title: Eastern equine encephalitis virus in mice II: pathogenesis is dependent on route of exposure.
abstract: BACKGROUND
  Eastern equine encephalitis virus (EEEV) is an alphavirus with a case fatality rate estimated to be as high as 75 % in humans and 90 % in horses. Surviving patients often have long-lasting and severe neurological sequelae. At present, there is no licensed vaccine or therapeutic for EEEV infection. This study completes the clinical and pathological analysis of mice infected with a North American strain of EEEV by three different routes: aerosol, intranasal, and subcutaneous. Such an understanding is imperative for use of the mouse model in vaccine and antiviral drug development.
  
  
  METHODS
  Twelve-week-old female BALB/c mice were infected with EEEV strain FL93-939 by the intranasal, aerosol, or subcutaneous route. Mice were euthanized 6 hpi through 8 dpi and tissues were harvested for histopathological and immunohistochemical analysis.
  
  
  RESULTS
  Viral antigen was detected in the olfactory bulb as early as 1-2 dpi in aerosol and intranasal infected mice. However, histologic lesions in the brain were evident about 24 hours earlier (3 dpi vs 4 dpi), and were more pronounced following aerosol infection relative to intranasal infection. Following subcutaneous infection, viral antigen was also detected in the olfactory bulb, though not as routinely or as early. Significant histologic lesions were not observed until 6 dpi.
  
  
  CONCLUSIONS
  These pathologic studies suggest EEEV enters the brain through the olfactory system when mice are exposed via the intranasal and aerosol routes. In contrast, the histopathologic lesions were delayed in the subcutaneous group and it appears the virus may utilize both the vascular and olfactory routes to enter the brain when mice are exposed to EEEV subcutaneously.
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.|Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, 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. 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: 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
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
mesh_terms: D000280:Administration, Inhalation; D000281:Administration, Intranasal; D018354:Alphavirus Infections / Q000473:pathology* / Q000821:virology*; D000825:Animal Structures / Q000473:pathology / Q000821:virology; D000818:Animals; D004195:Disease Models, Animal; D004663:Encephalitis Virus, Eastern Equine / Q000254:growth & development* / Q000502:physiology*; D005260:Female; D006651:Histocytochemistry; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D051379:Mice; D008807:Mice, Inbred BALB C; D008853:Microscopy