The Use of Large-Particle Aerosol Exposure to Nipah Virus to Mimic Human Neurological Disease Manifestations in the African Green Monkey - PubMed (original) (raw)
. 2020 May 11;221(Suppl 4):S419-S430.
doi: 10.1093/infdis/jiz502.
Dima A Hammoud 2, Yu Cong 1, Louis M Huzella 1, Marcelo A Castro 1, Jeffrey Solomon 3, Joseph Laux 1, Matthew Lackemeyer 1, J Kyle Bohannon 1, Oscar Rojas 1, Russ Byrum 1, Ricky Adams 1, Danny Ragland 1, Marisa St Claire 1, Vincent Munster 4, Michael R Holbrook 1
Affiliations
- PMID: 31687756
- PMCID: PMC7368178
- DOI: 10.1093/infdis/jiz502
The Use of Large-Particle Aerosol Exposure to Nipah Virus to Mimic Human Neurological Disease Manifestations in the African Green Monkey
Ji Hyun Lee et al. J Infect Dis. 2020.
Abstract
Nipah virus (NiV) is an emerging virus associated with outbreaks of acute respiratory disease and encephalitis. To develop a neurological model for NiV infection, we exposed 6 adult African green monkeys to a large-particle (approximately 12 μm) aerosol containing NiV (Malaysian isolate). Brain magnetic resonance images were obtained at baseline, every 3 days after exposure for 2 weeks, and then weekly until week 8 after exposure. Four of six animals showed abnormalities reminiscent of human disease in brain magnetic resonance images. Abnormalities ranged from cytotoxic edema to vasogenic edema. The majority of lesions were small infarcts, and a few showed inflammatory or encephalitic changes. Resolution or decreased size in some lesions resembled findings reported in patients with NiV infection. Histological lesions in the brain included multifocal areas of encephalomalacia, corresponding to known ischemic foci. In other regions of the brain there was evidence of vasculitis, with perivascular infiltrates of inflammatory cells and rare intravascular fibrin thrombi. This animal model will help us better understand the acute neurological features of NiV infection and develop therapeutic approaches for managing disease caused by NiV infection.
Keywords: Computed tomography; Magnetic resonance imaging; Nipah virus; Paramyxovirus; pathology.
Published by Oxford University Press for the Infectious Diseases Society of America 2019.
Figures
Figure 1.
Incidence of survival in African green monkeys after Nipah virus (NiV) challenge and resulting viremia and cerebrospinal fluid (CSF) concentrations. (A), Kaplan-Meier survival curve. B–F, Viral RNA copy concentrations in whole blood (B), serum (C), CSF (D), oral swab (E), and nasal swab (F) samples. Viral RNA was detected in 4 of 6 animals, with no detectable viral RNA in oral (E) and nasal (F) mucosa in animal 8168, which succumbed on day 5 after exposure, or in 1 survivor (8212). The other survivor (8671) had peak viral replication in mucosa on day 9 after exposure, which then dropped to normal on day 12 after exposure.
Figure 2.
(A), A small focal lesion (arrows) appeared on day 15 after exposure in the left frontal subcortical white matter in 1 animal (8078). (B), Progression of disease is noted on day 17 (terminal day), with a total of 7 abnormal signal intensities now seen bilaterally. Incidental note is made of a preexisting congenital abnormality in this animal (colpocephaly, dilatation of the left posterior occipital horn). Abbreviations: DW, diffusion weighted; FLAIR, fluid-attenuated inversion-recovery; trace (DT), trace of diffusion tensor.
Figure 3.
Magnetic resonance imaging of animal 8233 shows a focal lesion with increased T2-weighted and fluid-attenuated inversion-recovery (FLAIR) signal intensity on the right side of the midbrain on day 20 after exposure. This lesion demonstrated facilitated (non-restricted) diffusion (white arrows). Four other smaller lesions with similar characteristics were seen in this animal (not shown). Abbreviations: DW, diffusion weighted; trace (DT), trace of diffusion tensor.
Figure 4.
Longitudinal changes on fluid-attenuated inversion-recovery images in a survivor (8671). Focal area of increased signal in the left cerebellar hemisphere (arrows) appeared on day 15 after exposure and decreased in size over time. The lesion was still noted, but to a lesser extent, on day 56 after exposure, the study end point.
Figure 5.
Histopathological findings showing encephalitis (8233). (A), Hematoxylin-eosin (HE) staining of brain with perivascular infiltrates of inflammatory cells extending into surrounding parenchyma. (B–F), Immunohistochemistry (IHC) signal changes_, (B),_ Focal ionized calcium-binding adaptor molecule 1 (Iba1) IHC signal indicating microglial response (inset; original magnification ×200). (C), Perivascular CD3-positive T-cell infiltrates, extending into surrounding parenchyma (inset; original magnification ×200). (D), CD68 positive monocyte/macrophage infiltrates penetrating the surrounding parenchyma in conjunction with T-cell infiltrates (inset; original magnification ×200). (E), Locally absent neuronal nuclei (NeuN) IHC signal. (F), Focal extensive areas of positivity for cleaved caspase 3 (CC3) (inset; original magnification ×200) indicate areas with cellular apoptosis.
Figure 6.
Ischemia-related encephalomalacia within the frontal lobe of animal 8078. (A), Large area of encephalomalacia with parenchymal loss with adjacent, nonsuppurative encephalitis (inset; original magnification ×200). Left inset shows specific NiV antigen staining of neurons; right inset, perivascular inflammatory infiltrates and vasculitis. (B–F), Immunohistochemistry (IHC) signal changes. (B), No significant ionized calcium-binding adaptor molecule 1 (Iba1) IHC signal. (C), Perivascular CD3 positive T-cell infiltrates, extending into surrounding parenchyma (inset; original magnification ×200). (D), Minimal CD68 positive monocyte/macrophage infiltrates (inset; original magnification ×200). (E), locally absent neuronal nuclei (NeuN) IHC signal in the area of the lesion, strongly present in areas not affected. (F), focal extensive areas of positivity for cleaved caspase (CC3) (inset; original magnification ×200) indicate areas with cellular apoptosis. Abbreviation: HE, hematoxylin-eosin.
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