Lymphocytic choriomeningitis virus/physiology* ; Allosteric Regulation ; Nucleotidyltransferases

OBJECTIVES: Varicella-zoster virus (VZV) is one of the most common etiologies of viral meningitis/encephalitis. The early clinical manifestations and cerebrospinal fluid (CSF) changes of VZV meningitis/encephalitis lack specificity, and it is easy to be misdiagnosed as other viral encephalitides or tuberculous meningitis. This study aims to investigate whether the clinical characteristics, CSF analysis findings, and CSF cytokine levels could distinguish VZV meningitis/encephalitis from central nervous system (CNS) herpes simplex virus (HSV) and Mycobacterium tuberculosis (MTB) infections. METHODS: The medical records from 157 CNS infections, including 49 HSV (45 HSV-1, 4 HSV-2), 55 VZV, and 53 MTB infections between January 2018 and June 2021 in the Cytology Laboratory, Department of Neurology, Third Xiangya Hospital of Central South University were retrospectively reviewed. The data of 3 groups included demographic characteristics, laboratory results, radiographic findings, and outcomes. The levels of 12 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, IFN-γ, IFN-α, and TNF-α) in the CSF of 68 patients (13 HSV, 22 VZV, and 33 MTB infection cases) were quantified. Clinical and laboratory data were compared among the 3 groups. RESULTS: The most common clinical manifestations in the 3 groups were fever, headache, vomiting, and neck stiffness. The clinical manifestations of HSV and VZV CNS disease were similar, although fever and altered consciousness were less common in the VZV group than those in the HSV and MTB groups (63.6% vs 87.8% vs 96.2%, P<0.001, and 14.5% vs 26.5% vs 47.2%, P=0.004, respectively). Seven patients (7/55, 12.7%) presented cutaneous zoster in the VZV group. CSF leukocyte count was significantly higher in the VZV group (230×10⁶ cells/mL) and MTB groups (276×10⁶ cells/mL) than that in the HSV group (87×10⁶ cells/mL, P=0.002). CSF protein level was significantly higher in the VZV than that in the HSV group (1 034 mg/L vs 694 mg/L, P=0.011) but lower than that in the MTB group (1 744 mg/L, P<0.001). IL-6 (VZV vs HSV vs MTB: 2 855.93 pg/mL vs 2 128.26 pg/mL vs 354.77 pg/mL, P=0.029) and IL-8 (VZV vs HSV vs MTB: 4 001.46 pg/mL vs 1 578.11 pg/mL vs 1 023.25 pg/mL, P=0.046) levels were significantly different among the 3 groups and were elevated in the VZV group.Post hoc analysis revealed that IL-6 and IL-8 were significantly higher in the VZV group than those in the MTB group (P=0.002 and P=0.035, respectively), but not in the HSV group (P>0.05). CONCLUSIONS VZV meningitis/encephalitis presents with CSF hypercellularity and proteinemia, challenging the classical view of CSF profiles in viral encephalitis. CSF IL-6 and IL-8 levels are elevated in patients with VZV meningitis/encephalitis, indicating a more intense inflammatory response in these patients.
Humans ; Central Nervous System Infections ; Encephalitis ; Encephalitis, Varicella Zoster/diagnosis* ; Encephalitis, Viral/diagnosis* ; Herpesvirus 3, Human ; Interleukin-6 ; Interleukin-8 ; Meningitis ; Retrospective Studies

Acute viral infection or vaccination generates highly functional memory CD8 T cells following the Ag resolution. In contrast, persistent antigenic stimulation in chronic viral infection and cancer leads to a state of T-cell dysfunction termed T-cell exhaustion. We and other have recently identified a novel subset of exhausted CD8 T cells that act as stem cells for maintaining virus-specific CD8 T cells in a mouse model of chronic lymphocytic choriomeningitis virus infection. This stem cell-like CD8 T-cell subset has been also observed in both mouse and human tumor models. Most importantly, in both chronic viral infection and tumor models, the proliferative burst of Ag-specific CD8 T cells driven by PD-1-directed immunotherapy comes exclusively from this stem cell-like CD8 T-cell subset. Therefore, a better understanding of the mechanisms how CD8 T-cell subsets are regulated during chronic viral infection and cancer is required to improve the current immunotherapies that restore the function of exhausted CD8 T cells. In this review, we discuss the differentiation of virus-specific CD8 T cells during chronic viral infection, the characteristics and function of CD8 T-cell subsets, and the therapeutic intervention of PD-1-directed immunotherapy in cancer.
Animals ; Humans ; Immunotherapy ; Lymphocytic choriomeningitis virus ; Memory ; Mice ; Stem Cells ; T-Lymphocyte Subsets ; T-Lymphocytes ; Vaccination

CD80 is mainly expressed on Ag-presenting cells (APCs) as a costimulatory molecule but is also detected on T cells. However, the origin and physiological role of CD80 on CD8⁺ T cells remain unclear. In the present study, we demonstrated that effector and memory CD8⁺ T cells, but not naïve CD8⁺ T cells, displayed CD80 molecules on their surfaces after acute lymphocytic choriomeningitis virus infection. Using adoptive transfer of CD80-knockout (KO) CD8⁺ T cells into a wild type or CD80-KO recipient, we demonstrated that the effector CD8⁺ T cells displayed CD80 by both intrinsic expression and extrinsic acquisition, while memory CD8⁺ T cells displayed CD80 only by extrinsic acquisition. Interestingly, the extrinsic acquisition of CD80 by CD8⁺ T cells was observed only in the lymphoid organs but not in the periphery, indicating the trogocytosis of CD80 molecules via interaction between CD8⁺ T cells and APCs. We compared the recall immune responses by memory CD8⁺ T cells that either extrinsically acquired CD80 or were deficient in CD80, and found that CD80, presented by memory CD8⁺ T cells, played a role in limiting their expansion and IL-2 production upon exposure to secondary challenge. Our study presents the in vivo dynamics of the extrinsic acquisition of CD80 by Ag-specific CD8⁺ T cells and its role in the regulation of recall immune responses in memory CD8+ T cells.
Adoptive Transfer ; Antigens, CD80 ; Interleukin-2 ; Lymphocytic choriomeningitis virus ; Memory ; T-Lymphocytes

During virus infection, T cells must be adapted to activation and lineage differentiation states via metabolic reprogramming. Whereas effector CD8⁺ T cells preferentially use glycolysis for their rapid proliferation, memory CD8⁺ T cells utilize oxidative phosphorylation for their homeostatic maintenance. Particularly, enhanced AMP-activated protein kinase (AMPK) activity promotes the memory T cell response through different pathways. However, the level of AMPK activation required for optimal memory T cell differentiation remains unclear. A new metformin derivative, IM156, formerly known as HL156A, has been reported to ameliorate various types of fibrosis and inhibit in vitro and in vivo tumors by inducing AMPK activation more potently than metformin. Here, we evaluated the in vivo effects of IM156 on antigen-specific CD8⁺ T cells during their effector and memory differentiation after acute lymphocytic choriomeningitis virus infection. Unexpectedly, our results showed that in vivo treatment of IM156 exacerbated the memory differentiation of virus-specific CD8⁺ T cells, resulting in an increase in short-lived effector cells but decrease in memory precursor effector cells. Thus, IM156 treatment impaired the function of virus-specific memory CD8⁺ T cells, indicating that excessive AMPK activation weakens memory T cell differentiation, thereby suppressing recall immune responses. This study suggests that metabolic reprogramming of antigen-specific CD8⁺ T cells by regulating the AMPK pathway should be carefully performed and managed to improve the efficacy of T cell vaccine.
AMP-Activated Protein Kinases ; Cell Differentiation ; Fibrosis ; Glycolysis ; Immunologic Memory ; In Vitro Techniques ; Lymphocytic choriomeningitis virus ; Lymphocytic Choriomeningitis ; Memory ; Metformin ; Oxidative Phosphorylation ; T-Lymphocytes

PURPOSE: We report two cases of uveo-meningeal syndrome involving the retina, uvea, and optic disc in both eyes after viral meningitis. CASE SUMMARY: A 16-year-old female was referred to our department with blurred vision in both eyes. She was hospitalized in the pediatric ward with viral meningitis. She showed a norma best-corrected visual acuity (BCVA) and normal intraocular pressure in both eyes, but had severe inflammation in the anterior chamber on slit lamp examination, and optic disc edema and multiple whitish lesions on fundus examination. She was treated with intravenous antibiotic injections and steroid eye drops. After close observation, inflammation in the anterior chamber, optic disc edema, and the multiple whitish lesions in the retina were improved. A 27-year-old male who was treated for viral meningitis at the neurology department was referred to us with blurred vision in both eyes. His BCVAs were 0.7 (right eye) and 0.6 (left eye). The intraocular pressure was normal in both eyes. Slit lamp examination revealed inflammation in the anterior chamber and optic disc edema, and a fundus examination revealed multiple infiltrations. He received treatment for presumed herpes virus infection. After close observation, inflammation in the anterior chamber, optic disc edema, and multiple infiltrations with hemorrhage in the retina were improved. CONCLUSIONS: Clinicians should consider the possibility of uveo-meningeal syndrome, which can cause inflammation in the uvea,retina, and optic disc simultaneous with viral meningitis accompanying blurred vision.
Adolescent ; Adult ; Anterior Chamber ; Edema ; Female ; Hemorrhage ; Humans ; Inflammation ; Intraocular Pressure ; Male ; Meningitis ; Meningitis, Viral ; Neurology ; Ophthalmic Solutions ; Retina ; Slit Lamp ; Uvea ; Vision Disorders ; Visual Acuity

Echovirus 30 is one of the major causes of meningitis in children and adults. The purpose of our current study was to investigate whether selected antiviral drugs could provide antiviral activity against echovirus 30. Using RD cells, we assessed the cytopathic effect of echovirus 30, including viral RNA levels as indicators of viral replication. The effects of gemcitabine were compared to rupintrivir, a well-known antiviral drug. To understand the activity gemcitabine exerts on the viral life cycle, time course and time-of-addition assays were implemented. The most effective compounds against echovirus 30 were gemcitabine and rupintrivir, as demonstrated by their concentration-dependent activity. Gemcitabine affects the early stages of echovirus 30 infection by disrupting viral replication. However, gemcitabine failed to directly inactivate echovirus 30 particles or impede viral uptake into the RD cells. Gemcitabine can be considered as a lead candidate in the development of echovirus 30 antiviral drugs, specifically in the early stages of echovirus 30 replication.
Adult ; Antiviral Agents ; Child ; Enterovirus B, Human ; Humans ; In Vitro Techniques ; Life Cycle Stages ; Meningitis ; RNA, Viral

Neurologic complications associated with varicella zoster virus (VZV) are rare in children. A 13-year-old boy was hospitalized due to headache, fever, and vomiting. Aseptic viral meningitis was strongly suspicious based on findings on physical exam, cerebrospinal fluid examination, and brain magnetic resonance imaging. On the second day of hospitalization, typical zosteriform rashes developed on his left chest wall across the T7-T8 dermatome. Tzanck test of the skin lesion was positive and polymerase chain reaction test for VZV was positive on the second cerebrospinal fluid examination. Serum immunoglobulin levels were within normal range. Intravenous acyclovir was started and symptoms and signs of meningitis gradually improved and the patient was discharged without any complications. In immunocompetent children, VZV meningitis is rare and requires rapid diagnosis and treatment. Therefore, it is necessary to prompt diagnosis and treatment thorough medical history, physical examination and laboratory examination.
Acyclovir ; Adolescent ; Brain ; Cerebrospinal Fluid ; Chickenpox* ; Child* ; Diagnosis ; Exanthema ; Fever ; Headache ; Herpes Zoster* ; Herpesvirus 3, Human ; Hospitalization ; Humans ; Immunoglobulins ; Magnetic Resonance Imaging ; Male ; Meningitis* ; Meningitis, Viral ; Physical Examination ; Polymerase Chain Reaction ; Reference Values ; Skin ; Thoracic Wall ; Vomiting

BACKGROUND: Tuberculous meningitis (TBM) is associated with high mortality and morbidity despite administering anti-tuberculous chemotherapy to the patients. Differential diagnosis between TBM and viral meningitis (VM) is difficult in some clinical situations. METHODS: We reviewed and analyzed records of adult patients who were admitted and diagnosed with TBM or VM at a tertiary hospital in Korea, between January 2006 and December 2015. Diagnostic criteria for TBM were categorized into three groups: definite, probable, and possible TBM. The VM group included patients with no evidence of other meningitis who achieved complete recovery with only conservative treatments. Clinical, laboratory and radiological findings, as well as outcomes, were compared between the TBM and VM groups. RESULTS: Ninety-eight patients were enrolled. Among the study patients, 47 had TBM and 51 had VM. Based on univariate analysis and multivariate logistic regression, sodium < 135 mmol/L in serum (hyponatremia), lactate dehydrogenase > 70 (U/L) in cerebrospinal fluid (CSF), protein > 160 (mg/dL) in CSF, voiding difficulty, and symptoms of cranial nerve palsy were significant predictive factors for TBM in the final model. We constructed a weighted scoring system with predictive factors from multiple regression analyses. Receiver operating characteristic curve analyses and decision tree analyses were plotted to reveal an optimum cutoff point as 4 with this scoring system (range: 0–13). CONCLUSION: For differential diagnosis between TBM and VM, we created a new weighted scoring system. This scoring system and decision tree analysis are simple and easy to apply in clinical practice to differentiate TBM from VM.
Adult ; Cerebrospinal Fluid ; Cranial Nerve Diseases ; Decision Trees ; Diagnosis, Differential* ; Drug Therapy ; Humans ; Korea ; L-Lactate Dehydrogenase ; Logistic Models ; Meningitis ; Meningitis, Viral* ; Mortality ; ROC Curve ; Sodium ; Tertiary Care Centers ; Tuberculosis, Meningeal*

PURPOSE: To report two cases of acute retinal necrosis following viral meningitis. CASE SUMMARY: A 52-year-old woman who has had viral meningitis presented with visual loss of right eye. Slit-lamp examination showed conjunctival injection and inflammatory cells (2+) in the anterior chamber of the right eye. Funduscopic examination showed multiple yellow-whitish spots in the peripheral retina. Fluorescein fundus angiography showed early hypofluorescence and the late vascular leak in the peripheral retina. After the patient was diagnosed with Acute retinal necrosis (ARN), intravenous acyclovir (2,100 mg/m²/day) was administered. During the treatment period, the retinal detachment of the right eye was found, so the authors performed pars plana vitrectomy. After the surgery, new retinal lesions weren't observed in both eyes during follow-up. A 57-year-old man previously treated with possible viral meningitis presented with visual loss of his right eye. Funduscopic examination showed multiple yellow-whitish spots in the peripheral retina. Fluorescein fundus angiography showed the late vascular leak in the peripheral retina. In the systemic evaluation, Herpes simplex virus and Cytomegalovirus immunoglobulin G were detected. With the impression of ARN, intravenous acyclovir (2,100 mg/m²/day) was administered. No new retinal lesions were observed in both eyes during follow-up. CONCLUSIONS: We report rare cases of ARN occurring after viral meningitis. Uveitis in patients with recent history of meningitis should be examined carefully under the suspicion of ARN.
Acyclovir ; Angiography ; Anterior Chamber ; Cytomegalovirus ; Female ; Fluorescein ; Follow-Up Studies ; Humans ; Immunoglobulin G ; Meningitis ; Meningitis, Viral* ; Middle Aged ; Retina ; Retinal Detachment ; Retinal Necrosis Syndrome, Acute* ; Retinaldehyde ; Simplexvirus ; Uveitis ; Vitrectomy