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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

PTAH staining of Lassa virus-infected cynomolgus monkey tissues. Polymerized fibrin (arrows) in the marginal zone of spleen (A), sinusoids (B) and vessels (C) in liver, and medullary vessels of the kidney (D) at day 15. Original magnifications, ×10 (D), ×20 (B), ×40 (A), ×60 (C).
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Figure 7: PTAH staining of Lassa virus-infected cynomolgus monkey tissues. Polymerized fibrin (arrows) in the marginal zone of spleen (A), sinusoids (B) and vessels (C) in liver, and medullary vessels of the kidney (D) at day 15. Original magnifications, ×10 (D), ×20 (B), ×40 (A), ×60 (C).

Mentions: At day 7, LASV immunostaining was noted in cells morphologically consistent with dendritic cells primarily in the marginal zone (Figure 6B) and to a lesser extent in monocytes and tissue macrophages in the marginal zones and red pulp. Mild lymphocytolysis was noted in 2/3 animals. PTAH staining demonstrated infrequent deposition of polymerized fibrin in the red pulp and marginal zone of 1/3 animals at this time point. By terminal time points (days 13.5-17) LASV immunopositive dendritic cells were detected in spleen of all animals (3/3) (Figure 6E) but were less frequently observed than in day 7 animals. Increased numbers of immunopositive endothelial cells were detected in spleen of all terminal animals (3/3). Splenic lymphocytes were consistently LASV immunonegative in all animals at all time points (6/6). There appeared to be a slight increase in TUNEL-positive lymphocytes and scattered tingible body macrophages with cytoplasmic TUNEL-positive debris in the terminal animals (3/3). Detection of polymerized fibrin by PTAH staining was occasionally present in the red pulp and marginal zones of terminal animals (3/3) (Figure 7A) with deposits being most prominent in the animal that succumbed on day 15.


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)

PTAH staining of Lassa virus-infected cynomolgus monkey tissues. Polymerized fibrin (arrows) in the marginal zone of spleen (A), sinusoids (B) and vessels (C) in liver, and medullary vessels of the kidney (D) at day 15. Original magnifications, ×10 (D), ×20 (B), ×40 (A), ×60 (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: PTAH staining of Lassa virus-infected cynomolgus monkey tissues. Polymerized fibrin (arrows) in the marginal zone of spleen (A), sinusoids (B) and vessels (C) in liver, and medullary vessels of the kidney (D) at day 15. Original magnifications, ×10 (D), ×20 (B), ×40 (A), ×60 (C).
Mentions: At day 7, LASV immunostaining was noted in cells morphologically consistent with dendritic cells primarily in the marginal zone (Figure 6B) and to a lesser extent in monocytes and tissue macrophages in the marginal zones and red pulp. Mild lymphocytolysis was noted in 2/3 animals. PTAH staining demonstrated infrequent deposition of polymerized fibrin in the red pulp and marginal zone of 1/3 animals at this time point. By terminal time points (days 13.5-17) LASV immunopositive dendritic cells were detected in spleen of all animals (3/3) (Figure 6E) but were less frequently observed than in day 7 animals. Increased numbers of immunopositive endothelial cells were detected in spleen of all terminal animals (3/3). Splenic lymphocytes were consistently LASV immunonegative in all animals at all time points (6/6). There appeared to be a slight increase in TUNEL-positive lymphocytes and scattered tingible body macrophages with cytoplasmic TUNEL-positive debris in the terminal animals (3/3). Detection of polymerized fibrin by PTAH staining was occasionally present in the red pulp and marginal zones of terminal animals (3/3) (Figure 7A) with deposits being most prominent in the animal that succumbed on day 15.

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