Role of peripheral immune response in microglia activation and regulation of brain chemokine and proinflammatory cytokine responses induced during VSV encephalitis.

We report herein that neuroinvasion by vesicular stomatitis virus (VSV) activates microglia and induces a peripheral dendritic cell (DC)-dependent inflammatory response in the central nervous system (CNS). VSV neuroinvasion rapidly induces multiple brain chemokine and proinflammatory cytokine mRNAs that display bimodal kinetics. Peripheral DC ablation or T cell depletion suppresses the second wave of this response demonstrating that infiltrating T cells are primarily responsible for the bimodal characteristics of this response. The robust infiltrate associated with VSV encephalitis likely depends on sustained production of brain CCL19 and CCR7 expression on infiltrating inflammatory cells.

Innate resistance to flavivirus infection in mice controlled by Flv is nitric oxide-independent.

Innate resistance to flaviviruses in mice is active in the brain where it restricts virus replication. This resistance is controlled by a single genetic locus, FLV, located on mouse chromosome 5 near the locus encoding the neuronal form of nitric oxide synthase (Nos1). Since nitric oxide (NO) has been implicated in antiviral activity, its involvement in natural resistance to flaviviruses has been hypothesized. Here we present data on NO production before and during flavivirus infection in both brain tissue and peritoneal macrophages from two flavivirus-resistant (FLV(r)) and one congenic susceptible (FLV(s)) mouse strains. This study provides evidence that NO is not involved in the expression of flavivirus resistance controlled by FLV since: (a) there is no difference in brain tissue NO levels between susceptible and resistant mice, and (b) lipopolysaccharide-induced NO does not abrogate the difference in flavivirus replication in peritoneal macrophages from susceptible and resistant mice.

The severity of murray valley encephalitis in mice is linked to neutrophil infiltration and inducible nitric oxide synthase activity in the central nervous system.

A study of immunopathology in the central nervous system (CNS) during infection with a virulent strain of Murray Valley encephalitis virus (MVE) in weanling Swiss mice following peripheral inoculation is presented. It has previously been shown that virus enters the murine CNS 4 days after peripheral inoculation, spreads to the anterior olfactory nucleus, the pyriform cortex, and the hippocampal formation at 5 days postinfection (p.i.), and then spreads throughout the cerebral cortex, caudate putamen, thalamus, and brain stem between 6 and 9 days p.i. (P. C. McMinn, L. Dalgarno, and R. C. Weir, Virology 220:414-423, 1996). Here we show that the encephalitis which develops in MVE-infected mice from 5 days p.i. is associated with the development of a neutrophil inflammatory response in perivascular regions and in the CNS parenchyma. Infiltration of neutrophils into the CNS was preceded by increased expression of tumor necrosis factor alpha and the neutrophil-attracting chemokine N51/KC within the CNS. Depletion of neutrophils with a cytotoxic monoclonal antibody (RB6-8C5) resulted in prolonged survival and decreased mortality in MVE-infected mice. In addition, neutrophil infiltration and disease onset correlated with expression of the enzyme-inducible nitric oxide synthase (iNOS) within the CNS. Inhibition of iNOS by aminoguanidine resulted in prolonged survival and decreased mortality in MVE-infected mice. This study provides strong support for the hypothesis that Murray Valley encephalitis is primarily an immunopathological disease.

C-reactive protein in CNS infection.

Serum and CSF levels of CRP were measured by radial immunoassay in 99 subjects consisting of 20 controls, 34 pyogenic meningitis (PM), 21 tuberculous meningitis (TBM) and 24 viral encephalitis (VE). There was significant difference in the CRP levels (p less than 0.01) depending on the type of disease in both serum and CSF. The initial serum and CSF levels of CRP in patients with TBM was intermediate between those of PM and VE and were found to be significantly (p less than 0.001) low when compared with three days post treatment levels in children with PM. Both serum and CSF-CRP levels were significantly high (p less than 0.001) in patients succumbing to death than those who survived. Measurement of CRP in serum and CSF is a useful parameter in differentiating partially treated PM from TBM.

Factors in serum and cerebrospinal fluid from children with viral encephalopathies impair glucose transport.

Since glucose transport appears to be inhibited in viral infections, we looked for inhibitors in cerebrospinal fluid (CSF) and serum of children with febrile convulsions (FC) and Singapore syndrome (SS). When incubated with rat and human adipocytes both fluids from FCs inhibited the utilization of glucose supplied in the medium as exhibited by decreased synthesis of triglycerides. Sera in the acute stage of the illness were more inhibitory than those from convalescents. There was competition between 3-0 methyl glucose and the CSF factors suggesting competitive inhibition at the plasma membrane. This may be due to anti-idiotypic antibodies. The likelihood of a second inhibitor is suggested by (1) the inhibitory activity of the larger of two fractions (about 80,000 molecular weight, corresponding to albumin) obtained in gel filtration chromatography of pooled CSF and (2) failure to observe a decrease in inhibitory activity with recovery from SS following management with hyperglycaemia-producing infusions. These observations are consistent with glycated albumin as a possible factor. Further characterization is called for to ascertain the genesis of viral encephalopathies.

Altered sensorium in neurological infections and the homeostasis of Mg, Zn, Cu and Ca.

In a grave illness the homeostasis of some elements may be upset either by the disease process per se, or by the therapy adopted. Patients with pyogenic, viral and tubercular meningo-encephalitis were targets of interest. 108 subjects' serum and cerebrospinal fluid (CSF) compartments were assayed for magnesium, calcium, zinc and copper, by atomic absorption spectrometry. Results showed that the serum pool was more intensely altered than the CSF pool in the case of magnesium and calcium but the reverse occurred for zinc and copper. No organism-dependent change was noted, but comatosed patients were the worst effected. These findings are discussed with respect to the relative brain and CSF content of each element and the patho-physiology which could alter the compartments studied.

Early intrathecal synthesis of interferon in herpes encephalitis.

Large quantities of type I interferon were detected in the cerebrospinal fluid (CSF) collected at the onset of herpes encephalitis. This interferon was synthesized intrathecally and disappeared about 10 days after the beginning of neurological signs. In 12 cases of post-eruptive measles encephalitis and in four post-rubella encephalitis, type I interferon was present only in low amounts, or not found at all, even in the CSF collected early. The existence of an intrathecal synthesis of interferon during encephalitis provides a valuable contribution to both the early diagnosis of herpes encephalitis and the study of the pathogenesis of virus infection of the central nervous system (CNS).

Uptake of 5(125I) iodo-2-deoxyuridine (IDU) in plasma and cerebrospinal fluid in a case of herpes encephalitis with a comparative study on the uptake in plasma, cerebrospinal fluid and brain tissue in dogs.

A case of herpes encephalitis diagnosed by brain biopsy and treated with 5-iodo-2-deoxyuridine (IDU) is presented. The infection occurred in a previously well 19-year-old female patient. Plasma and cerebrospinal fluid (CSF) uptake of the substance was determined using 125I labelled IDU. Top CSF levels of IUD and metabolites of less than 4 microgram/ml, about 1/10 of the corresponding plasma level, were obtained after 6 hours of continuous infusion. The result is discussed and compared with a similar study made on 5 healthy beagle dogs where in addition the levels obtained in various parts of the brain were determined. In the animal experiment a mean value of 2.5 microgram/ml of IDU and metabolites was obtained in the CSF after 8 hours, less than 1/20 of the plasma level. The levels in brain tissue were only slightly higher than in the CSF. The causes of therapeutic failures with IDU treatment are discussed.