Arthur Löve

Induction of class I and class II transplantation antigens in rat brain during fatal and non-fatal measles virus infection

Abstract Measles virus induced a marked increase in the expression of MHC-coded class I and class II antigens as detected by immunostaining during both fatal and non-fatal brain infections in rats. The distribution of these molecules in the brain was much more widespread than the occurence of viral antigen suggesting a soluble factor for their induction. In 14-day-old rats with a non-fatal infection there was a marked infiltration of T lymphocytes of ‘cytotoxic/suppressor’ phenotype in the brain parenchyma, whereas T ‘helper’ cell phenotypes mainly were located perivascularly. In brains from newborn rats with a fatal infection no or only few lymphocytes were detected.

Non-Lethal Infection of Aminergic Reticular Core Neurons: Age-Dependent Spread of ts Mutant Vesicular Stomatitis Virus from the Nose

In order to induce a non-lethal infection restricted to central aminergic neurons projecting to the olfactory bulbs a series of temperature sensitive (ts) and G-protein monoclonal antibody escape mutants of vesicular stomatitis virus ( VSV) were instilled into the nasal cavity of mice. In three-week (wk)-old NMRI mice four monoclonal antibody escape mutants caused an extensive infection of the olfactory epithelium and, like a wild type strain, a lethal brain infection after spread along olfactory pathways. Three ts mutant strains showed an attenuated pathogenic potential. Strain G31 caused a lethal infection with a somewhat prolonged course while the strain G11 failed to invade the nervous system. Strain G41 showed minimal invasion of central nervous system in three-wk-old mice and caused a lethal infection in newborn and one-wk-old mice. In contrast, two-wk-old mice survived infection with this mutant, which spread along olfactory pathways and rather selectively affected aminergic reticular core neurons in the diagonal band, the locus ceruleus and the raphe nuclei in the brainstem. Thus, an age-dependent virus infection of the olfactory pathways can cause restricted lesions in the brain providing a model for studies of virus-induced changes in aminergic neurotransmission.

Antigenic Variation of Envelope and Internal Proteins of Mumps Virus Strains Detected with Monoclonal Antibodies

Antigenic characteristics of nine mumps virus strains were determined by immunofluorescence and radioimmunoprecipitation assay (RIPA) using a collection of 44 monoclonal antibodies. These antibodies were directed against five different structural components of mumps virus, the haemagglutinin-neuraminidase (HN), fusion (F), matrix (M), phospho- (P) and nucleocapsid (NP) proteins. The nine mumps virus strains could be divided into two groups according to their antigenic characteristics. One group included two strains isolated more than a decade ago and the Jeryl Lynn vaccine strain. These three strains reacted with a wider range of monoclonal antibodies than the second group of six recently isolated strains of different geographical origin. In the F, M and P proteins variations were only found in single antigenic determinants. In the HN and NP components, RIPA revealed variations in three and seven determinants respectively. The Jeryl Lynn vaccine strain showed a unique lack of reaction with one anti-HN antibody clone in the RIPA.

Persistence of measles virus in rat brain neurons is promoted by depletion of CD8+ T cells

Fourteen-day-old Lewis rats were injected intracerebrally with the hamster neurotropic (HNT) strain of measles virus. At the same time, CD8+ T cytotoxic cells were eliminated by a single injection of a mouse monoclonal antibody (Ox8) directed against this lymphocyte phenotype. The lymphocyte depletion, which endured for more than 7 weeks, markedly reduced the elimination of measles virus antigen from the brain, but did not affect the induction of major histocompatibility complex (MHC) molecules in the early phase of infection. These results demonstrate a role for MHC class I-restricted CD8+ T cells in controlling persistence of measles virus infection in neurons.

Selection of mutants of mumps virus with altered structure and pathogenicity by passage in vivo.

The neurotropic Kilham strain of mumps virus was serially passaged in newborn hamster brains in order to assess possible changes in viral characteristics. Two modes of passage were employed, one with a 4-5 day interval between inoculation and harvest and the other with a 10-12 day interval. After 10 and 8 passages, respectively, two viral variants were isolated which differed in antigen characteristics and in pathogenicity. In Vero cell cultures the variant derived from the short-term passage, designated as RK, showed much greater fusion capacity than the other, designated as SK. The highly fusing variant was highly lethal and caused much more extensive necrosis and grew to higher titers in the brain. With a series of monoclonal antibodies directed against the structural proteins of mumps virus marked differences between the variants could be detected in the nucleocapsid (NP) protein and also slight changes in the hemagglutinin-neuraminidase (HN) and phospho- (P) proteins. Differences were found in the preference of the viral variants to infect various regions of the brain. The RK variant heavily infected the caudate nucleus whereas the SK variant did not. This study demonstrates that different modes of passage can affect characteristics of virion components and disease pattern.

Protective effects of monoclonal antibodies against parainfluenza virus type 3-induced brain infection in hamsters.

A collection of monoclonal antibodies (MAbs) against the haemagglutinin-neuraminidase (HN) and fusion (F) glycoproteins of parainfluenza virus type 3 (PIV3) was used for passive immunization of intracerebrally infected newborn hamsters. A significant degree of protection was obtained with MAbs against both the HN and F viral proteins, but no individual antibody conferred complete protection against disease. MAbs against different epitopes provided different degrees of protection. A MAb to the Sendai virus HN protein was found to confer protection against PIV3 brain infection.

Paramyxovirus infections alter certain functional properties in cultured sensory neurons

Functional properties of cultured mouse dorsal root ganglion cells infected with paramyxoviruses have been studied using intracellular recording techniques. Mumps virus, which causes a persistent non-lytic infection, and Sendai virus, which causes an infection that leads to cell lysis after about a week were used. In the early phase of the infection (24-48 h) both viruses caused a reduction in the influx of calcium ions during the action potential, but did not alter resting membrane potential, action potential amplitude or input resistance. At later times functional properties became normal in mumps infected neurons. In contrast, Sendai virus infected neurons showed a reduction of action potential amplitude and input resistance at 48-72 h after infection, and finally there was also a reduction of membrane potential before the cells disintegrated. These results show that different paramyxovirus infections may cause different types of alterations in the functional properties of neurons. The reduced calcium influx resulting from mumps infection suggests that a non-lytic viral infection may have selective effects on important regulators of neuronal functions. Moreover, a lethal viral infection (Sendai) may influence specific membrane properties, such as calcium channel activation, several days prior to general structural and functional degeneration.

Developmental Disturbances in the Hamster Retina Caused by a Mutant of Mumps Virus

Newborn hamsters were inoculated intracerebrally with either the neurovirulent Kilham strain of mumps virus or a mutant (M13) strain of this virus. The M13 strain has an alteration in the haemagglutinin-neuraminidase protein of its envelope and causes a low-grade infection of the brain. Both strains spread consistently to the retina where the Kilham strain caused an extensive necrotizing infection. In contrast, the M13 strain predominantly caused an infection of the retinal pigment epithelium (RPE) with the involvement of scattered neurons in the retina. Only minimal degenerative or inflammatory changes were seen, but at 12 days of age developmental alterations were seen in all eyes. These included stretches with failure of photoreceptor segment development and the formation of folds in the outer nuclear layer. The former changes occurred in areas with loss of RPE cells and the latter generally in connection with displaced pigment-loaded cells from the RPE layer. It is suggested that these retinal alterations are mainly secondary to the RPE infection with the M13 strain.