Eastern equine encephalitis virus in mice I: clinical course and outcome are dependent on route of exposure

Honnold, Shelley P.; Mossel, Eric C.; Bakken, Russell R.; Fisher, Diana; Lind, Cathleen M.; Cohen, Jeffrey W.; Eccleston, Lori T.; Spurgers, Kevin B.; Erwin-Cohen, Rebecca; Bradfute, Steven B.; Maheshwari, Radha K.; Glass, Pamela J.

doi:10.1186/s12985-015-0386-1

Cited by 18 publications

(20 citation statements)

References 17 publications

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“…The mean time to death for high virulence strains was 5–6 days post-challenge, as opposed to 4–5 days by the aerosol route seen here. This is also in-line with a related encephalitic alphavirus, EEEV, where virus was first found in the brain at 6 h after aerosol challenge, and 24 h after intranasal challenge [ 21 ].…”

Section: Discussionsupporting

confidence: 62%

“…However, studies often use intra-nasal inoculation as a surrogate for aerosol exposure. In a recent study examining the clinical course of a closely-related Alphavirus, EEEV, adult Balb/c mice were infected by the intra-nasal and aerosol routes, yielding 100% lethality, with rapid neuroinvasion and acute onset of clinical signs [ 21 ]. In this study, a number of parameters were comparable between the two exposure routes (weight, clinical scores, cytokine expression), although importantly, virus was detected in the brain of aerosol exposed mice at 6 h post-infection.…”

Section: Introductionmentioning

confidence: 99%

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Susceptibility and Lethality of Western Equine Encephalitis Virus in Balb/c Mice When Infected by the Aerosol Route

Phelps

O’Brien

Eastaugh

et al. 2017

Viruses

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Western equine encephalitis virus (WEEV) naturally cycles between mosquitos and birds or rodents, with a case fatality rate of up to 15% in humans during epizootic outbreaks. There are no medical countermeasures to treat WEEV infection, and accidental aerosol exposure increases the case fatality rate up to 40%. Understanding the pathogenesis of infection is required to develop and assess medical countermeasures. This study describes the clinical and pathological findings of mice infected with WEEV by the aerosol route, and use as a model for WEEV infection in humans. Balb/c mice were infected by the aerosol route with a dose range of high-virulence WEEV strain Fleming to establish the median lethal dose (MLD). The disease course was acute, culminating in severe clinical signs, neuroinvasion, and dose-dependent mortality. Further groups of mice were exposed by the aerosol route, periodically sacrificed, and tissues excised for histopathological examination and virology. Viral titres peaked four days post-challenge in the brain and lungs, corresponding with severe bilateral lesions in rostroventral regions of the encephalon, especially in the olfactory bulb and piriform cortex. Recapitulation of the most serious clinical presentations of human WEEV disease in mice may prove a useful tool in the evaluation of medical countermeasures.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Susceptibility and Lethality of Western Equine Encephalitis Virus in Balb/c Mice When Infected by the Aerosol Route

Phelps

O’Brien

Eastaugh

et al. 2017

Viruses

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“…This and other calculations of mouse aerosol LD 50 [4, 5] are similar to the MLD observed in our study, where mice were exposed in a nose-only exposure protocol. Honnold et al [7] have characterised EEEV disease in Balb/c mice infected with the virulent FL93–939 strain by three different routes of infection, including aerosol. Virus was detected as early as 6 h post infection, although the difference in the age of Balb/c mice (8–10 weeks old), and more likely, the differences in aerosolisation protocol (whole-body), challenge preparation (sucrose purified), concentration (100 × LD 50 ) and strain (FL93–939), may account for the later onset of neuro-invasion with 5.5 × MLD EEEV strain Pe-6.…”

Section: Discussionmentioning

confidence: 99%

“…Venezuelan equine encephalitis virus (VEEV) infected mice exposed by the aerosol route however, do not present with seizures, but paralysis is evident. In recent studies, adult Balb/c mice were exposed to EEEV strain FL93–939 by the aerosol (whole body exposure), intra-nasal and sub-cutaneous routes of infection, fully characterizing the clinical course of disease and pathogenesis of this strain [7, 8]. The severity, lethality and onset of disease is route dependent.…”

Section: Introductionmentioning

confidence: 99%

Aerosol infection of Balb/c mice with eastern equine encephalitis virus; susceptibility and lethality

Phelps¹,

O’Brien²,

Eastaugh³

et al. 2019

Virol J

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BackgroundEastern equine encephalitis virus is an alphavirus that naturally cycles between mosquitoes and birds or rodents in Eastern States of the US. Equine infection occurs by being bitten by cross-feeding mosquitoes, with a case fatality rate of up to 75% in humans during epizootic outbreaks. There are no licensed medical countermeasures, and with an anticipated increase in mortality when exposed by the aerosol route based on anecdotal human data and experimental animal data, it is important to understand the pathogenesis of this disease in pursuit of treatment options. This report details the clinical and pathological findings of mice infected with EEEV by the aerosol route, and use as a model for EEEV infection in humans.MethodsMice were exposed by the aerosol route to a dose range of EEEV to establish the median lethal dose. A pathogenesis study followed whereby mice were exposed to a defined dose of virus and sacrificed at time-points thereafter for histopathological analysis and virology.ResultsClinical signs of disease appeared within 2 days post challenge, culminating in severe clinical signs within 24 h, neuro-invasion and dose dependent lethality. EEEV was first detected in the lung 1 day post challenge, and by day 3 peak viral titres were observed in the brain, spleen and blood, corresponding with severe meningoencephalitis, indicative of encephalitic disease. Lethality follows severe neurological signs, and may be linked to a threshold level of virus replication in the brain. Effective medical countermeasures for EEEV may necessitate early inoculation to inhibit infection of the brain in zoonotic incidents, and be able to traverse the blood-brain barrier to sufficiently interrupt replication in the brain in cases of aerosol infection.ConclusionsThere is little human data on the hazard posed by aerosol infection with encephalitic alphaviruses, and use of EEEV as a bioweapon may be by the aerosol route. A well characterized model of aerosol exposure that recapitulates some of the most severe human clinical features is necessary to evaluate the efficacy of putative medical countermeasures, and to increase our understanding about how this route of infection induces such rapid neuro-invasion and resulting disease.

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“…eeeV susceptibility in mouse models is correlated with age, with younger mice being more susceptible than adults. Importantly, eeeV pathogenesis is dependent on route of infection with delayed progression upon subcutaneous (subQ) exposure (Honnold et al, 2015). Newborn mice display neuronal damage with rapid disease progression, resulting in death (Murphy and Whitfield, 1970).…”

Section: Norwalk Virusmentioning

confidence: 99%

Animal Models of Human Viral Diseases

Ruiz

Zumbrun

Nalca

2017

Animal Models for the Study of Human Disease

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Eastern equine encephalitis virus in mice I: clinical course and outcome are dependent on route of exposure

Cited by 18 publications

References 17 publications

Susceptibility and Lethality of Western Equine Encephalitis Virus in Balb/c Mice When Infected by the Aerosol Route

Susceptibility and Lethality of Western Equine Encephalitis Virus in Balb/c Mice When Infected by the Aerosol Route

Aerosol infection of Balb/c mice with eastern equine encephalitis virus; susceptibility and lethality

Animal Models of Human Viral Diseases

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