hybrid capture shotgun sequencing detected unexpected viruses in the cerebrospinal fluid of children with acute meningitis and encephalitis.

PURPOSE: Investigation of undiagnosed cases of infectious neurological diseases, especially in the paediatric population, remains a challenge. This study aimed to enhance understanding of viruses in CSF from children with clinically diagnosed meningitis and/or encephalitis (M/ME) of unknown aetiology using shotgun sequencing enhanced by hybrid capture (HCSS). METHODS: A single-centre prospective study was conducted at Sant Joan de Déu University Hospital, Barcelona, involving 40 M/ME episodes of unknown aetiology, recruited from May 2021 to July 2022. All participants had previously tested negative with the FilmArray Meningitis/Encephalitis Panel. HCSS was used to detect viral nucleic acid in the patients' CSF. Sequencing was performed on Illumina NovaSeq platform. Raw sequence data were analysed using CZ ID metagenomics and PikaVirus bioinformatics pipelines. RESULTS: Forty episodes of M/ME of unknown aetiology in 39 children were analysed by HCSS. A significant viral detection in 30 CSF samples was obtained, including six parechovirus A, three enterovirus ACD, four polyomavirus 5, three HHV-7, two BKV, one HSV-1, one VZV, two CMV, one EBV, one influenza A virus, one rhinovirus, and 13 HERV-K113 detections. Of these, one sample with BKV, three with HHV-7, one with EBV, and all HERV-K113 were confirmed by specific PCR. The requirement for Intensive Care Unit admission was associated with HCSS detections. CONCLUSION: This study highlights HCSS as a powerful tool for the investigation of undiagnosed cases of M/ME. Data generated must be carefully analysed and reasonable precautions must be taken before establishing association of clinical features with unexpected or novel virus findings.

Bovine astrovirus and its role in lymphocytic encephalitis in cattle in Ontario, Canada, 1988-2019.

Astroviruses have been found in cattle and other species with encephalitis. Our objective was to determine the frequency of neurotropic bovine astrovirus (BoAstV) in cases of encephalitis in cattle ≥ 4-mo-old. Of 56 cases of idiopathic lymphocytic encephalitis examined retrospectively (1988-2019), fixed brain from 11 cases (19%) tested positive by semi-quantitative RT-PCR for BoAstV CH13/NeuroS1. None of the control cases tested positive, including 32 with other forms of encephalitis and 40 with no neurologic disease. Most astrovirus-positive cases were 1-2-y-old, with a range of 7 mo to 7 y, and affected both beef and dairy breeds with wide geographic distribution. BoAstV-positive cases had acute onset of neurologic signs of 12 h to 7 d before death or euthanasia. Affected cattle had lymphocytic inflammation throughout the brain including cerebrum, thalamus, midbrain, cerebellum, medulla oblongata, and spinal cord, and affecting gray and white matter. Further PCR testing identified a possible cause in 9 of the 45 (20%) remaining idiopathic cases of lymphocytic encephalitis, including eastern equine encephalitis virus, Listeria monocytogenes, bovine viral diarrhea virus, bovine alphaherpesvirus 1, and ovine gammaherpesvirus 2 (malignant catarrhal fever); we found no cases of infection by West Nile virus, rabies virus, or Chlamydia spp. No cause was identified in 36 of 56 (64%) cases of lymphocytic encephalitis. We frequently identified neurotropic BoAstV in cases of lymphocytic encephalitis that had no previously identified cause. Neurotropic BoAstV infections had gone undetected for decades, but the frequency of BoAstV infections has not increased among contemporary cases.

Genetic Comparison of Human Parainfluenza Virus Type 3 Detected in Respiratory Samples from Patients with Encephalopathy and Airway Inflammation in Aichi Prefecture, Japan.

Human parainfluenza virus type 3 (HPIV-3, human respirovirus 3) is the second most frequently detected virus in lower respiratory tract infections in children after human respiratory syncytial virus (HRSV). HPIV-3, similar to related respiratory viruses such as HRSV and influenza virus, may cause encephalopathy; however, the relevance of HPIV-3 as a pathogenic factor in encephalopathy is unknown. We attempted to detect HPIV-1, HPIV-2, HPIV-3, HPIV-4, HRSV, and human metapneumovirus (HMPV) in 136 patients with encephalitis/encephalopathy or suspected encephalitis/encephalopathy during a 6-year period from 2014 to 2019. HPIV-3 was detected in 6 patients, followed by HRSV in 3 patients. The HPIV-3 strains detected were closely related to those detected in a patient with respiratory disease during the same period. Although HPIV-3 is less widely recognized than HRSV as a triggering virus of encephalopathy, our results suggest that HPIV-3 is as important as HRSV. Surveillance of the causative viruses of encephalopathy, including HPIV-3, would help clarify the causes of encephalopathy in Japan, as the cause is currently reported in less than half of cases in Japan.

Neural-Cell-Intrinsic NF-κB Signaling Enhances Reovirus Virulence.

Pathological effects of apoptosis associated with viral infections of the central nervous system are an important cause of morbidity and mortality. Reovirus is a neurotropic virus that causes apoptosis in neurons, leading to lethal encephalitis in newborn mice. Reovirus-induced encephalitis is diminished in mice with germ line ablation of NF-κB subunit p50. It is not known whether the proapoptotic function of NF-κB is mediated by neural-cell-intrinsic (neural-intrinsic) processes, NF-κB-regulated cytokine production by inflammatory cells, or a combination of both. To determine the contribution of cell type-specific NF-κB signaling in reovirus-induced neuronal injury, we established mice that lack NF-κB p65 expression in neural cells using the Cre/loxP recombination system. Following intracranial inoculation of reovirus, 50% of wild-type (WT) mice succumbed to infection, whereas more than 90% of mice lacking neural cell NF-κB p65 (Nsp65-/-) survived. While viral loads in brains of WT and Nsp65-/- mice were comparable, histological analysis revealed that reovirus antigen-positive areas in the brains of WT mice displayed increased immunoreactivity for cleaved caspase-3, a marker of apoptosis, relative to Nsp65-/- mice. These data suggest that neural-intrinsic NF-κB-dependent factors are essential mediators of reovirus neurovirulence. RNA sequencing analysis of reovirus-infected brain cortices of WT and Nsp65-/- mice suggests that NF-κB activation in neuronal cells upregulates genes involved in innate immunity, inflammation, and cell death following reovirus infection. A better understanding of the contribution of cell type-specific NF-κB-dependent signaling to viral neuropathogenesis could inform development of new therapeutics that target and protect highly vulnerable cell populations. IMPORTANCE Viral encephalitis contributes to illness and death in children and adults worldwide and has limited treatment options. Identifying common host factors upregulated by neurotropic viruses can enhance an understanding of virus-induced neuropathogenesis and aid in development of therapeutics. Although many neurotropic viruses activate NF-κB during infection, mechanisms by which NF-κB regulates viral neuropathogenesis and contributes to viral encephalitis are not well understood. We established mice in which NF-κB expression is ablated in neural tissue to study the function of NF-κB in reovirus neurovirulence and identify genes activated by NF-κB in response to reovirus infection in the central nervous system. Encephalitis following reovirus infection was dampened in mice lacking neural cell NF-κB. Reovirus induced a chemokine profile in the brain that was dependent on NF-κB signaling and was similar to chemokine profiles elicited by other neurotropic viruses. These data suggest common underlying mechanisms of encephalitis caused by neurotropic viruses and potentially shared therapeutic targets.

Human Borna disease virus 1 (BoDV-1) encephalitis cases in the north and east of Germany.

In 2021, three encephalitis cases due to the Borna disease virus 1 (BoDV-1) were diagnosed in the north and east of Germany. The patients were from the states of Thuringia, Saxony-Anhalt, and Lower Saxony. All were residents of known endemic areas for animal Borna disease but without prior diagnosed human cases. Except for one recently detected case in the state of Brandenburg, all >30 notified cases had occurred in, or were linked to, the southern state of Bavaria. Of the three detected cases described here, two infections were acute, while one infection was diagnosed retrospectively from archived brain autopsy tissue samples. One of the acute cases survived, but is permanently disabled. The cases were diagnosed by various techniques (serology, molecular assays, and immunohistology) following a validated testing scheme and adhering to a proposed case definition. Two cases were classified as confirmed BoDV-1 encephalitis, while one case was a probable infection with positive serology and typical brain magnetic resonance imaging, but without molecular confirmation. Of the three cases, one full virus genome sequence could be recovered. Our report highlights the need for awareness of a BoDV-1 etiology in cryptic encephalitis cases in all areas with known animal Borna disease endemicity in Europe, including virus-endemic regions in Austria, Liechtenstein, and Switzerland. BoDV-1 should be actively tested for in acute encephalitis cases with residence or rural exposure history in known Borna disease-endemic areas.

Characterization of Pathogenesis and Inflammatory Responses to Experimental Parechovirus Encephalitis.

Human parechovirus type 3 (PeV-A3) infection has been recognized as an emerging etiologic factor causing severe nerve disease or sepsis in infants and young children. But the neuropathogenic mechanisms of PeV-A3 remain unknown. To understand the pathogenesis of PeV-A3 infection in the neuronal system, PeV-A3-mediated cytopathic effects were analyzed in human glioblastoma cells and neuroblastoma cells. PeV-A3 induced interferons and inflammatory cytokine expression in these neuronal cells. The pronounced cytopathic effects accompanied with activation of death signaling pathways of apoptosis, autophagy, and pyroptosis were detected. A new experimental disease model of parechovirus encephalitis was established. In the disease model, intracranial inoculation with PeV-A3 in C57BL/6 neonatal mice showed body weight loss, hindlimb paralysis, and approximately 20% mortality. PeV-A3 infection in the hippocampus and cortex regions of the neonatal mouse brain was revealed. Mechanistic assay supported the in vitro results, indicating detection of PeV-A3 replication, inflammatory cytokine expression, and death signaling transduction in mouse brain tissues. These in vitro and in vivo studies revealed that the activation of death signaling and inflammation responses is involved in PeV-A3-mediated neurological disorders. The present results might account for some of the PeV-A3-associated clinical manifestations.

Innate Immune Signaling and Role of Glial Cells in Herpes Simplex Virus- and Rabies Virus-Induced Encephalitis.

The environment of the central nervous system (CNS) represents a double-edged sword in the context of viral infections. On the one hand, the infectious route for viral pathogens is restricted via neuroprotective barriers; on the other hand, viruses benefit from the immunologically quiescent neural environment after CNS entry. Both the herpes simplex virus (HSV) and the rabies virus (RABV) bypass the neuroprotective blood-brain barrier (BBB) and successfully enter the CNS parenchyma via nerve endings. Despite the differences in the molecular nature of both viruses, each virus uses retrograde transport along peripheral nerves to reach the human CNS. Once inside the CNS parenchyma, HSV infection results in severe acute inflammation, necrosis, and hemorrhaging, while RABV preserves the intact neuronal network by inhibiting apoptosis and limiting inflammation. During RABV neuroinvasion, surveilling glial cells fail to generate a sufficient type I interferon (IFN) response, enabling RABV to replicate undetected, ultimately leading to its fatal outcome. To date, we do not fully understand the molecular mechanisms underlying the activation or suppression of the host inflammatory responses of surveilling glial cells, which present important pathways shaping viral pathogenesis and clinical outcome in viral encephalitis. Here, we compare the innate immune responses of glial cells in RABV- and HSV-infected CNS, highlighting different viral strategies of neuroprotection or Neuroinflamm. in the context of viral encephalitis.

Lyssaviruses and the Fatal Encephalitic Disease Rabies.

Lyssaviruses cause the disease rabies, which is a fatal encephalitic disease resulting in approximately 59,000 human deaths annually. The prototype species, rabies lyssavirus, is the most prevalent of all lyssaviruses and poses the greatest public health threat. In Africa, six confirmed and one putative species of lyssavirus have been identified. Rabies lyssavirus remains endemic throughout mainland Africa, where the domestic dog is the primary reservoir - resulting in the highest per capita death rate from rabies globally. Rabies is typically transmitted through the injection of virus-laden saliva through a bite or scratch from an infected animal. Due to the inhibition of specific immune responses by multifunctional viral proteins, the virus usually replicates at low levels in the muscle tissue and subsequently enters the peripheral nervous system at the neuromuscular junction. Pathogenic rabies lyssavirus strains inhibit innate immune signaling and induce cellular apoptosis as the virus progresses to the central nervous system and brain using viral protein facilitated retrograde axonal transport. Rabies manifests in two different forms - the encephalitic and the paralytic form - with differing clinical manifestations and survival times. Disease symptoms are thought to be due mitochondrial dysfunction, rather than neuronal apoptosis. While much is known about rabies, there remain many gaps in knowledge about the neuropathology of the disease. It should be emphasized however, that rabies is vaccine preventable and dog-mediated human rabies has been eliminated in various countries. The global elimination of dog-mediated human rabies in the foreseeable future is therefore an entirely feasible goal.

Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients.

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRß in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood-brain barrier.

Polarization of Type 1 Macrophages Is Associated with the Severity of Viral Encephalitis Caused by Japanese Encephalitis Virus and Dengue Virus.

Infection with flaviviruses causes mild to severe diseases, including viral hemorrhagic fever, vascular shock syndrome, and viral encephalitis. Several animal models explore the pathogenesis of viral encephalitis, as shown by neuron destruction due to neurotoxicity after viral infection. While neuronal cells are injuries caused by inflammatory cytokine production following microglial/macrophage activation, the blockade of inflammatory cytokines can reduce neurotoxicity to improve the survival rate. This study investigated the involvement of macrophage phenotypes in facilitating CNS inflammation and neurotoxicity during flavivirus infection, including the Japanese encephalitis virus, dengue virus (DENV), and Zika virus. Mice infected with different flaviviruses presented encephalitis-like symptoms, including limbic seizure and paralysis. Histology indicated that brain lesions were identified in the hippocampus and surrounded by mononuclear cells. In those regions, both the infiltrated macrophages and resident microglia were significantly increased. RNA-seq analysis showed the gene profile shifting toward type 1 macrophage (M1) polarization, while M1 markers validated this phenomenon. Pharmacologically blocking C-C chemokine receptor 2 and tumor necrosis factor-α partly retarded DENV-induced M1 polarization. In summary, flavivirus infection, such as JEV and DENV, promoted type 1 macrophage polarization in the brain associated with encephalitic severity.

REPORT-Mild encephalitis/encephalopathy with a reversible splenial lesion associated with mumps infection: A case report.

We describe for the first time an child who demonstrated Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) after mumps infection in China. In this report, a 12-year-old boy came to Children's Hospital Affiliated to Zhengzhou University due to fever, swelling and pain under the earlobe for 4 days, and headache and vomiting for half of a day. Laboratory examinations showed a blood sodium level of 125mmol/L, both the Immunoglobulin M and Polymerase Chain Reaction results for the serum mumps virus were positive. Brain Magnetic Resonance Imaging (MRI) showed slight hypointense on T1 weighted images, hyperintense on T2-weighted images, fluid attenuated inversion recovery, diffusion-weighted images in the splenium of the corpus callosum indicative of MERS. On the 8th day, the patient no longer had swelling and pain around the parotid salivary glands, the sodium levels returned to normal. Onset of 14th d, follow-up brain MRI did not reveal any abnormalities. The case given to us indicates that MERS should be considered when patients after mumps infection presents with neurological symptoms and MRI should be performed to evaluate the splenium of the corpus callosum.

A Nanobody-Mediated Virus-Targeting Drug Delivery Platform for the Central Nervous System Viral Disease Therapy.

Viral diseases of the central nervous system (CNS) represent a major global health concern. Difficulties in treating these diseases are caused mainly by the biological tissues and barriers, which hinder the transport of drugs into the CNS. To counter this, a nanobody-mediated virus-targeting drug delivery platform (SWCNTs-P-A-Nb) is constructed for CNS viral disease therapy. Viral encephalopathy and retinopathy (VER), caused by nervous necrosis virus (NNV), is employed as a disease model. SWCNTs-P-A-Nb is successfully constructed by employing single-walled carbon nanotubes, amantadine, and NNV-specific nanobody (NNV-Nb) as the nanocarrier, anti-NNV drug, and targeting ligand, respectively. Results showed that SWCNTs-P-A-Nb has a good NNV-targeting ability in vitro and in vivo, improving the specific distribution of amantadine in NNV-infected sites under the guidance of NNV-Nb. SWCNTs-P-F-A-Nb can pass through the muscle and gill and be excreted by the kidney. SWCNTs-P-A-Nb can transport amantadine in a fast manner and prolong the action time, improving the anti-NNV activity of amantadine. Results so far have indicated that the nanobody-mediated NNV-targeting drug delivery platform is an effective method for VER therapy, providing new ideas and technologies for control of the CNS viral diseases. IMPORTANCE CNS viral diseases have resulted in many deadly epidemics throughout history and continue to pose one of the greatest threats to public health. Drug therapy remains challenging due to the complex structure and relative impermeability of the biological tissues and barriers. Therefore, development in the intelligent drug delivery platform is highly desired for CNS viral disease therapy. In the study, a nanobody-mediated virus-targeting drug delivery platform is constructed to explore the potential application of targeted therapy in CNS viral diseases. Our findings hold great promise for the application of targeted drug delivery in CNS viral disease therapy.

COVID-19 and the Eye: Ocular Manifestations, Treatment and Protection Measures.

The novel pandemic coronavirus disease 2019 (COVID-19) leading to health and economic problems worldwide is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 mainly occurs as a lower respiratory tract infection, there is multiorgan involvement in infected patients. The disease is transmitted from person to person through air droplets or contact with contaminated surfaces. SARS-CoV-2 leads to this systemic involvement by attaching to angiotensin-converting enzyme 2 (ACE2) receptors located on several human cells. Since SARS-CoV-2 RNA has been found in tears of infected patients, ocular surface may allow the virus to transmit to nasopharynx via the nasolacrimal duct. This narrative review aims to sum up all segmental ocular complications, ocular adverse effects of COVID-19 treatment, and preventive measures suggested to minimize the SARS-CoV-2 transmission between patients and ophthalmologists by reviewing currently available literature.