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

Honnold SP, Mossel EC, Bakken RR, Fisher D, Lind CM, Cohen JW, Eccleston LT, Spurgers KB, Erwin-Cohen R, Bradfute SB, Maheshwari RK, Glass PJ - Virol. J. (2015)

Bottom Line: 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.Aerosol exposure to EEEV results in acute onset of clinical signs, rapid neuroinvasion, and 100 % mortality.

View Article: PubMed Central - PubMed

Affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. shelley.p.honnold.mil@mail.mil.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Serum analysis of soluble proteins in mice infected with EEEV strain FL93-939 by the intranasal, aerosol, or subcutaneous route. Infected mice were euthanized at specified time points. Soluble proteins in the serum were determined using BD Cytometric Bead Array mouse soluble protein flex sets and analyzed using FCAP Array software. Values represent the group mean at each time point (n = 6), bars represent the standard deviation. Mean baseline values (0 dpi) were determined from uninfected controls (n = 6)
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Fig4: Serum analysis of soluble proteins in mice infected with EEEV strain FL93-939 by the intranasal, aerosol, or subcutaneous route. Infected mice were euthanized at specified time points. Soluble proteins in the serum were determined using BD Cytometric Bead Array mouse soluble protein flex sets and analyzed using FCAP Array software. Values represent the group mean at each time point (n = 6), bars represent the standard deviation. Mean baseline values (0 dpi) were determined from uninfected controls (n = 6)

Mentions: To characterize and compare route-specific induction of inflammatory and immunomodulatory cytokines and chemokines, a subset of serum samples were analyzed from the IN, AE, and SC studies for the presence of 25 soluble proteins (sCD62E, sCD62L, G-CSF, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, I L-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12/IL23p40, IL-13, IL-17A, IL-21, KC/CXCL1, MCP-1/CCL2, MIG.CXCL9, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, and TNF). There were no significant differences in any of the 25 cytokines and chemokines tested between aerosol and intranasal infection at any time point. However, there were several differences between subcutaneous and intranasal or aerosol infections (Fig. 4). Subcutaneous infection resulted in an increase of IFN-γ, MIP-1β, RANTES, and MIG at 1 dpi compared to aerosol or intranasal infection, followed by a return to baseline at 2 dpi. These same cyto/chemokines were increased in aerosol and intranasal infection at 2 dpi relative to subcutaneous infection. Infection by all three routes generated a late increase in G-CSF levels: 4 dpi following IN or AE infection and 6–7 dpi after SC infection.Fig. 4


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

Honnold SP, Mossel EC, Bakken RR, Fisher D, Lind CM, Cohen JW, Eccleston LT, Spurgers KB, Erwin-Cohen R, Bradfute SB, Maheshwari RK, Glass PJ - Virol. J. (2015)

Serum analysis of soluble proteins in mice infected with EEEV strain FL93-939 by the intranasal, aerosol, or subcutaneous route. Infected mice were euthanized at specified time points. Soluble proteins in the serum were determined using BD Cytometric Bead Array mouse soluble protein flex sets and analyzed using FCAP Array software. Values represent the group mean at each time point (n = 6), bars represent the standard deviation. Mean baseline values (0 dpi) were determined from uninfected controls (n = 6)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4588493&req=5

Fig4: Serum analysis of soluble proteins in mice infected with EEEV strain FL93-939 by the intranasal, aerosol, or subcutaneous route. Infected mice were euthanized at specified time points. Soluble proteins in the serum were determined using BD Cytometric Bead Array mouse soluble protein flex sets and analyzed using FCAP Array software. Values represent the group mean at each time point (n = 6), bars represent the standard deviation. Mean baseline values (0 dpi) were determined from uninfected controls (n = 6)
Mentions: To characterize and compare route-specific induction of inflammatory and immunomodulatory cytokines and chemokines, a subset of serum samples were analyzed from the IN, AE, and SC studies for the presence of 25 soluble proteins (sCD62E, sCD62L, G-CSF, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, I L-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12/IL23p40, IL-13, IL-17A, IL-21, KC/CXCL1, MCP-1/CCL2, MIG.CXCL9, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, and TNF). There were no significant differences in any of the 25 cytokines and chemokines tested between aerosol and intranasal infection at any time point. However, there were several differences between subcutaneous and intranasal or aerosol infections (Fig. 4). Subcutaneous infection resulted in an increase of IFN-γ, MIP-1β, RANTES, and MIG at 1 dpi compared to aerosol or intranasal infection, followed by a return to baseline at 2 dpi. These same cyto/chemokines were increased in aerosol and intranasal infection at 2 dpi relative to subcutaneous infection. Infection by all three routes generated a late increase in G-CSF levels: 4 dpi following IN or AE infection and 6–7 dpi after SC infection.Fig. 4

Bottom Line: 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.Aerosol exposure to EEEV results in acute onset of clinical signs, rapid neuroinvasion, and 100 % mortality.

View Article: PubMed Central - PubMed

Affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, 21702, USA. shelley.p.honnold.mil@mail.mil.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus