title: Eastern equine encephalitis virus in mice I: clinical course and outcome are dependent on route of exposure.
abstract: BACKGROUND
  Eastern equine encephalitis virus (EEEV), an arbovirus, is an important human and veterinary pathogen belonging to one of seven antigenic complexes in the genus Alphavirus, family Togaviridae. EEEV is considered the most deadly of the mosquito-borne alphaviruses due to the high case fatality rate associated with clinical infections, reaching up to 75 % in humans and 90 % in horses. In patients that survive acute infection, neurologic sequelae are often devastating. Although natural infections are acquired by mosquito bite, EEEV is also highly infectious by aerosol. This fact, along with the relative ease of production and stability of this virus, has led it to being identified as a potential agent of bioterrorism.
  
  
  METHODS
  To characterize the clinical course and outcome of EEEV strain FL93-939 infection, we compared clinical parameters, cytokine expression, viremia, and viral titers in numerous tissues of mice exposed by various routes. Twelve-week-old female BALB/c mice were infected by the intranasal, aerosol, or subcutaneous route. Mice were monitored for clinical signs of disease and euthanized at specified time points (6 hpi through 8 dpi). Blood and tissues were harvested for cytokine analysis and/or viral titer determination.
  
  
  RESULTS
  Although all groups of animals exhibited similar clinical signs after inoculation, the onset and severity differed. The majority of those animals exposed by the aerosol route developed severe clinical signs by 4 dpi. Significant differences were also observed in the viral titers of target tissues, with virus being detected in the brain at 6 hpi in the aerosol study.
  
  
  CONCLUSIONS
  The clinical course and outcome of EEEV infection in mice is dependent on route of exposure. Aerosol exposure to EEEV results in acute onset of clinical signs, rapid neuroinvasion, and 100 % mortality.
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. shelley.p.honnold.mil@mail.mil.|Integrated Toxicology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. shelley.p.honnold.mil@mail.mil.|Present address: Department of Internal Medicine, Center for Global Health, University of New Mexico, Albuquerque, NM, 87131, USA. shelley.p.honnold.mil@mail.mil.
authors.forename: Shelley P
authors.initials: SP
authors.lastname: Honnold
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. eric.c.mossel.mil@mail.mil.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Mossel
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. Russell.r.bakken.civ@mail.mil.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Bakken
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. Diana.fisher@nih.gov.
authors.forename: Diana
authors.initials: D
authors.lastname: Fisher
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. rc.lind@verizon.net.
authors.forename: Cathleen M
authors.initials: CM
authors.lastname: Lind
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. cohenjw@hotmail.com.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Cohen
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. lori.t.eccleston.ctr@mail.mil.
authors.forename: Lori T
authors.initials: LT
authors.lastname: Eccleston
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. kevinspurgers@yahoo.com.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Spurgers
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. Rebecca.a.erwin-cohen.civ@mail.mil.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Erwin-Cohen
authors.affiliation: Integrated Toxicology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. sbradfute@salud.unm.edu.|Present address: Department of Internal Medicine, Center for Global Health, University of New Mexico, Albuquerque, NM, 87131, USA. sbradfute@salud.unm.edu.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bradfute
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA. Radha.maheshwari@usuhs.edu.
authors.forename: Radha K
authors.initials: RK
authors.lastname: Maheshwari
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. pamela.j.glass.civ@mail.mil.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Glass
mesh_terms: D000280:Administration, Inhalation; D000281:Administration, Intranasal; D018354:Alphavirus Infections / Q000473:pathology* / Q000821:virology; D000825:Animal Structures / Q000473:pathology / Q000821:virology; D000818:Animals; D001826:Body Fluids / Q000821:virology; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004663:Encephalitis Virus, Eastern Equine / Q000254:growth & development* / Q000472:pathogenicity*; D005260:Female; D007279:Injections, Subcutaneous; D008807:Mice, Inbred BALB C; D016019:Survival Analysis; D019562:Viral Load
chemical_list: D016207:Cytokines