New world origin of canine distemper: Interdisciplinary insights.

OBJECTIVE: Canine distemper virus (CDV), human measles virus (HMV), and rinderpest virus (RPV) of cattle are morbilliviruses that have caused devastating outbreaks for centuries. This paper seeks to reconstruct the evolutionary history of CDV. MATERIALS AND METHODS: An interdisciplinary approach is adopted, synthesizing paleopathological analysis of 96 Pre-Columbian dogs (750-1470 CE) from the Weyanoke Old Town, Virginia site, with historical reports, molecular analysis and morbilliviral epidemiology. RESULTS: Both measles (c.900CE) and rinderpest (c. 376 BCE) were first reported in Eurasia, while canine distemper was initially described in South America much later (1735 CE); there are no paleopathological indications of CDV in Weyanoke Old Town dogs. Molecularly, CDV is closely related to HMV, while viral codon usage indicates CDV may have previously infected humans; South American measles epidemics occurred prior to the emergence of canine distemper and would have facilitated HMV transmission and adaptation to dogs. CONCLUSIONS: The measles epidemics that decimated indigenous South American populations in the 1500-1700 s likely facilitated the establishment of CDV as a canine pathogen, which eventually spread to Europe and beyond. SIGNIFICANCE: Understanding the historical and environmental conditions that have driven morbilliviral evolution provides important insights into potential future threats of animal/human cross-species infections. LIMITATIONS: Interpreting historical disease descriptions is difficult and the archaeological specimens are limited. Molecular sequence data and codon usage analyses rely on modern viruses. SUGGESTIONS FOR FURTHER RESEARCH: Interdisciplinary approaches are increasingly needed to understand diseases of the past and present, as critical information and knowledge is scattered in different disciplines.

Down regulation of melanin concentrating hormone in virally induced obesity.

Obesity is a complex disease involving genetic components and environmental factors and probably associated with the dysregulation of central homeostasis normally maintained by the hypothalamic neuroendocrine/neurotransmitter network. We previously reported that canine distemper virus (CDV), which is closely related to human measles virus, can target hypothalamic nuclei, and lead to obesity syndrome in the late stages of infection. Here, using differential display PCR, we demonstrate specific down-regulation of melanin-concentrating hormone precursor mRNA (ppMCH) in infected-obese mice. Although ppMCH was down-regulated in all infected mice during the acute stage of infection, this was only seen during the late stage of infection in infected-obese mice. In addition, ppMCH mRNA and protein expression in the lateral hypothalamus was decreased in the absence of neuronal death. These results show the importance of ppMCH in the establishment and maintenance of obesity and the involvement of a virus as an environmental factor.

Alteration of the leptin network in late morbid obesity induced in mice by brain infection with canine distemper virus.

Viruses can induce progressive neurologic disorders associated with diverse pathological manifestations, and therefore, viral infection of the brain can impair differentiated neural functions, depending on the initial viral tropism. We have previously reported that canine distemper virus (CDV) targets certain mouse brain structures, including the hypothalamus, early and selectively. Infected mice exhibit acute encephalitis, with late disease, characterized by motor impairment or obesity syndrome, appearing in some of the surviving mice several months after the initial viral replication. In the present study, we show viral persistence in the hypothalami of obese mice, as demonstrated by low, but still significant, levels of CDV nucleoprotein transcripts, associated with a dramatic decrease in F gene mRNAs. Given the pivotal role of the hypothalamus in obesity (eating behavior, energy consumption, and neuroendocrine function) and that of leptin, the adipose tissue-derived satiety factor acting through hypothalamic receptors, we analyzed the leptin networks in both obese and nonobese mice. The discrepancy found between the chronic and dramatic increase in blood leptin levels and the occurrence of obesity may be due to leptin resistance in the brain. In fact, expression of the long leptin receptor isoform, representing the functional leptin receptor, was specifically downregulated in the hypothalami of obese mice, explaining their inability to generate an adequate response to leptin in the brain. Intriguingly, during the acute phase of infection, its expression was increased in CDV-targeted structures in all infected mice and remained high in obese mice in all CDV-targeted structures, except for the hypothalamus. The biphasic change in hypothalamic leptin receptor expression seen during the progression of CDV-induced obesity provides a new paradigm for understanding mechanisms of neuroendocrinological, virus-induced abnormalities.

Brain structures selectively targeted by canine distemper virus in a mouse model infection.

Paramyxoviruses such as measles virus or canine distemper virus are etiological agents for acute and chronic encephalitis (measles inclusion body encephalitis, subacute sclerosing panencephalitis and chronic distemper encephalitis or old dog encephalitis). The mechanisms by which viral injury leads to neurological diseases have not yet been fully elucidated. We have developed an experimental model in mice in order to analyze the spatial and temporal distribution of canine distemper virus in the central nervous system. Cerebral target structures for viral replication were examined for the presence of viral material (proteins and mRNA) during the two stages of the biphasic disease. During the acute stage of infection all target areas could be identified by day 6 with a similar anatomical distribution in all the animals examined, which were either intracranially or intracerebroventricularly infected. Viral mRNA and proteins were selectively localized in certain brain structures such as the thalamus, hypothalamus, substantia nigra (pars compacta), locus ceruleus and raphe nuclei (dorsalis and centralis), and limbic system (hippocampus, septum, entorhinal and cingulate cortex, amygdala). The virus was apparently unable to replicate in cerebellum, striatum, a large part of cortex, or endothelial cells. During the subacute disease, viral material was no longer detectable except in a few structures such as hypothalamus up to 4-6 weeks after inoculation. After this time, all target structures were devoid of any labeling in spite of the occurrence of pathology (obesity, paralysis) during this viral quiescent phase. These results suggest that after the initial viral exposure, expression of viral genes in defined structures might disrupt central homeostasis and finally may lead to neurological or neuroendocrine diseases, even in the absence of the hallmarks of the virus.

Virus-induced obesity in mice: association with a hypothalamic lesion.

In an earlier study we found that a substantial percentage of mice surviving infection with canine distemper virus (CDV) slowly developed a morbid obesity syndrome. In the present study we wished to explore the role of the virus in the development of this syndrome. The distribution of viral antigen(s) in brains of pre-obese animals shortly after intracerebral infection was mapped using immunocytochemical procedures. A distinctive pattern of cell labeling was found, extending from the anterior periventricular hypothalamus ventrally and caudally toward the posterior hypothalamus. The heaviest concentration of labeled cells was found in the arcuate-ventromedial area. Viral antigen-containing cells were not found in obese brain specimens. However, the latter revealed, by glial fibrillary acidic protein immunostaining, a gliotic lesion of the hypothalamus that approximated topographically the pattern of virus tropism. Examination of the arcuate area revealed a significant reduction in tyrosine hydroxylase immunoreactive and pro-opiomelanocortin mRNA positive perikarya. We suggest that the loss of critical populations of hypothalamic neurons as a result of an antecedent viral infection led ultimately to the development of morbid obesity.