Electrocardiography Abnormalities in Macaques after Infection with Encephalitic Alphaviruses.

Ma Ma,Hartman Hartman,Lundy Lundy,Klimstra Klimstra,O'malley O'Malley,Reed Reed

doi:10.3390/pathogens8040240

Abstract

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

Highlights

Equine encephalitis viruses (EEVs) constitute a subset of the alphavirus genus of Family Togaviridae.The alphaviruses are grouped into New World and Old World viruses, which generally correspond with groups of signs of clinical disease; New World alphaviruses are more likely to cause encephalitis while Old World viruses tend to cause arthralgia [1,2,3,4]
In the 1930s, these mosquito-borne viruses were among the first alphaviruses to be discovered, and both the United States and Soviet Union experimented with Venezuelan Equine Encephalitis (VEEV) as a potential biological warfare agent after it was realized that VEEV was highly infectious when aerosolized [5,6,7,8,9,10]
To explore the utility of monitoring ECG changes associated with EEEV-induced viral encephalitis caused by New World-alphaviruses, four macaques were exposed to small-particle (≤5 μm mass mean aerodynamic diameter) aerosols containing EEEV

Summary

Introduction

Equine encephalitis viruses (EEVs) constitute a subset of the alphavirus genus of Family Togaviridae.The alphaviruses are grouped into New World and Old World viruses, which generally correspond with groups of signs of clinical disease; New World alphaviruses are more likely to cause encephalitis while Old World viruses tend to cause arthralgia [1,2,3,4]. In the 1930s, these mosquito-borne viruses were among the first alphaviruses to be discovered, and both the United States and Soviet Union experimented with Venezuelan Equine Encephalitis (VEEV) as a potential biological warfare agent after it was realized that VEEV was highly infectious when aerosolized [5,6,7,8,9,10]. These pathogens remain important medical and veterinary pathogens to this day [11].

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