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Pathogenesis of Lassa fever in cynomolgus macaques.

Hensley LE, Smith MA, Geisbert JB, Fritz EA, Daddario-DiCaprio KM, Larsen T, Geisbert TW - Virol. J. (2011)

Bottom Line: Tissues from three animals were examined at an early- to mid-stage of disease and compared with tissues from three animals collected at terminal stages of disease.Evidence of coagulopathy was noted; however, the degree of fibrin deposition in tissues was less prominent than has been reported in other viral hemorrhagic fevers.The sequence of pathogenic events identified in this study begins to shed light on the development of disease processes during Lassa fever and also may provide new targets for rational prophylactic and chemotherapeutic interventions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Virology, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA.

ABSTRACT

Background: Lassa virus (LASV) infection causes an acute and sometimes fatal hemorrhagic disease in humans and nonhuman primates; however, little is known about the development of Lassa fever. Here, we performed a pilot study to begin to understand the progression of LASV infection in nonhuman primates.

Methods: Six cynomolgus monkeys were experimentally infected with LASV. Tissues from three animals were examined at an early- to mid-stage of disease and compared with tissues from three animals collected at terminal stages of disease.

Results: Dendritic cells were identified as a prominent target of LASV infection in a variety of tissues in all animals at day 7 while Kupffer cells, hepatocytes, adrenal cortical cells, and endothelial cells were more frequently infected with LASV in tissues of terminal animals (days 13.5-17). Meningoencephalitis and neuronal necrosis were noteworthy findings in terminal animals. Evidence of coagulopathy was noted; however, the degree of fibrin deposition in tissues was less prominent than has been reported in other viral hemorrhagic fevers.

Conclusion: The sequence of pathogenic events identified in this study begins to shed light on the development of disease processes during Lassa fever and also may provide new targets for rational prophylactic and chemotherapeutic interventions.

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Related in: MedlinePlus

Histopathology and immunohistochemistry of nervous tissue of Lassa virus-infected cynomolgus monkeys. (A) Histology of cerebellum showing meningitis at day 15; H&E stain. (B) Histology of cerebrum showing neuronal necrosis at day 13; H&E stain. (C), Optic neuritis; note immunopositive inflammatory foci (brown) at day 15. (D), Brain stem, immunopositive endothelium (arrow) and immunopositive inflammatory foci (brown) in the neuropil peripheral to a medium-sized blood vessel at day 13. (E) Immunopositive endothelial cells (brown) in cerebrum at day 15. (F) Choroid plexus, prominent immunostaining (brown) of the cuboidal epithelial cells lining the choroid at day 15. Original magnifications, ×20 (B-F), ×40 (A)
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Figure 9: Histopathology and immunohistochemistry of nervous tissue of Lassa virus-infected cynomolgus monkeys. (A) Histology of cerebellum showing meningitis at day 15; H&E stain. (B) Histology of cerebrum showing neuronal necrosis at day 13; H&E stain. (C), Optic neuritis; note immunopositive inflammatory foci (brown) at day 15. (D), Brain stem, immunopositive endothelium (arrow) and immunopositive inflammatory foci (brown) in the neuropil peripheral to a medium-sized blood vessel at day 13. (E) Immunopositive endothelial cells (brown) in cerebrum at day 15. (F) Choroid plexus, prominent immunostaining (brown) of the cuboidal epithelial cells lining the choroid at day 15. Original magnifications, ×20 (B-F), ×40 (A)

Mentions: No significant lesions were observed in the nervous system at day 7. However, LASV immunostaining was infrequently detected in circulating histiocytic cells (2/3) and in endothelial cells (2/3) at this timepoint. Substantial changes in lesions and the presence of LASV occurred in the neuropil by terminal time points. Noteworthy findings in terminal animals included: meningoencephalitis in the cerebrum, cerebellum (Figure 9A), and brainstem (3/3); neuronal necrosis and gliosis in cerebrum (Figure 9B) and brainstem (3/3); choroid plexitis (1/3); meningomyelitis (1/3); and neuritis of optic nerve (2/3) (Figure 9C). LASV antigen was detected multifocally in endothelial cells and histiocytic inflammatory cells of cerebrum (Figures 9D,E), cerebellum, brainstem, spinal cord, and optic nerve (Figure 9C) of terminal animals. In addition, LASV antigen was detected in glial cells in cerebrum of 2/3 animals and in choroid plexis epithelial cells in cerebrum of 1/3 animals (Figure 9F).


Pathogenesis of Lassa fever in cynomolgus macaques.

Hensley LE, Smith MA, Geisbert JB, Fritz EA, Daddario-DiCaprio KM, Larsen T, Geisbert TW - Virol. J. (2011)

Histopathology and immunohistochemistry of nervous tissue of Lassa virus-infected cynomolgus monkeys. (A) Histology of cerebellum showing meningitis at day 15; H&E stain. (B) Histology of cerebrum showing neuronal necrosis at day 13; H&E stain. (C), Optic neuritis; note immunopositive inflammatory foci (brown) at day 15. (D), Brain stem, immunopositive endothelium (arrow) and immunopositive inflammatory foci (brown) in the neuropil peripheral to a medium-sized blood vessel at day 13. (E) Immunopositive endothelial cells (brown) in cerebrum at day 15. (F) Choroid plexus, prominent immunostaining (brown) of the cuboidal epithelial cells lining the choroid at day 15. Original magnifications, ×20 (B-F), ×40 (A)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104370&req=5

Figure 9: Histopathology and immunohistochemistry of nervous tissue of Lassa virus-infected cynomolgus monkeys. (A) Histology of cerebellum showing meningitis at day 15; H&E stain. (B) Histology of cerebrum showing neuronal necrosis at day 13; H&E stain. (C), Optic neuritis; note immunopositive inflammatory foci (brown) at day 15. (D), Brain stem, immunopositive endothelium (arrow) and immunopositive inflammatory foci (brown) in the neuropil peripheral to a medium-sized blood vessel at day 13. (E) Immunopositive endothelial cells (brown) in cerebrum at day 15. (F) Choroid plexus, prominent immunostaining (brown) of the cuboidal epithelial cells lining the choroid at day 15. Original magnifications, ×20 (B-F), ×40 (A)
Mentions: No significant lesions were observed in the nervous system at day 7. However, LASV immunostaining was infrequently detected in circulating histiocytic cells (2/3) and in endothelial cells (2/3) at this timepoint. Substantial changes in lesions and the presence of LASV occurred in the neuropil by terminal time points. Noteworthy findings in terminal animals included: meningoencephalitis in the cerebrum, cerebellum (Figure 9A), and brainstem (3/3); neuronal necrosis and gliosis in cerebrum (Figure 9B) and brainstem (3/3); choroid plexitis (1/3); meningomyelitis (1/3); and neuritis of optic nerve (2/3) (Figure 9C). LASV antigen was detected multifocally in endothelial cells and histiocytic inflammatory cells of cerebrum (Figures 9D,E), cerebellum, brainstem, spinal cord, and optic nerve (Figure 9C) of terminal animals. In addition, LASV antigen was detected in glial cells in cerebrum of 2/3 animals and in choroid plexis epithelial cells in cerebrum of 1/3 animals (Figure 9F).

Bottom Line: Tissues from three animals were examined at an early- to mid-stage of disease and compared with tissues from three animals collected at terminal stages of disease.Evidence of coagulopathy was noted; however, the degree of fibrin deposition in tissues was less prominent than has been reported in other viral hemorrhagic fevers.The sequence of pathogenic events identified in this study begins to shed light on the development of disease processes during Lassa fever and also may provide new targets for rational prophylactic and chemotherapeutic interventions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Virology, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA.

ABSTRACT

Background: Lassa virus (LASV) infection causes an acute and sometimes fatal hemorrhagic disease in humans and nonhuman primates; however, little is known about the development of Lassa fever. Here, we performed a pilot study to begin to understand the progression of LASV infection in nonhuman primates.

Methods: Six cynomolgus monkeys were experimentally infected with LASV. Tissues from three animals were examined at an early- to mid-stage of disease and compared with tissues from three animals collected at terminal stages of disease.

Results: Dendritic cells were identified as a prominent target of LASV infection in a variety of tissues in all animals at day 7 while Kupffer cells, hepatocytes, adrenal cortical cells, and endothelial cells were more frequently infected with LASV in tissues of terminal animals (days 13.5-17). Meningoencephalitis and neuronal necrosis were noteworthy findings in terminal animals. Evidence of coagulopathy was noted; however, the degree of fibrin deposition in tissues was less prominent than has been reported in other viral hemorrhagic fevers.

Conclusion: The sequence of pathogenic events identified in this study begins to shed light on the development of disease processes during Lassa fever and also may provide new targets for rational prophylactic and chemotherapeutic interventions.

Show MeSH
Related in: MedlinePlus