Comparative respiratory tract pathology of emerging viral infections
Increases in the number of infectious disease outbreaks affecting humans have been reported nearly every decade since the 1940’s. Many of these outbreaks have been caused by emerging zoonotic viruses. It has recently been estimated that there are at least 320,000 viruses in mammals that have yet to be discovered, some of which may affect humans. As humans continue to encroach upon previously isolated areas and have greater contact with wildlife, it is likely that zoonotic viruses will continue to emerge. Since many of these emerging viruses cause significant disease or death in humans it is vital that we study their pathology and pathogenesis in order to detect patterns in their mechanisms of disease, which could then be used to develop broad spectrum antivirals or vaccines. As such, we focused our studies on two recently emerged viruses, Nipah virus and the Middle East respiratory syndrome coronavirus (MERS-CoV), which have caused significant respiratory disease and death in humans. We used a Syrian hamster model to investigate whether differences in case fatality rates and prevalence of respiratory disease reported for Nipah virus outbreaks in Malaysia and Bangladesh were caused by intrinsic differences in the genomes of virus isolates from these outbreaks. We showed that hamsters developed similar end-stage respiratory lesions regardless of the Nipah virus isolate. These results suggest that differences reported between the outbreaks in Malaysia and Bangladesh were not due to viral genome heterogeneity. Rather, differences in transmission routes, viral dose, availability of healthcare facilities or willingness to seek medical care early in the infection may be responsible for the differences noted between these outbreaks. Additionally, we used Syrian hamsters to elucidate the early pathogenesis of Nipah virus. Nipah virus first targeted the lung and nasal cavity; virus replication was identified at 8 hours post inoculation (hpi). Virus then spread to the larynx and trachea. Even at 48 hpi we did not detect infectious virus in the brain or infection of blood vessels in multiple organs. Results suggest that early administration of antivirals into the respiratory tract may prevent widespread infection of the vasculature and virus replication in the brain. Since development of animal models is vital for studying novel viruses, we evaluated the available animal models of MERS-CoV infection. We found that transgenic mice expressing human dipeptidyl peptidase 4 were well-suited for screening antivirals and vaccines. Rhesus macaques and common marmosets were both suitable for transmission studies and confirming vaccine efficacy, while marmosets were ideal for confirming antiviral efficacy. Additionally, we compared the rhesus macaque and common marmoset models of MERS-CoV infection. We found that the increased clinical disease severity observed in marmosets, as compared to macaques, was most likely caused by increased pulmonary virus replication and development of more extensive acute bronchointerstitial pneumonia. These results suggest that treatments aimed at decreasing virus replication rates may dampen the acute pulmonary inflammatory response, thus decreasing disease severity and potentially human case fatality rates.
Feldmann, Purdue University.
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