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Human cytomegalovirus (HCMV) infection of the neonatal CNS results in long-term neurologic sequelae. To define the pathogenesis of fetal HCMV CNS infections, we investigated mechanisms of virus clearance from the CNS of neonatal Balb/c mice infected with murine CMV (MCMV). Virus titers peaked in the CNS between post-natal (PN) days 10–14 and infectious virus was undetectable by PN day 21. Congruent with virus clearance was the recruitment of CD8+ T-cells into the CNS. Depletion of CD8+ T cells resulted in death by postnatal day 15 in MCMV infected animals and increased viral loads in the liver, spleen and the CNS suggesting an important role for these cells in the control of MCMV replication in the newborn brain. Examination of brain mononuclear cells revealed that CD8+ T-cell infiltrates expressed high levels of CD69, CD44 and CD49d. IE1168 specific CD8+ T-cells accumulated in the CNS and produced IFN-γ and TNF-α but not IL-2 following peptide stimulation. Moreover, adoptive transfer of brain mononuclear cells resulted in decreased virus burden in immunodepleted MCMV infected syngeneic mice. Depletion of the CD8+ cell population following transfer eliminated control of virus replication. In summary, these results show that functionally mature virus specific CD8+ T-cells are recruited to the CNS in mice infected with MCMV as neonates.

In children with symptomatic congenital CMV infection involving the CNS, viremia during early infancy is associated with hearing loss and systemic CMV disease.

Congenital human cytomegalovirus (HCMV) occurs in 0.5–1% of live births and approximately 10% of infected infants develop hearing loss. The mechanism(s) of hearing loss remain unknown. We developed a murine model of CMV induced hearing loss in which murine cytomegalovirus (MCMV) infection of newborn mice leads to hematogenous spread of virus to the inner ear, induction of inflammatory responses, and hearing loss. Characteristics of the hearing loss described in infants with congenital HCMV infection were observed including, delayed onset, progressive hearing loss, and unilateral hearing loss in this model and, these characteristics were viral inoculum dependent. Viral antigens were present in the inner ear as were CD3+ mononuclear cells in the spiral ganglion and stria vascularis. Spiral ganglion neuron density was decreased after infection, thus providing a mechanism for hearing loss. The lack of significant inner ear histopathology and persistence of inflammation in cochlea of mice with hearing loss raised the possibility that inflammation was a major component of the mechanism(s) of hearing loss in MCMV infected mice.

Human cytomegalovirus (HCMV) is the most frequent cause of congenital viral infections in humans and

We report 3 cases of herpes simplex virus encephalitis in patients receiving tumor necrosis factor-alpha (TNF-α) inhibitors for rheumatologic disorders. Although TNF-α inhibitors have been reported to increase the risk of other infectious diseases, to our knowledge, an association between anti–TNF-α drugs and herpes simplex virus encephalitis has not been previously described.

Human isolates of serotype III Streptococcus agalactiae (group B streptococcus [GBS]) can be divided into three separate phylogenetic lineages based on analysis of the restriction digest patterns (RDPs) of chromosomal DNA. Nine DNA sequences that are present in all isolates of the RDP III-3 phylogenetic lineage, but not in the other lineages, were identified by genomic subtractive hybridization. A complete physical map of a III-3 chromosome was constructed. Six of the nine III-3-specific sequences mapped to a 340-kb Sse8387I fragment which contains or is located close to known GBS virulence genes. One of the III-3-specific probes, AW-10, encodes part of GBSi1, a group II intron that is inserted at two sites within the GBS genome. The second chromosomal site for GBSi1 was isolated, sequenced, and mapped to a location near the locus responsible for hemolysin production. These findings suggest that the genetic variation that distinguishes the RDP type III-3 strains from other serotype III strains occurs largely within localized areas of the genome containing known or putative virulence genes.Streptococcus agalactiae bacteria (group B streptococci [GBS]) are the most common cause of serious bacterial disease in neonates and an important pathogen in pregnant women and adults with underlying illnesses (3). GBS are subclassified into nine serotypes based on the immunologic reactivity of the polysaccharide capsule. Types I, II, III, and V GBS cause the majority of neonatal human GBS diseases (3, 4). Serotype III GBS are of particular importance because these bacteria cause considerable early-onset (within the first week of life) and most late-onset (after the first week of life) disease in human neonates and the vast majority of neonatal GBS meningitis (3).It was previously reported that serotype III GBS isolates from Tokyo, Japan, and Salt Lake City, Utah, can be subclassified by analysis of HindIII and Sse8387I restriction digest patterns (RDPs) of chromosomal DNA into three major phylogenetic lineages, or RDP types III-1, III-2, and III-3 (21, 22). The overwhelming majority (91%) of invasive isolates from neonates were RDP type III-3, suggesting that these strains are more virulent than the other RDP types (21).Characterization of the genetic differences between virulent III-3 and less virulent III-2 strains will help us understand the phylogenetic relationships between different GBS strains. We used genomic subtractive hybridization to identify nine short DNA sequences that are found in all III-3 strains, but not in III-2 or III-1 strains, and thus appear to be markers of the RDP type III-3 phylogenetic lineage (5). In the present study, we constructed a physical map of the III-3 GBS chromosome and identified the location of the III-3-specific probes and other previously described GBS genes.(This work was presented in part at the 14th Lancefield International Symposium on Streptococci and Streptococcal Diseases, 11 to 15 October 1999, Auckland, New Zealand.) MATERIALS AND METHODSProbes. The details of methods used t...

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