Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques

Evidence that Dendritic Cells are Early and Sustained Targets of Infection

Thomas Geisbert, Lisa E. Hensley, Tom Larsen, Howard A. Young, Douglas S. Reed, Joan B. Geisbert, Dana P. Scott, Elliott Kagan, Peter B. Jahrling, Kelly J. Davis

Research output: Contribution to journalArticle

392 Citations (Scopus)

Abstract

Ebola virus (EBOV) infection causes a severe and fatal hemorrhagic disease that in many ways appears to be similar in humans and nonhuman primates; however, little is known about the development of EBOV hemorrhagic fever. In the present study, 21 cynomolgus monkeys were experimentally infected with EBOV and examined sequentially over a 6-day period to investigate the pathological events of EBOV infection that lead to death. Importantly, dendritic cells in lymphoid tissues were identified as early and sustained targets of EBOV, implicating their important role in the immunosuppression characteristic of EBOV infections. Bystander lymphocyte apoptosis, previously described in end-stage tissues, occurred early in the disease-course in intravascular and extravascular locations. Of note, apoptosis and loss of NK cells was a prominent finding, suggesting the importance of innate immunity in determining the fate of the host. Analysis of peripheral blood mononuclear cell gene expression showed temporal increases in tumor necrosis factor-related apoptosis-inducing ligand and Fas transcripts, revealing a possible mechanism for the observed bystander apoptosis, while up-regulation of NAIP and cIAP2 mRNA suggest that EBOV has evolved additional mechanisms to resist host defenses by inducing protective transcripts in cells that it infects. The sequence of pathogenetic events identified in this study should provide new targets for rational prophylactic and chemotherapeutic interventions.

Original languageEnglish (US)
Pages (from-to)2347-2370
Number of pages24
JournalAmerican Journal of Pathology
Volume163
Issue number6
StatePublished - Dec 2003
Externally publishedYes

Fingerprint

Ebola Hemorrhagic Fever
Ebolavirus
Macaca
Dendritic Cells
Apoptosis
Infection
Fas Ligand Protein
Macaca fascicularis
Lymphoid Tissue
Innate Immunity
Natural Killer Cells
Immunosuppression
Primates
Blood Cells
Up-Regulation
Tumor Necrosis Factor-alpha
Lymphocytes
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Geisbert, T., Hensley, L. E., Larsen, T., Young, H. A., Reed, D. S., Geisbert, J. B., ... Davis, K. J. (2003). Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques: Evidence that Dendritic Cells are Early and Sustained Targets of Infection. American Journal of Pathology, 163(6), 2347-2370.

Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques : Evidence that Dendritic Cells are Early and Sustained Targets of Infection. / Geisbert, Thomas; Hensley, Lisa E.; Larsen, Tom; Young, Howard A.; Reed, Douglas S.; Geisbert, Joan B.; Scott, Dana P.; Kagan, Elliott; Jahrling, Peter B.; Davis, Kelly J.

In: American Journal of Pathology, Vol. 163, No. 6, 12.2003, p. 2347-2370.

Research output: Contribution to journalArticle

Geisbert, T, Hensley, LE, Larsen, T, Young, HA, Reed, DS, Geisbert, JB, Scott, DP, Kagan, E, Jahrling, PB & Davis, KJ 2003, 'Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques: Evidence that Dendritic Cells are Early and Sustained Targets of Infection', American Journal of Pathology, vol. 163, no. 6, pp. 2347-2370.
Geisbert, Thomas ; Hensley, Lisa E. ; Larsen, Tom ; Young, Howard A. ; Reed, Douglas S. ; Geisbert, Joan B. ; Scott, Dana P. ; Kagan, Elliott ; Jahrling, Peter B. ; Davis, Kelly J. / Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques : Evidence that Dendritic Cells are Early and Sustained Targets of Infection. In: American Journal of Pathology. 2003 ; Vol. 163, No. 6. pp. 2347-2370.
@article{c0975583a30d45b38b99439d99c9bf44,
title = "Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques: Evidence that Dendritic Cells are Early and Sustained Targets of Infection",
abstract = "Ebola virus (EBOV) infection causes a severe and fatal hemorrhagic disease that in many ways appears to be similar in humans and nonhuman primates; however, little is known about the development of EBOV hemorrhagic fever. In the present study, 21 cynomolgus monkeys were experimentally infected with EBOV and examined sequentially over a 6-day period to investigate the pathological events of EBOV infection that lead to death. Importantly, dendritic cells in lymphoid tissues were identified as early and sustained targets of EBOV, implicating their important role in the immunosuppression characteristic of EBOV infections. Bystander lymphocyte apoptosis, previously described in end-stage tissues, occurred early in the disease-course in intravascular and extravascular locations. Of note, apoptosis and loss of NK cells was a prominent finding, suggesting the importance of innate immunity in determining the fate of the host. Analysis of peripheral blood mononuclear cell gene expression showed temporal increases in tumor necrosis factor-related apoptosis-inducing ligand and Fas transcripts, revealing a possible mechanism for the observed bystander apoptosis, while up-regulation of NAIP and cIAP2 mRNA suggest that EBOV has evolved additional mechanisms to resist host defenses by inducing protective transcripts in cells that it infects. The sequence of pathogenetic events identified in this study should provide new targets for rational prophylactic and chemotherapeutic interventions.",
author = "Thomas Geisbert and Hensley, {Lisa E.} and Tom Larsen and Young, {Howard A.} and Reed, {Douglas S.} and Geisbert, {Joan B.} and Scott, {Dana P.} and Elliott Kagan and Jahrling, {Peter B.} and Davis, {Kelly J.}",
year = "2003",
month = "12",
language = "English (US)",
volume = "163",
pages = "2347--2370",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Pathogenesis of Ebola Hemorrhagic Fever in Cynomolgus Macaques

T2 - Evidence that Dendritic Cells are Early and Sustained Targets of Infection

AU - Geisbert, Thomas

AU - Hensley, Lisa E.

AU - Larsen, Tom

AU - Young, Howard A.

AU - Reed, Douglas S.

AU - Geisbert, Joan B.

AU - Scott, Dana P.

AU - Kagan, Elliott

AU - Jahrling, Peter B.

AU - Davis, Kelly J.

PY - 2003/12

Y1 - 2003/12

N2 - Ebola virus (EBOV) infection causes a severe and fatal hemorrhagic disease that in many ways appears to be similar in humans and nonhuman primates; however, little is known about the development of EBOV hemorrhagic fever. In the present study, 21 cynomolgus monkeys were experimentally infected with EBOV and examined sequentially over a 6-day period to investigate the pathological events of EBOV infection that lead to death. Importantly, dendritic cells in lymphoid tissues were identified as early and sustained targets of EBOV, implicating their important role in the immunosuppression characteristic of EBOV infections. Bystander lymphocyte apoptosis, previously described in end-stage tissues, occurred early in the disease-course in intravascular and extravascular locations. Of note, apoptosis and loss of NK cells was a prominent finding, suggesting the importance of innate immunity in determining the fate of the host. Analysis of peripheral blood mononuclear cell gene expression showed temporal increases in tumor necrosis factor-related apoptosis-inducing ligand and Fas transcripts, revealing a possible mechanism for the observed bystander apoptosis, while up-regulation of NAIP and cIAP2 mRNA suggest that EBOV has evolved additional mechanisms to resist host defenses by inducing protective transcripts in cells that it infects. The sequence of pathogenetic events identified in this study should provide new targets for rational prophylactic and chemotherapeutic interventions.

AB - Ebola virus (EBOV) infection causes a severe and fatal hemorrhagic disease that in many ways appears to be similar in humans and nonhuman primates; however, little is known about the development of EBOV hemorrhagic fever. In the present study, 21 cynomolgus monkeys were experimentally infected with EBOV and examined sequentially over a 6-day period to investigate the pathological events of EBOV infection that lead to death. Importantly, dendritic cells in lymphoid tissues were identified as early and sustained targets of EBOV, implicating their important role in the immunosuppression characteristic of EBOV infections. Bystander lymphocyte apoptosis, previously described in end-stage tissues, occurred early in the disease-course in intravascular and extravascular locations. Of note, apoptosis and loss of NK cells was a prominent finding, suggesting the importance of innate immunity in determining the fate of the host. Analysis of peripheral blood mononuclear cell gene expression showed temporal increases in tumor necrosis factor-related apoptosis-inducing ligand and Fas transcripts, revealing a possible mechanism for the observed bystander apoptosis, while up-regulation of NAIP and cIAP2 mRNA suggest that EBOV has evolved additional mechanisms to resist host defenses by inducing protective transcripts in cells that it infects. The sequence of pathogenetic events identified in this study should provide new targets for rational prophylactic and chemotherapeutic interventions.

UR - http://www.scopus.com/inward/record.url?scp=10744224131&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744224131&partnerID=8YFLogxK

M3 - Article

VL - 163

SP - 2347

EP - 2370

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 6

ER -