Increased West Nile Virus Infection And Pathology In The Spontaneously Hypertensive Rat

Introduction: West Nile virus (WNV), a mosquito-borne flavivirus, causes grave neuroinvasive disease and death, and has been reported in over 55,000 people in the US since 1999. Patients >55 years and those with hypertension are most at risk for WNV-associated mortality. Understanding how hypertension correlates with WNV morbidity and mortality may reduce the burden of this disease. Investigation of WNV in hypertensive people is limited to basic epidemiology. Without an animal model, understanding the causal relationship between hypertension and WNV-associated pathology remains elusive. Here, we tested a novel hypothesis that hypertension will promote WNV infection and pathology in a rodent model of age-dependent chronic hypertension, the spontaneously hypertensive rat (SHR). Methods: Male adult SHR and normotensive WKY rats were implanted with radiotelemetry transmitters for measurements of blood pressure and heart rate. Following baseline measurements, SHR and WKY rats (N=9/gp) were injected with WNV (1 X 10 4 PFU/ml, i.p.). Vehicle injection (PBS, i.p.) was performed in additional WKY and SHR (N=2-3/gp). Each rat was observed for clinical abnormalities, and body weight, blood pressure, and heart rate were measured daily. Rats were sacrificed on days 9 and 10 post-infection (PI). At endpoint, several tissues were processed for measurement of viral load by RT-qPCR and histopathology. Bone marrow and circulating immune cells (CD4 + , CD8 + , CD68 + ) were quantified at endpoint by flow cytometry. Results: One SHR rat developed neurological symptoms and was euthanized on day 4 PI. Viral load was significantly increased in the SHR kidney and spleen (P<0.001) in SHR compared to WKY rats. In addition, WNV-infection elevated heart rate in the SHR but not the WKY (P<0.0001). SHR also showed elevated circulating CD68 + monocytes (P<0.05), and a significant increase (P<0.05) in renal pathology was observed in the SHR following WNV infection. Conclusions: We demonstrate, for the first time, a positive interaction between high blood pressure and severity of WNV infection in a rodent model of chronic hypertension. Further studies are needed to elucidate the mechanisms of this interaction for new therapeutic targets of WNV disease.