PATHOGENESIS OF MEASLES VIRUS INFECTIONS

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Measles remains a major world health problem, but the pathogenesis of this disease has been difficult to study and is incompletely understood. The infection causes immune suppression, probably due in part to replication within cells of the immune system. Measles is also associated with certain neurological complications, related to deficient (inclusion body encephalitis) or inappropriate (postinfectious encephalomyelitis) immune responses, or to defective viral replication (subacute sclerosing panencephalitis). Age-related differences in the incidence of these complications suggest that the maturation state of the host at the time of infection is important. A murine model of measles virus infection of the central nervous system has been developed in which newborn mice develop acute encephalitis with a productive virus infection while weanling mice develop a non-inflammatory encephalopathy with a non-productive virus infection. In the weanling mouse viral antigens are synthesized, but nucleocapsids are not assembled. This model provides an example of altered virus expression due to host cell maturation and offers the opportunity to study the effects of a maturing nervous system on measles virus replication. Using recently developed clones of DNA sequences complementary to measles RNA, coupled with new techniques of in situ hybridization and simultaneous immunocytochemistry, we propose to study this model, as well as specimens from patients with natural measles virus infection, with the following specific aims: (1) To determine if the age-dependent restriction of measles virus replication in the mouse brain occurs at the level of replication of genomic-length RNA, by using separate probes for positive and negative sense RNA. (2) To determine the susceptibility of specific subclasses of leukocytes to infection with measles virus in both experimental murine and natural human infections by identifying the cell type with use of monoclonal antibody immunoperoxidase histochemistry and simultaneously detecting measles RNA by in situ hybridization. (3) To determine the cell and organ distribution of measles virus in fatal human cases with and without encephalitis, by using simultaneous immunocytochemistry and in situ hybridization. The significance of this work lies in its contribution to the understanding of measles virus infection and how it affects the immune system and central nervous system, and potentially to understanding fundamental principles of the influence of host cell maturation stage on viral replication.