Modeling Emergent Diseases: Lessons From Middle East Respiratory Syndrome.

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In the summer of 2012, a patient died in Saudi Arabia following a flu-like illness with severe respiratory disease. A novel betacoronavirus was isolated from this case and is now called Middle East respiratory syndrome coronavirus (MERS-CoV). At the time of this writing (Jan 16, 2016, www.who.int), the World Health Organization reports 1626 laboratory-confirmed cases of MERS-CoV infection with a mortality rate of about 36%, most dying with severe respiratory disease. While person-toperson transmission has been documented, it is relatively inefficient and the risks for sustained person-to-person transmission is currently low. Its similarity to another zoonotic coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), raised early concerns about potential animal reservoirs for the virus or questions about overt animal morbidity from MERS-CoV. Evidence suggests dromedary camels may be a relevant zoonotic reservoir for human exposure through routine handling, husbandry and food sources (eg, milk, meat); however, bats and/or other animals may also serve as possible reservoirs for the virus. In this issue of Veterinary Pathology, Baseler and colleagues review the breadth of recently developed animal models to study MERS-CoV infection. The authors highlight the advantages of the different models and compare their specific relevance for study of MERS-CoV. From this review, several important considerations can be made regarding outbreaks of emergent diseases. First, testing a range of models is important at the onset of an emergent disease outbreak so research can identify relevant models and efficiently advance. As pointed out Baseler et al, only a subset of the animal models had an experimental phenotype that sufficiently replicated human disease, but these results could not have been predicted prior to methodical testing and validation. Alternatively, recent studies have identified SARS-like coronaviruses circulating in bats that have potential for future emergence in humans. Could testing of these viruses in animal models provide a novel and proactive approach that provides information relevant to rapid investigation and control of future viral zoonoses? Second, animal models can often help clarify clinical understanding of a disease. In the recent MERS-CoV outbreak, cultural restrictions prevented autopsies on the patients that died; thus, pathological evaluations of the lungs and other tissues have been reported in only one autopsy case. X-ray computed tomography on some patients with clinically severe lung disease suggested that MERS-CoV caused an acute respiratory distress syndrome (ARDS)–like condition. Several animal models have developed lesions that could be consistent with an early ARDS-like phenotype and better animal models continue to be developed for further characterizing MERS-CoV lung pathology. Thus, animal models provide insights into the morphology and pathogenesis of MERS-CoV infection, partially filling the gap left by the paucity of studies on human tissues. Thirdly, the risk for MERS-CoV infection and fatality appears to be higher for individuals with comorbidities (eg, diabetes, obesity, and lung disease to name a few). A recent study of the MERS-CoV receptor (dipeptidyl peptidase-4, DPP4) in human lung suggests that chronic lung disease (eg, cystic fibrosis or chronic obstructive pulmonary disease) may upregulate DPP4 expression to increase availability of the receptor for the virus. While this potential cause for enhanced disease in patients with comorbidities is interesting, the mechanism cannot be tested in humans. Animal models can provide an excellent system by which to test this theory and better understand how comorbidities may contribute to MERSCoV disease pathogenesis. Last, the origin of the MERS-CoV outbreak in Saudi Arabia was not just a regional event. In May 2015 a 68-year-old man in South Korea was diagnosed with MERS-CoV 9 days after returning from a trip to the Middle East, and this index case led to 186 people being infected and 36 deaths. The example highlights how in today’s society, the convenience of worldwide travel allows for potentially rapid dissemination of disease exposure from one country to another. Early action to develop new or better animal models for MERS-CoV and other emergent diseases can expedite their use for study of much-needed vaccines and therapeutics to potentially mitigate the extent and severity of outbreaks worldwide.