The Sustained Alteration Of Brain Waves In Cynomolgus Macaques Following Aerosol Infection With Venezuelan Equine Encephalitis Virus Subtype IAB
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Venezuelan equine encephalitis virus subtype IAB (VEEV-IAB) is a mosquito-borne virus that can cause fatal encephalitis in humans and equids. During the 20th century, sporadic but widespread outbreaks occurred throughout the Americas. In addition, VEEV-IAB was investigated as a potential biological warfare agent during the Cold War. Currently, no countermeasures are available to treat or prevent human infection. A critical impediment to understanding VEEV-IAB pathogenesis and developing countermeasures is the lack of a detailed disease course in a susceptible animal model. This study evaluated VEEV-IAB disease progression in cynomolgus macaques using advanced telemetry technology to continuously monitor physiological parameters, including temperature, respiration, activity, heart rate, blood pressure, electrocardiography (ECG), and electroencephalography (EEG), following an aerosol challenge of 6.0 log 10 PFU. Following infection, all parameters were altered relative to baseline; temperature (+3.1 to +4.0°C), respiration rate (+45 to +91%), activity [daytime (- 29 to -55%) and nighttime (+14 to +34%)], heart rate (-27 to +191%), systolic (+11 to +39%) and diastolic blood pressure (+7 to +39%). Cardiac abnormalities included increases in QTc (Bazett), PR interval, and QRS duration. All EEG frequency bands were rapidly altered (−250% to +4,800%) and did not return to baseline during the 28-day post-infection period. Despite these profound physiological changes, brain tissues collected at 28 dpi showed minimal evidence of viral persistence or pathology. These data demonstrate that VEEV-IAB aerosol infection rapidly and markedly alters physiological parameters regulated by the autonomic nervous system, as well as provides new insights into VEEV-IAB pathogenesis and countermeasure development.
IMPORTANCE
VEEV-IAB is a high-consequence arbovirus that can cause fatal neurological disease, however, currently there are no approved vaccines or therapeutics. In this proof-of-concept study, we utilized state-of-the-art telemetry technology to characterize the disease course following VEEV-IAB infection in a susceptible macaque model by measuring multiple physiological parameters relevant to human disease. VEEV-IAB infection rapidly induces substantial alterations in autonomic nervous system functions including temperature, respiration, activity, heart rate, blood pressure, ECG, and EEG. Most notable findings were the extreme and sustained alterations of brain activity despite pathological changes in the brain. These findings establish a framework for disease assessment through quantification of critical physiological biomarkers and provide a platform for evaluating the efficacy of vaccine and therapeutic candidates against VEEV-IAB.
