A wide range of viruses from different virus families in different geographical areas, may cause immediate or delayed neuropathological changes and neurological manifestations in humans and animals. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the central nervous system, frequently leaving the patient or affected animal with a poor or fatal prognosis. Mechanisms that govern neuropathogenesis and immunopathogenesis of viral infections are highlighted, using examples of well-studied virus infections that are associated with these alterations in different populations throughout the world. A better understanding of the molecular, epidemiological and biological characteristics of these infections and in particular of mechanisms that underlie their clinical manifestations may be expected to provide tools for the development of more effective intervention strategies and treatment regimens.

Measles virus (MV) is hypothesized to enter the host by infecting epithelial cells of the respiratory tract, followed by viremia mediated by infected monocytes. However, neither of these cell types express signaling lymphocyte activation molecule (CD150), which has been identified as the receptor for wild-type MV. We have infected rhesus and cynomolgus macaques with a recombinant MV strain expressing enhanced green fluorescent protein (EGFP); thus bringing together the optimal animal model for measles and a virus that can be detected with unprecedented sensitivity. Blood samples and broncho-alveolar lavages were collected every 3 d, and necropsies were performed upon euthanasia 9 or 15 d after infection. EGFP production by MV-infected cells was visualized macroscopically, in both living and sacrificed animals, and microscopically by confocal microscopy and FACS analysis. At the peak of viremia, EGFP fluorescence was detected in skin, respiratory and digestive tract, but most intensely in all lymphoid tissues. B- and T-lymphocytes expressing CD150 were the major target cells for MV infection. Highest percentages (up to 30%) of infected lymphocytes were detected in lymphoid tissues, and the virus preferentially targeted cells with a memory phenotype. Unexpectedly, circulating monocytes did not sustain productive MV infection. In peripheral tissues, large numbers of MV-infected CD11c⁺ MHC class-II⁺ myeloid dendritic cells were detected in conjunction with infected T-lymphocytes, suggesting transmission of MV between these cell types. Fluorescent imaging of MV infection in non-human primates demonstrated a crucial role for lymphocytes and dendritic cells in the pathogenesis of measles and measles-associated immunosuppression. Measles remains one of the most important causes of childhood mortality in developing countries. The virus is highly infectious and is spread via the respiratory route. According to textbook descriptions, measles virus first infects respiratory epithelial cells, followed by viremia mediated by infected monocytes. However, this order of events is inconsistent with current knowledge about receptor usage by measles virus strains. In this paper we have revisited the pathogenesis of measles by infecting non-human primates with a recombinant measles virus expressing enhanced green fluorescent protein. An important advantage of this system is that infected cells become fluorescent and can be detected with high sensitivity in living animals as well as tissue samples. Strikingly, at the peak of virus replication all lymphoid tissues were strongly fluorescent, and up to 10% of T-lymphocytes and 30% of B-lymphocytes were infected. In peripheral tissues the virus predominantly infected lymphocytes and dendritic cells, although to a lesser extent respiratory epithelial cells were also infected. We hypothesize that measles virus, like human immunodeficiency virus, utilizes dendritic cells as a vehicle to establish infection of the lymphoid system and cause immunosuppression. This study reshapes our basic view of measles pathogenesis.

Measles virus (MV) is highly infectious, and has long been thought to enter the host by infecting epithelial cells of the respiratory tract. However, epithelial cells do not express signaling lymphocyte activation molecule (CD150), which is the high-affinity cellular receptor for wild-type MV strains. We have generated a new recombinant MV strain expressing enhanced green fluorescent protein (EGFP), based on a wild-type genotype B3 virus isolate from Khartoum, Sudan (KS). Cynomolgus macaques were infected with a high dose of rMV^KSEGFP by aerosol inhalation to ensure that the virus could reach the full range of potential target cells throughout the entire respiratory tract. Animals were euthanized 2, 3, 4 or 5 days post-infection (d.p.i., n = 3 per time point) and infected (EGFP⁺) cells were identified at all four time points, albeit at low levels 2 and 3 d.p.i. At these earliest time points, MV-infected cells were exclusively detected in the lungs by fluorescence microscopy, histopathology and/or virus isolation from broncho-alveolar lavage cells. On 2 d.p.i., EGFP⁺ cells were phenotypically typed as large mononuclear cells present in the alveolar lumen or lining the alveolar epithelium. One to two days later, larger clusters of MV-infected cells were detected in bronchus-associated lymphoid tissue (BALT) and in the tracheo-bronchial lymph nodes. From 4 d.p.i. onward, MV-infected cells were detected in peripheral blood and various lymphoid tissues. In spite of the possibility for the aerosolized virus to infect cells and lymphoid tissues of the upper respiratory tract, MV-infected cells were not detected in either the tonsils or the adenoids until after onset of viremia. These data strongly suggest that in our model MV entered the host at the alveolar level by infecting macrophages or dendritic cells, which traffic the virus to BALT or regional lymph nodes, resulting in local amplification and subsequent systemic dissemination by viremia. Measles remains an important vaccine-preventable cause of morbidity and mortality in developing countries. The causative agent, measles virus (MV), is one of the most contagious viruses known. Measles has an incubation time of approximately two weeks, and surprisingly little is known about the early events after MV infection. Epithelial cells in the upper respiratory tract have long been considered as early target cells, but more recently alveolar macrophages (AM) and dendritic cells (DC) have been proposed as alternatives. We have infected cynomolgus macaques with a high dose of a recombinant EGFP-expressing MV strain via aerosol inhalation, to ensure that the virus had access to the entire respiratory tract. At 2 days post-infection, MV-infected mononuclear cells were detectable in the alveolar lumen but not in the upper respiratory tract. These infected cells migrated through the bronchus-associated lymphoid tissue to the draining tracheo-bronchial lymph node at 3 days post-infection. Systemic infection was initiated from this point, as observed in macaques euthanized 4 or 5 days post-infection. Thus, even though the aerosolized virus had access to epithelial cells and lymphoid tissues along the entire respiratory tract, AM and DC in the lungs were the first cells that sustained MV replication.

The global increase in measles vaccination has resulted in a significant reduction of measles mortality. The standard route of administration for the live-attenuated measles virus (MV) vaccine is subcutaneous injection, although alternative needle-free routes, including aerosol delivery, are under investigation.In vitro, attenuated MV has a much wider tropism than clinical isolates, as it can use both CD46 and CD150 as cellular receptors. To compare thein vivotropism of attenuated and pathogenic MV, we infected cynomolgus macaques with pathogenic or attenuated recombinant MV expressing enhanced green fluorescent protein (GFP) (strains IC323 and Edmonston, respectively) via the intratracheal or aerosol route. Surprisingly, viral loads and cellular tropism in the lungs were similar for the two viruses regardless of the route of administration, and CD11c-positive cells were identified as the major target population. However, only the pathogenic MV caused significant viremia, which resulted in massive virus replication in B and T lymphocytes in lymphoid tissues and viral dissemination to the skin and the submucosa of respiratory epithelia. Attenuated MV was rarely detected in lymphoid tissues, and when it was, only in isolated infected cells. Following aerosol inhalation, attenuated MV was detected at early time points in the upper respiratory tract, suggesting local virus replication. This contrasts with pathogenic MV, which invaded the upper respiratory tract only after the onset of viremia. This study shows that despitein vitrodifferences, attenuated and pathogenic MV show highly similarin vivotropism in the lungs. However, systemic spread of attenuated MV is restricted.