Prior murine neurotropic coronavirus infection ameliorates experimental autoimmune encephalitis.

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Mouse hepatitis virus (MHV) infection causes meningoencephalitis by disrupting the neuro-glial and glial-pial homeostasis. Recent studies suggest that MHV infection alters gap junction protein connexin 43 (Cx43)-mediated intercellular communication in brain and primary cultured astrocytes. In addition to astrocytes, meningeal fibroblasts also express high levels of Cx43. Fibroblasts in the meninges together with the basal lamina and the astrocyte endfeet forms the glial limitans superficialis as part of the blood–brain barrier (BBB). Alteration of glial-pial gap junction intercellular communication (GJIC) in MHV infection has the potential to affect the integrity of BBB. Till date, it is not known if viral infection can modulate Cx43 expression and function in cells of the brain meninges and thus affect BBB permeability. In the present study, we have investigated the effect of MHV infection on Cx43 localization and function in mouse brain meningeal cells and primary meningeal fibroblasts. Our results show that MHV infection reduces total Cx43 levels and causes its intracellular retention in the perinuclear compartments reducing its surface expression. Reduced trafficking of Cx43 to the cell surface in MHV-infected cells is associated with loss functional GJIC. Together, these data suggest that MHV infection can directly affect expression and cellular distribution of Cx43 resulting in loss of Cx43-mediated GJIC in meningeal fibroblasts, which may be associated with altered BBB function observed in acute infection.

Coronaviruses (CoV) infect a variety of organs, including the liver, respiratory and enteric tracts, and the central nervous system (CNS). Viral cellular and tissue tropism affects both the quality and quantity of the immune response, which ultimately determine viral control and pathogenesis. This chapter focuses primarily on the in vivo interactions between the immune system and the infected CNS as a target of neurotropic mouse hepatitis virus (MHV) infection because these interactions have been examined in the greatest detail. Immune responses to additional viruses, e.g., transmissible gastroenteritis virus (TGEV), infectious bronchitis virus (IBV), and feline infectious peritonitis virus (FIPV), associated with diseases in other tissues are included, as well as the various MHV strains with distinct tissue tropisms. Control of infections by enveloped viruses involves a coordinated immune response that is initiated and subsequently orchestrated by innate immune mediators such as macrophages, dendritic cells (DCs), interferon (IFN)- α/ β, and chemokines. These factors provide both an initial antiviral response and the appropriate milieu for activation of both cellular and humoral immune responses.

Lymphocyte infiltration into the central nervous system (CNS) following viral infection represents an important component of host defense and is required for control of viral replication. However, the mechanisms governing inflammation in response to viral infection of the CNS are not well understood. Following intracranial (i.c.) infection of susceptible mice with mouse hepatitis virus (MHV), mice develop an acute encephalomyelitis followed by a chronic demyelinating disease. The CXC chemokine ligand 10 (CXCL10) is expressed following MHV infection and signals T cells to migrate into the CNS. The functional contribution of the CXCL10 receptor CXCR3 in host defense and disease in response to MHV infection was evaluated. The majority of CD4+ and CD8+ T cells infiltrating the CNS following MHV infection express CXCR3. Administration of anti-CXCR3 antibody reduced CD4+ T cell infiltration (p<or=0.05), while CD8+ T cell trafficking was not affected. Anti-CXCR3 treatment during chronic disease correlated with improved motor skills and reduced demyelination. The selective effect of anti-CXCR3 treatment on CD4+ T cells was not the result of either reduced proliferation or modulation in chemokine receptor gene expression. Therefore, CXCR3 signaling has a non-redundant role in T cell subset trafficking in response to viral infection.

Natural infection by mouse hepatitis virus (MHV) can affect interpretation of immunological studies in mice. MHV, a collective term describing a group of corona viruses, is found in natural infections in over 70% of laboratory mouse populations in the U.S.A. and Canada. Natural outbreaks of MHV in our animal colony afforded us the opportunity to study MHV-induced immunosuppression as well as the effects of MHV infection on neurotransmitter immunomodulation. Concanavalin A (Con A)-stimulated DNA synthesis by spleen T lymphocytes from MHV-infected mice was 20-50% that of non-infected mice. The MHV infection also altered neurotransmitter modulation of spleen T-lymphocyte activation. In contrast to noradrenaline ablation of Con A-activated DNA synthesis by spleen lymphocytes from non-infected mice, DNA synthesis by the infected group was not inhibited by noradrenaline or dibutyryl-cAMP. These effects of MHV infection were specific for spleen T lymphocytes since MHV infection did not alter Con A stimulation of thymocytes, lipopolysaccharide stimulation of spleen B lymphocytes, or noradrenaline inhibition of thymocyte and B-cell DNA synthesis. MHV infection also did not alter spleen T-lymphocyte subset proportions. Thus, MHV infection inhibits spleen T-lymphocyte activation and blocks in vitro catecholamine and cAMP regulation of spleen T-cell activation but does not affect activation of thymic cells or spleen B cells.

The role of apoptosis in mouse hepatitis virus (MHV) infection is still controversial. To better assess the role of apoptosis in MHV infection, we used three different biologic phenotypes of MHV to examine their differential effect on the induction of apoptosis. MHV-A59 produces acute hepatitis, meningoencephalitis, and chronic demyelination. MHV-2 causes only acute hepatitis and meningitis, whereas Penn98-1 produces acute hepatitis and meningoencephalitis without demyelination. We detected TdT-mediated dUTP nick-end labeling (TUNEL) staining in the livers and meninges of MHV-A59-, MHV-2-, and Penn98-1-infected mice. TUNEL staining in brain parenchyma was only detected in MHV-A59- and Penn98-1-infected mice. We detected apoptosis by electron-microscopy in olfactory neurons during acute infection with MHV-A59. The kinetics and distribution of TUNEL staining correlated with the pathologic damage and colocalized with viral antigen in some cells. At 1 month, TUNEL staining was found exclusively in areas of demyelination in the spinal cord of MHV-A59-infected mice; however, it was not found in nondemyelinated mice infected with MHV-2 or Penn98-1, or in mock-infected mice. TUNEL-positive cells were identified as macrophage/microglial cells, some astrocytes, and some oligodendrocytes, by colabeling with cell-specific markers. The presence of TUNEL staining in oligodendrocytes suggests that apoptosis may play an important role in MHV-induced demyelination.

ObjectiveWheat has become a main staple globally. We studied the effect of defined pro-inflammatory dietary proteins, wheat amylase trypsin inhibitors (ATI), activating intestinal myeloid cells via toll-like receptor 4, in...

Theacrine and strictinin of Yunnan Kucha tea prepared from a mutant variety of wild Pu’er tea plants were two major ingredients responsible for the anti-influenza activity. As the COVID-19 outbreak is still lurking, developing safe and cost-effective therapeutics is an urgent need. This study aimed to evaluate the effects of these tea compounds on the infection of mouse hepatitis virus (MHV), a β-coronavirus serving as a surrogate for SARS-CoV. Treatment with strictinin (100 μM), but not theacrine, completely eliminated MHV infection, as indicated by a pronounced reduction in plaque formation, nucleocapsid protein expression, and progeny production of MHV. Subsequently, a time-of-drug addition protocol, including pre-, co-, or post-treatment, was exploited to further evaluate the possible mechanism of antiviral activity mediated by strictinin, and remdesivir, a potential drug for the treatment of SARS-CoV-2, was used as a positive control against MHV infection. The results showed that all three treatments of remdesivir (20 μM) completely blocked MHV infection. In contrast, no significant effect on MHV infection was observed when cells were pre-treated with strictinin (100 μM) prior to infection, while significant inhibition of MHV infection was observed when strictinin was introduced upon viral adsorption (co-treatment) and after viral entry (post-treatment). Of note, as compared with the co-treatment group, the inhibitory effect of strictinin was more striking in the post-treatment group. These results indicate that strictinin suppresses MHV infection by multiple mechanisms; it possibly interferes with viral entry and also critical step(s) of viral infection. Evidently, strictinin significantly inhibited MHV infection and might be a suitable ingredient for protection against coronavirus infection.

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Background and study aim:Egypt is an endemic area with Central nervous system (CNS) infections, which associated with high complications and death rates so it is considered a medical emergency.In spite of emerging of new potent antibiotics and availability of specific vaccination accompanied with improving of medical care, morbidity rates accompanied with CNS infection remains unacceptably high.There is dramatic change in the epidemiology of CNS infection that leads to incomplete understanding of its pathogenesis which interferes with the initiation of effective empirical antimicrobial treatment.There is a growing need for more researches to uncover these changes.The aim of the study is to assess the pattern of CNS infections, identify the causative organisms, course and outcome of the CNS infections to implement standard management approaches and improve outcome.Patients and Methods: One hundred twenty-four patients, recruited from Suez Fever and General Hospitals with suspected CNS infection, were enrolled in this study.CNS infection was confirmed by cerebrospinal fluid results supported by clinical diagnosis and in some patients brain imaging was performed.Results: In our study streptococcus pneumonia was the main cause of septic meningitis; males infected more than females, children were the most vulnerable group; among children Haemophilus influenzae was the commonest cause of septic meningitis.Mycobacterium meningitis was the leading cause of death among studied patient and deafness was the main neurological complication. Conclusion:Early clinical suspicion of CNS infection and immediate management are crucial factors in reduction of the still high morbidity and mortality rates.The changes in the pattern of causative organisms must be considered when starting empiric antibiotic.

Coronavirus infection of the murine central nervous system (CNS) provides a model for studies of viral encephalitis and demyelinating disease. Mouse hepatitis virus (MHV) neurotropism varies by strain: MHV-A59 causes mild encephalomyelitis and demyelination, while the highly neurovirulent strain JHM.SD (MHV-4) causes fatal encephalitis with extensive neuronal spread of virus. In addition, while neurons are the predominant CNS cell type infected in vivo, the canonical receptor for MHV, the carcinoembryonic antigen family member CEACAM1a, has been demonstrated only on endothelial cells and microglia. In order to investigate whether CEACAM1a is also expressed in other cell types, ceacam1a mRNA expression was quantified in murine tissues and primary cells. As expected, among CNS cell types, microglia expressed the highest levels of ceacam1a, but lower levels were also detected in oligodendrocytes, astrocytes, and neurons. Given the low levels of neuronal expression of ceacam1a, primary neurons from wild-type and ceacam1a knockout mice were inoculated with MHV to determine the extent to which CEACAM1a-independent infection might contribute to CNS infection. While both A59 and JHM.SD infected small numbers of ceacam1a knockout neurons, only JHM.SD spread efficiently to adjacent cells in the absence of CEACAM1a. Quantification of mRNA for the ceacam1a-related genes ceacam2 and psg16 (bCEA), which encode proposed alternative MHV receptors, revealed low ceacam2 expression in microglia and oligodendrocytes and psg16 expression exclusively in neurons; however, only CEACAM2 mediated infection in human 293T cells. Therefore, neither CEACAM2 nor PSG16 is likely to be an MHV receptor on neurons, and the mechanism for CEACAM1a-independent neuronal spread of JHM.SD remains unknown.

Whereas most of laboratory mouse strains are susceptible to mouse hepatitis virus (MHV) infection, only SJL mouse strain is resistant (Smith et al, 1984). MHV susceptible mouse strains have CEACAM1a (MHVR1) as a receptor for MHV, while SJL mice have CEACAM1b (MHVR2) (Ohtsuka and Taguchi, 1997). Although these molecules are functional receptors for MHV (Yokomori and Lai, 1992), there is a striking difference in receptor functionality between these two proteins. MHVR1 has 250∼500 times higher receptor-binding activity relative to MHVR2 as examined by a virus overlay protein blot assay and 10∼30 times higher receptor activity when expressed on cells without MHV receptor (Ohtsuka et al., 1996, Rao et al., 1997). These findings suggest that the difference in susceptibility to MHV infection between MHV-susceptible mouse strains and SJL could result from the difference in receptor functionality found between MHVR1 and MHVR2.

We have previously shown that intranasal infection of mice with mouse hepatitis virus (MHV) strain UAB (MHV-UAB) increases their resistance to Salmonella typhimurium injected intravenously 6 days later. To study how salmonella resistance was induced, BALB/cAnNCr mice were infected with salmonella strains carrying specific genetic alterations. One set of studies compared the effect of MHV infection on subsequent salmonella infections with AroA- (avirulent) and Aro+ (virulent) salmonellae. Unlike its effect on Aro+ salmonellae, MHV failed to reduce the number of AroA- salmonellae recovered from mice. Because AroA- S. typhimurium shows almost no growth in vivo, this failure indicated that the effect of MHV on salmonella resistance required growth of the infecting salmonellae. In other studies, the effect of MHV infection on both growth and killing were monitored simultaneously in mice with growing salmonellae carrying a single copy of the temperature-sensitive pHSG422 plasmid, which is unable to replicate in vivo. MHV infection reduced salmonella growth but caused no increase in salmonella killing. MHV infection of mice given wild-type salmonellae also resulted in no increase in salmonella killing 4 h after salmonella challenge. These studies demonstrate that MHV-UAB infection increases host resistance to salmonellae by enhancing suppression of bacterial growth instead of by increasing the amount of salmonella killing.

Purpose: This work aimed to assess whether elevated levels of cerebrospinal fluid (CSF) S100B are associated with brain injury and unfavorable outcomes at discharge in children with central nervous system (CNS) infections. Methods: CSF S100B and associated clinical parameters were retrospectively analyzed in 83 children with CNS infections and 88 children without neurological pathology served as controls. Children with CNS infections were divided into an infectious encephalitis group and an infectious meningitis group based on whether cerebral parenchyma was involved, and CSF S100B levels in different age subgroups between the two groups were compared. The predictive value of CSF S100B in children with infectious encephalitis was evaluated by multivariate logistic regression analysis, and the discriminative power was investigated by receiver operating characteristic (ROC) analysis. Results: CSF S100B levels in the infectious encephalitis group were significantly higher than the infectious meningitis and the control group at each age range. CSF S100B ≥ 0.96 μg/L had 62.9% sensitivity and 76.2% specificity for diagnosing cerebral parenchyma injury in children with CNS infections. Increased CSF S100B levels were proven to be an independent predictor of unfavorable outcomes in children with infectious encephalitis and the optimal cut-off value (1.77 μg/L of CSF S100B) for predicting unfavorable outcomes in children with infectious encephalitis showed 61.1% sensitivity and 96.2% specificity. Conclusions: This study has demonstrated that elevated levels of CSF S100B are associated with brain injury and could be used as an independent predictor of clinically unfavorable outcomes at discharge in children with CNS infections.

Connections between the immune system and the nervous system.