Infection with Encephalitic Alphaviruses

Eastern (EEEV) and Venezuelan (VEEV) equine encephalitis viruses (EEVs) are related, 10 (+)ssRNA arboviruses that can cause severe, sometimes fatal, encephalitis in humans. EEVs are 11 highly infectious when aerosolized, raising concerns for potential use as biological weapons. No 12 licensed medical countermeasures exist; given the severity/rarity of natural EEV infections, efficacy 13 studies require animal models. Cynomolgus macaques exposed to EEV aerosols develop fever, 14 encephalitis, and other clinical signs similar to humans. Fever is nonspecific for encephalitis in 15 macaques. Electrocardiography (ECG) metrics may predict onset, severity, or outcome of 16 EEV-attributable disease. Macaques were implanted with thermometry/ECG radiotransmitters and 17 exposed to aerosolized EEV. Data was collected continuously, and repeated-measures ANOVA 18 and frequency-spectrum analyses identified differences between courses of illness and between 19 pre-exposure and post-exposure states. EEEV-infected macaques manifested widened 20 QRS-intervals in severely ill subjects post-exposure. Moreover, QT-intervals and RR-intervals 21 decreased during the febrile period. VEEV-infected macaques suffered decreased QT-intervals and 22 RR-intervals with fever onset. Frequency-spectrum analyses revealed differences in the 23 fundamental frequencies of multiple metrics in the post-exposure and febrile periods compared to 24 baseline and confirmed circadian dysfunction. Heart rate variability (HRV) analyses revealed 25 diminished variability post-exposure. These analyses support using ECG data alongside fever and 26 clinical laboratory findings for evaluating medical countermeasure efficacy. 27