Neuroinvasive Virus Research Articles

Molecular Insights into The Mechanisms of Rabies Virus Neuroinvasion And Pathogenicity: A Review Article

Molecular Insights into The Mechanisms of Rabies Virus Neuroinvasion And Pathogenicity: A Review Article

Investigating human monocyte adhesion, migration and transmigration and their modulation by Zika virus

Human circulating monocytes are established targets for Zika virus (ZIKV) infection. Because of their important migratory properties toward any tissues, including the central nervous system (CNS), a better understanding of the mechanisms underlying monocyte transmigration upon ZIKV infection is required. Here, we monitored adhesion, migration and transmigration properties of monocytes exposed to ZIKV. We found that ZIKV enhanced monocyte adhesion on collagen compared to mock-exposed samples, and that pharmacological inhibition of mDia and Cdc42 function induced a significant decrease of adhesion in both mock- and ZIKV-exposed monocytes. In contrast, monocyte migration through collagen was inhibited by most of the tested small molecules targeting regulators of actin polymerization, including Rac1, ROCK, Cdc42, mDia, Arp2/3, Myosin-II and LFA-1. ZIKV-exposed monocyte migration showed a very similar profile to that of their mock-exposed counterparts. Finally, assessment of monocyte transmigration through human cerebral microvascular endothelial cells (hCMEC/D3) showed dependency on Rac1, ROCK, and Cdc42, independently of their infection status. In contrast, we identified that BIRT377, an antagonist of LFA-1, significantly inhibited transmigration of ZIKV-exposed but not mock-exposed monocytes. As BIRT377 increased adhesion of ZIKV-exposed monocytes, we propose that LFA-1 might be involved in a post-adhesion step to enhance viro-induced transmigration. These data suggest that ZIKV exposure triggers specific migratory properties of monocytes that are not exploited under physiological conditions. This work provides further insights on virus-host interactions important for viral neuroinvasion and offers novel targets to specifically inhibit the infiltration of infected cells to the CNS. Summary sentenceMonocyte transmigration involves massive actin cytoskeleton reorganization regulated by small Rho GTPases and integrins, which can be subverted by viruses.

A Disease Hidden in Plain Sight: Pathways and Mechanisms of Neurological Complications of Post-acute Sequelae of COVID-19 (NC-PASC).

The global impact of coronavirus disease 2019 (COVID-19) marked by numerous pandemic peaks is attributed to its high variability and infectious nature, transforming it into a persistent global public health concern. With hundreds of millions of cases reported globally, the illness is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite its initial classification as an acute respiratory illness, recent evidence indicates that lingering effects on various bodily systems, such as cardiovascular, pulmonary, nervous, gastrointestinal (GI), and musculoskeletal, may endure well beyond the acute phase. These persistent manifestations following COVID-19, commonly known as long COVID, have the potential to affect individuals across the entire range of illness severity, with a tendency to be more prevalent in mild to moderate cases. At present, there are no established criteria for diagnosing long COVID. Nonetheless, it is conceptualized as a multi-organ disorder encompassing a diverse array of clinical manifestations. The most common, persistent, and debilitating symptoms of long COVID may be neurological, known as neurological complications of post-acute sequelae of COVID-19 (NC-PASC). More than one-third of individuals with a prior SARS-CoV-2 infection show involvement of both the central nervous system (CNS) and peripheral nervous system (PNS), as evidenced by an approximately threefold higher incidence of neurological symptoms in observational studies. The persistent neurological symptoms of long COVID encompass fatigue, headache, cognitive decline, "brain fog", dysautonomia, neuropsychiatric issues, loss of smell (anosmia), loss of taste (ageusia), and peripheral nerve problems (peripheral neuropathy). Reported pathogenic mechanisms encompass viral persistence and neuro-invasion by SARS-CoV-2, neuroinflammation, autoimmunity, coagulopathy, and endotheliopathy. Raising awareness of potential complications is crucial for preventing and alleviating the long-term effects of long COVID and enhancing the prognosis for affected patients. This review explores the hypothetical pathophysiological mechanisms and pathways of NC-PASC with a sole aim to increase awareness about this crippling disease.

Targeting monocytic Occludin impairs transendothelial migration and HIV neuroinvasion

Transmigration of circulating monocytes from the bloodstream to tissues represents an early hallmark of inflammation. This process plays a pivotal role during viral neuroinvasion, encephalitis, and HIV-associated neurocognitive disorders. How monocytes locally unzip endothelial tight junction-associated proteins (TJAPs), without perturbing impermeability, to reach the central nervous system remains poorly understood. Here, we show that human circulating monocytes express the TJAP Occludin (OCLN) to promote transmigration through endothelial cells. We found that human monocytic OCLN (hmOCLN) clusters at monocyte-endothelium interface, while modulation of hmOCLN expression significantly impacts monocyte transmigration. Furthermore, we designed OCLN-derived peptides targeting its extracellular loops (EL) and show that transmigration of treated monocytes is inhibited in vitro and in zebrafish embryos, while preserving vascular integrity. Monocyte transmigration toward the brain is an important process for HIV neuroinvasion and we found that the OCLN-derived peptides significantly inhibit HIV dissemination to cerebral organoids. In conclusion, our study identifies an important role for monocytic OCLN during transmigration and provides a proof-of-concept for the development of mitigation strategies to prevent monocyte infiltration and viral neuroinvasion.

The mutation of Japanese encephalitis virus envelope protein residue 389 attenuates viral neuroinvasiveness

The envelope (E) protein of the Japanese encephalitis virus (JEV) is a key protein for virus infection and adsorption of host cells, which determines the virulence of the virus and regulates the intensity of inflammatory response. The mutation of multiple aa residues in the E protein plays a critical role in the attenuated strain of JEV. This study demonstrated that the Asp to Gly, Ser, and His mutation of the E389 site, respectively, the replication ability of the viruses in cells was significantly reduced, and the viral neuroinvasiveness was attenuated to different degrees. Among them, the mutation at E389 site enhanced the E protein flexibility contributed to the attenuation of neuroinvasiveness. In contrast, less flexibility of E protein enhanced the neuroinvasiveness of the strain. Our results indicate that the mechanism of attenuation of E389 aa mutation attenuates neuroinvasiveness is related to increased flexibility of the E protein. In addition, the increased flexibility of E protein enhanced the viral sensitivity to heparin inhibition in vitro, which may lead to a decrease in the viral load entering brain. These results suggest that E389 residue is a potential site affecting JEV virulence, and the flexibility of the E protein of aa at this site plays an important role in the determination of neuroinvasiveness.

Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2

In the wake of the COVID-19 pandemic caused by SARS-CoV-2, questions emerged about the potential effects of Bacillus Calmette-Guérin (BCG) vaccine on the immune response to SARS-CoV-2 infection, including the neurodegenerative diseases it may contribute to. To explore this, an experimental study was carried out in BCG-stimulated and non-stimulated k18-hACE2 mice challenged with SARS-CoV-2. Viral loads in tissues determined by RT-qPCR, histopathology in brain and lungs, immunohistochemical study in brain (IHC) as well as mortality rates, clinical signs and plasma inflammatory and coagulation biomarkers were assessed. Our results showed BCG-SARS-CoV-2 challenged mice presented higher viral loads in the brain and an increased frequency of neuroinvasion, with the greatest differences observed between groups at 3–4 days post-infection (dpi). Histopathological examination showed a higher severity of brain lesions in BCG-SARS-CoV-2 challenged mice, mainly consisting of neuroinflammation, increased glial cell population and neuronal degeneration, from 5 dpi onwards. This group also presented higher interstitial pneumonia and vascular thrombosis in lungs (3–4 dpi), BCG-SARS-CoV-2 mice showed higher values for TNF-α and D-dimer values, while iNOS values were higher in SARS-CoV-2 mice at 3–4 dpi. Results presented in this study indicate that BCG stimulation could have intensified the inflammatory and neurodegenerative lesions promoting virus neuroinvasion and dissemination in this experimental model. Although k18-hACE2 mice show higher hACE2 expression and neurodissemination, this study suggests that, although the benefits of BCG on enhancing heterologous protection against pathogens and tumour cells have been broadly demonstrated, potential adverse outcomes due to the non-specific effects of BCG should be considered.

Clinical and Diagnostic Features of West Nile Virus Neuroinvasive Disease in New York City.

West Nile virus (WNV) neuroinvasive disease (WNND) occurs in approximately 1 percent of WNV-infected patients and typically presents as encephalitis, meningitis, or acute flaccid paralysis (AFP). WNND remains a difficult inpatient diagnosis, creating significant challenges for prognostication and therapy selection. We characterized the clinical and diagnostic features of WNND cases at two major academic medical centers in New York City in routine clinical practice. We retrospectively reviewed the charts of thirty-six patients with WNND, including twenty-six encephalitis, four meningitis, and six AFP cases. The most common presenting symptoms were fever (86.1%) and gastrointestinal symptoms (38.9%) in addition to altered mental status (72.2%), lethargy (63.9%), gait disturbances (46.2%), and headache (44.4%). Fourteen (48.3%) patients displayed acute magnetic resonance imaging (MRI) findings, particularly T2 hyperintensities in the bilateral thalami, brainstem, and deep white matter. New York State Department of Health WNV CSF IgM testing was utilized for diagnosis in 58.3% of patients; however, just 38.1% had the result by discharge, compared to 85.6% of those who underwent serum IgM testing. The median length of stay was 13.5 days, 38.9% were intubated, and three patients (8.9%) died during acute hospitalization. Our findings underscore the morbidity, mortality, and diagnostic challenges of WNND, suggesting the potential utility of serum IgM testing in combination with confirmatory CSF testing to expedite diagnosis in the acute setting.

Potential therapeutic strategies to halt viral neuroinvasion.

The viral infection of the central nervous system is a significant public health concern. So far, most clinical cases of viral neuroinvasion are dealt with supportive and/or symptomatic treatments due to the unavailability of specific treatments. Thus, developing specific therapies is required to alleviate neurological symptoms and disorders. In this review, we shed light on molecular aspects of viruses' entry into the brain which upon targeting with specific drugs have shown promising efficacy in vitro and in preclinical in vivo model systems. Further assessing the therapeutic potential of these drugs in clinical trials may offer opportunities to halt viral neuroinvasion in humans.

Neuroinvasive virus facilitates viral replication by employing lipid droplets to reduce arachidonic acid-induced ferroptosis

Lipids have been previously implicated in the lifecycle of neuroinvasive viruses. However, the role of lipids in programmed cell death and the relationship between programmed cell death and lipid droplets (LDs) in neuroinvasive virus infection remains unclear. Here, we found that the infection of neuroinvasive virus, such as rabies virus and encephalomyocarditis virus could enhance the LD formation in N2a cells, and decreasing LDs production by targeting diacylglycerol acyltransferase could suppress viral replication. The lipidomics analysis revealed that arachidonic acid (AA) was significantly increased after reducing LD formation by restricting diacylglycerol acyltransferase, and AA was further demonstrated to induce ferroptosis to inhibit neuroinvasive virus replication. Moreover, lipid peroxidation and viral replication inhibition could be significantly alleviated by a ferroptosis inhibitor, ferrostatin-1, indicating that AA affected neuroinvasive virus replication mainly through inducing ferroptosis. Furthermore, AA was demonstrated to activate the acyl-CoA synthetase long-chain family member 4-lysophosphatidylcholine acyltransferase 3-cytochrome P450 oxidoreductase axis to induce ferroptosis. Our findings highlight novel cross-talks among viral infection, LDs, and ferroptosis for the first time, providing a potential target for antiviral drug development.

Capsid protein mediated evasion of IRAK1-dependent signalling is essential to Sindbis virus neuroinvasion and virulence in mice

ABSTRACT Alphaviruses are arthropod-borne, single-stranded positive-sense RNA viruses that are recognized as rapidly emerging pathogens. Despite being exquisitely sensitive to the effects of the innate immune response alphaviruses can readily replicate, disseminate, and induce pathogenesis in immunologically competent hosts. Nonetheless, how alphaviruses evade the induction of an innate immune response prior to viral gene expression, or in non-permissive infections, is unknown. Previously we reported the identification of a novel host/pathogen interaction between the viral Capsid (CP) protein and the host IRAK1 protein. The CP/IRAK1 interaction was determined to negatively impact IRAK1-dependent PAMP detection in vitro, however, the precise importance of the CP/IRAK1 interaction to alphaviral infection remained unknown. Here we detail the identification of the CP/IRAK1 interaction determinants of the Sindbis virus (SINV) CP protein and examine the importance of the interaction to alphaviral infection and pathogenesis in vivo using an interaction deficient mutant of the model neurotropic strain of SINV. Importantly, these interaction determinants are highly conserved across multiple Old-World alphaviruses, including Ross River virus (RRV), Mayaro virus (MAYV), Chikungunya virus (CHIKV), and Semliki Forest virus (SFV). In the absence of a functional CP/IRAK1 interaction, SINV replication is significantly restricted and fails to disseminate from the primary site of inoculation due to the induction of a robust type-I Interferon response. Altogether these data indicate that the evasion of IRAK1-dependent signalling is critical to overcoming the host innate immune response and the in vivo data presented here demonstrate the importance of the CP/IRAK1 interaction to neurovirulence and pathogenesis.

A Review on Contentious Role of HSV1 in Alzheimer’s Disease and Natural Dietary Benefits to Prevent HSV

Herpes simplex virus 1 (HSV1) is a neuro-invasive virus causing lifelong latent infection in humans. It increases the risk of dementia by entering inside the brain. Herpesviruses have been implicated in Alzheimer’s disease (AD) development. More than 50 million people worldwide are affected by Alzheimer’s disease. Alzheimer’s disease is becoming more prevalent with the increase age-related neurodegenerative diseases, dementia, etc. Therefore, there is an urgent need for better understanding of the pathogenesis of AD as well as its early detection. HSV-1 is a risk factor of for the occurrence of neurodegenerative diseases, sporadic Alzheimer’s disease, prior diagnosis of disease cycle of Herpes Simplex Virus Type 1 in brain tissue will help us to prevent AD in elderly patients. Serological assays were the first choice of detection including whole-antigen-based (non-gG-specific) methods and western blotting (WB) assays, but quantitative PCR (qPCR) & genomic sequencing has shown better efficiency. Recently RNAscope, a novel in situ RNA hybridization assay is developed to visualize and detect the multiple phases of HSV-1. In this review, we discussed about early detection of tau and β-amyloid protein which are biomarkers of AD and track the deposition of amyloid plaques reminiscent in brain. We also discussed the current work on HSV detection through RNAscope hybridization technique & summarized the role of dietary habits as a precautionary measure of the infection as well as anthropological diversification of dementia in India and factors influencing it. We also pointed out some knowledge gaps that are further required to be taken after detection of the infection.

COVID-19 encephalopathy with severe neurological symptoms: a clinical case presentation with literature review

COVID-19 infection is affecting more and more people around the world, and as the number of recovered patients increases, so does the knowledge on the potential clinical signs of the disease. Although SARS-CoV-2 virus is commonly associated with damage to the respiratory system, it has been observed that about half of patients with COVID-19 infection may also develop various neurological symptoms such as anosmia, dysgeusia, headache, myalgia, or dizziness. Encephalopathy is singled out as one of the most severe complications of the central nervous system caused by SARS-CoV-2 virus and associated with longer duration of the disease, increased disability, and mortality. Acute encephalopathy is a disorder of the brain that clinically occurs with a sudden change in the level of consciousness in otherwise healthy patients before the onset of symptoms. Risk factors include older age, male gender, quicker hospitalization after the onset of symptoms, and chronic illnesses. In exceptional cases, encephalopathy may be an early or even a major symptom of COVID-19 in young patients. The pathogenesis of COVID-19 encephalopathy is not fully understood. However, the most likely etiology of encephalopathy is multifactorial: systemic disease response, inflammation, coagulopathy, direct viral neuroinvasion, endoartheritis, and possibly post-infectious autoimmune mechanisms. For patients with suspected changes in the level of consciousness due to coronavirus infection, it is recommended to perform a thorough examination of the cerebrospinal fluid (CSF), head imaging with a preference for magnetic resonance imaging (MRI), and electroencephalography (EEG) It is worth noting that blood or imaging tests often do not show specific changes in patients with encephalopathy. As revealed by some studies of CSF examinations, cytosis is usually absent or very low while the protein concentration remains normal. It is important to note that SARS-CoV-2 is detected in the cerebral fluid only in isolated cases. Although the EEG of patients with COVID-19 are often normal, they sometimes show specific encephalopathic changes including excessive generalized frontal delta waves, triphasic waves and lower amplitude alpha and beta waves. The MRI describes a spectrum of neurovisual abnormalities, the most common of which are foci of leukoencephalopathy, changes in diffusion restriction imaging in the white, rarely in the gray matter, signs of microhaemorrhage and leptomeningitis. Treatment for COVID-19 encephalopathy includes supportive care and symptomatic treatment. Some studies have shown that immune modulation therapy, including high-dose corticosteroids and intravenous immunoglobulins, is effective in some severely ill patients.

Long COVID, the Brain, Nerves, and Cognitive Function.

SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are an increasing issue in patients who have been infected with COVID-19 and may be a result of viral-associated systemic and central nervous system inflammation or may arise from a virus-induced hypercoagulable state. COVID-19 may incite changes in brain function with a wide range of lingering symptoms. Patients often experience fatigue and may note brain fog, sensorimotor symptoms, and sleep disturbances. Prolonged neurological and neuropsychiatric symptoms are prevalent and can interfere substantially in everyday life, leading to a massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection causes neurological sequelae are an important subject of ongoing research. Inflammation- induced blood-brain barrier permeability or viral neuro-invasion and direct nerve damage may be involved. Though the mechanisms are uncertain, the resulting symptoms have been documented from numerous patient reports and studies. This review examines the constellation and spectrum of nervous system symptoms seen in long COVID and incorporates information on the prevalence of these symptoms, contributing factors, and typical course. Although treatment options are generally lacking, potential therapeutic approaches for alleviating symptoms and improving quality of life are explored.

A Comparison of Oak Leaf and Fescue Hay Infusion-Baited Gravid Trap Collections-An Analysis Steeped in the Context of La Crosse Virus Vector Surveillance Effectiveness.

Neuroinvasive La Crosse virus disease remains the primary cause of pediatric arboviral encephalitis in the USA. In spite of the persistent public health burden, there are limited entomologic surveillance options that target both native and invasive La Crosse virus (LACV) vectors. In this study we used Reiter/Cummings tacklebox gravid traps to compare white oak (Quercus alba) and hay (predominately Festuca arundinacea) infusions within a LACV-endemic area of western North Carolina. Paired gravid traps (approximately 1,728 total trap-hours for each infusion) yielded 485 mosquitoes, with 3 species (Aedes japonicus [n = 265], Ae. triseriatus [n = 156], and Culex restuans [n = 45]) accounting for 96.1% of the total collection. The hay-infusion traps collected 2.5 times more Ae. triseriatus and 1.3 times more Ae. japonicus than the oak-infusion traps. The sum differences in overall collections for these 2 species by infusion type were statistically significant (χ2 = 9.61, df = 1, P = 0.0019). Poisson ratio tests to compare capture rates suggest that hay infusions were more effective for capturing Ae. triseriatus, but that hay and white oak leaf infusions had equivocal capture rates for Ae. japonicus (an invasive LACV accessory vector) and Cx. restuans (an enzootic West Nile virus vector). These results are discussed in the context of operational considerations for LACV vector surveillance.

The CH24H metabolite, 24HC, blocks viral entry by disrupting intracellular cholesterol homeostasis

Cholesterol-24-hydroxylase (CH24H or Cyp46a1) is a reticulum-associated membrane protein that plays an irreplaceable role in cholesterol metabolism in the brain and has been well-studied in several neuro-associated diseases in recent years. In the present study, we found that CH24H expression can be induced by several neuroinvasive viruses, including vesicular stomatitis virus (VSV), rabies virus (RABV), Semliki Forest virus (SFV) and murine hepatitis virus (MHV). The CH24H metabolite, 24-hydroxycholesterol (24HC), also shows competence in inhibiting the replication of multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 24HC can increase the cholesterol concentration in multivesicular body (MVB)/late endosome (LE) by disrupting the interaction between OSBP and VAPA, resulting in viral particles being trapped in MVB/LE, ultimately compromising VSV and RABV entry into host cells. These findings provide the first evidence that brain cholesterol oxidation products may play a critical role in viral infection.

Identification of age-specific gene regulators of La Crosse virus neuroinvasion and pathogenesis

One of the key events in viral encephalitis is the ability of virus to enter the central nervous system (CNS). Several encephalitic viruses, including La Crosse Virus (LACV), primarily induce encephalitis in children, but not adults. This phenomenon is also observed in LACV mouse models, where the virus gains access to the CNS of weanling animals through vascular leakage of brain microvessels, likely through brain capillary endothelial cells (BCECs). To examine age and region-specific regulatory factors of vascular leakage, we used genome-wide transcriptomics and targeted siRNA screening to identify genes whose suppression affected viral pathogenesis in BCECs. Further analysis of two of these gene products, Connexin43 (Cx43/Gja1) and EphrinA2 (Efna2), showed a substantial effect on LACV pathogenesis. Induction of Cx43 by 4-phenylbutyric acid (4-PBA) inhibited neurological disease in weanling mice, while Efna2 deficiency increased disease in adult mice. Thus, we show that Efna2 and Cx43 expressed by BCECs are key mediators of LACV-induced neuroinvasion and neurological disease.

The entry receptor LDLRAD3 is critical for Venezuelan equine encephalitis virus pathogenesis and neuroinvasion in mice

Abstract Alphaviruses are enveloped positive-stranded RNA viruses of the Togaviridae family. Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus responsible for epidemics in equine and human populations across the Americas. Its potential for use as an aerosolized bioterrorism weapon and the demonstrated risk it poses in research settings highlight the need for countermeasures. VEEV pathogenesis is characterized by a systemic inflammatory response and central nervous system (CNS) infection, which can result in severe neurological complications and sequelae. Our laboratory identified a novel entry receptor for VEEV, low-density lipoprotein receptor class A domain containing 3 (LDLRAD3). Ldlrad3 −/−mice demonstrate reduced, but not abrogated, VEEV infection in target tissues and are resistant to disease and lethality. Here we define a critical role for LDLRAD3 in controlling VEEV tissue tropism and pathogenesis by studying the kinetics of infection in wild-type and Ldlrad3 −/−mice. Using detailed analyses of viral RNA levels, immunohistochemistry, flow cytometry, and primary neuronal cultures, we observed that VEEV infects LDLRAD3-expressing cell types as early as 6 h after inoculation and once in the CNS, preferentially targets neurons, and not glial cells, in a LDLRAD3-dependent manner. Overall, our studies define the role of LDLRAD3 in VEEV tropism and how LDLRAD3-dependent infection of LDLRAD3 contributes to the host inflammatory responses against VEEV. Finally, our studies demonstrate LDLRAD3-independent infection in Ldlrad3 −/−mice, which suggests the existence of alternate receptors for VEEV. These findings may be relevant for the generation of novel receptor-targeted antiviral therapies. NIAID F30AI164842

Subacute Development of Parkinsonism as a Clinical Manifestation of Powassan Virus Neuroinvasive Disease (P8-10.003)

Subacute Development of Parkinsonism as a Clinical Manifestation of Powassan Virus Neuroinvasive Disease (P8-10.003)

Antiviral activity of glucosylceramide synthase inhibitors in alphavirus infection of the central nervous system.

Virus-induced CNS diseases impose a considerable human health burden worldwide. For many viral CNS infections, neither antiviral drugs nor vaccines are available. In this study, we examined whether the synthesis of glycosphingolipids, major membrane lipid constituents, could be used to establish an antiviral therapeutic target. We found that neuroinvasive Sindbis virus altered the sphingolipid levels early after infection in vitro and increased the levels of gangliosides GA1 and GM1 in the sera of infected mice. The alteration in the sphingolipid levels appears to play a role in neuroinvasive Sindbis virus replication, as treating infected cells with UDP-glucose ceramide glucosyltransferase (UGCG) inhibitors reduced the replication rate. Moreover, the UGCG inhibitor GZ-161 increased the survival rates of Sindbis-infected mice, most likely by reducing the detrimental immune response activated by sphingolipids in the brains of Sindbis virus-infected mice. These findings suggest a role for glycosphingolipids in the host immune response against neuroinvasive Sindbis virus and suggest that UGCG inhibitors should be further examined as antiviral therapeutics for viral infections of the CNS.

Epidemiology, Isolation, and Genetic Characterization of Toscana Virus in Algerian Patients Displaying Neurological Infection, 2016–2018

PurposeThe current study reports the results of the diagnosis of neuro-invasive Toscana virus (TOSV) infection in Algeria between 2016 and 2018 and describes the first isolation of TOSV strain from human samples in North Africa. Materiel and methodsCerebrospinal fluid (CSF) and sera samples were obtained from 720 hospitalized patients displaying neurological infection symptoms of unknown etiology, of which 604 were screened for TOSV. The diagnosis was performed by serological and/or RT-PCR tests. In addition, TOSV was isolated in vivo and in vitro from CSF and genetically characterized. Results23 cases of TOSV neurological infections were detected. Cases were located in 11 Wilayas (administrative provinces), mainly in northern Algeria. In addition, we report the isolation of TOSV strain belonging to lineage A from human samples with its complete coding sequence. ConclusionEven though the number of infections is probably underestimated, TOSV is endemic in Algeria, with several cases of neuro-invasive diseases in humans recorded each year. Therefore, the diagnosis of TOSV should be included in the differential diagnosis of neurological diseases, especially aseptic meningitis, during the period of activity of the phlebotomine vector. Further studies are required to measure precisely the nationwide prevalence of TOSV in Algeria.