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Infection of type I interferon receptor-deficient mice with various old world arenaviruses: a model for studying virulence and host species barriers.

Rieger T, Merkler D, Günther S - PLoS ONE (2013)

Bottom Line: Lassa fever-like pathology included acute hepatitis, interstitial pneumonia, and pronounced disturbance of splenic cytoarchitecture.Infiltrations of activated monocytes/macrophages expressing inducible nitric oxide synthase and T cells were found in liver and lung.In addition to the type I interferon system, T cells seem to regulate whether or not an arenavirus can productively infect non-host rodent species.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.

ABSTRACT
Lassa virus causes hemorrhagic Lassa fever in humans, while the related Old World arenaviruses Mopeia, Morogoro, and Mobala are supposedly apathogenic to humans and cause only inapparent infection in non-human primates. Here, we studied whether the virulence of Old World arenaviruses in humans and non-human primates is reflected in type I interferon receptor deficient (IFNAR(-/-)) mice by testing several strains of Lassa virus vs. the apathogenic viruses Mopeia, Morogoro, and Mobala. All Lassa virus strains tested-Josiah, AV, BA366, and Nig04-10-replicated to high titers in blood, lung, kidney, heart, spleen, brain, and liver and caused disease as evidenced by weight loss and elevation of aspartate and alanine aminotransferase (AST and ALT) levels with a high AST/ALT ratio. Lassa fever-like pathology included acute hepatitis, interstitial pneumonia, and pronounced disturbance of splenic cytoarchitecture. Infiltrations of activated monocytes/macrophages expressing inducible nitric oxide synthase and T cells were found in liver and lung. In contrast, Mopeia, Morogoro, and Mobala virus replicated poorly in the animals and acute inflammatory alterations were not noted. Depletion of CD4(+) and CD8(+) T cells strongly enhanced susceptibility of IFNAR(-/-) mice to the apathogenic viruses. In conclusion, the virulence of Old World arenaviruses in IFNAR(-/-) mice correlates with their virulence in humans and non-human primates. In addition to the type I interferon system, T cells seem to regulate whether or not an arenavirus can productively infect non-host rodent species. The observation that Lassa virus overcomes the species barrier without artificial depletion of T cells suggests it is able to impair T cell functionality in a way that corresponds to depletion.

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H/E-stained sections of liver and lung of infected IFNAR-/- mice.Animals were inoculated i.v. with 103 FFU of the indicated viruses and euthanized at day 9–10 p.i. to collect the organs.
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pone-0072290-g003: H/E-stained sections of liver and lung of infected IFNAR-/- mice.Animals were inoculated i.v. with 103 FFU of the indicated viruses and euthanized at day 9–10 p.i. to collect the organs.

Mentions: Collected organs (lung, kidney, heart, spleen, brain, and liver) of infected mice were assessed on H/E-stained sections and viral distribution in situ was assessed by immunostaining for NP at days 9–10 p.i. Pathological findings were largely identical for the Lassa virus strains and the apathogenic viruses, respectively. Therefore, they are described collectively for each group. Liver: Infection with Lassa virus was associated with acute hepatitis, as evidenced by periportal mononuclear inflammatory cell infiltrate disrupting the limiting plate of hepatocytes, and focal necrosis (Figure 3). The architecture of Iba-1-positive hepatic monocytes/macrophages (Kupffer cells) was disturbed (Figure 4). The cells were enlarged, rounded up, disorganized, and often accumulated in clusters (under physiological conditions, these cells form a flat layer along liver sinusoids). In addition, iNOS-expressing monocytes/macrophages, which are not present in normal liver, were detectable (Figure 4). These alterations are suggestive for monocyte/macrophage activation. T cells were scattered at moderate density throughout the liver parenchyma and in periportal inflammatory nodules. Lassa virus antigen was readily detected in a large fraction of hepatocytes and Kupffer cells (Figure 4). In contrast, Mobala, Mopeia, and Morogoro virus-infected animals were largely devoid of inflammatory infiltrates nor was viral antigen detectable (Figure 3). Lung: Lung tissue showed variable degree of interstitial pneumonia in Lassa virus-infected mice, but not in Mopeia, Morogoro, and Mobala virus-infected animals (Figure 3). Similar to the liver, the lung of Lassa virus-infected animals contained dense infiltrations of Iba-1-positive monocyte/macrophage lineage cells, iNOS-expressing monocytes/macrophages and accumulations of T cells (Figure 4). A large fraction of cells expressed Lassa virus antigen, consistent with the high virus titer in lung tissue. Spleen: Mice infected with Lassa virus showed pronounced alterations of follicular cytoarchitecture as evidenced by disturbed segregation of white and red pulpa. Immunostaining revealed widespread and numerous NP-positive cells in the parenchyma. In contrast, mice infected with Mobala, Mopeia, or Morogoro virus had a largely preserved follicular cytoarchitecture and infected cells were sparse or absent. Kidney, heart, and brain: In Lassa virus-infected mice, viral antigen could be detected in the endothelial cells of vasa recta (straight arterioles), in some glomeruli, and some interstitial cells of the kidney. Lassa virus antigen was sparsely present in the heart tissue with only few and focal spots of NP-positive endothelial cells, few macrophages, and isolated myocardiocytes. There were no signs of endo- or myocarditis. Brain samples showed focal Lassa virus NP-positive cells restricted to the brain coverings (ependymal cells and meninges) and some perivascular spots (most likely within astrocytes). In these perivascular areas, some activated microglial cells and isolated microglial nodules were noted that were associated with sparse lymphocytic infiltrates. Kidney, heart, and brain of Mobala, Mopeia, and Morogoro-virus infected mice showed no pathology and viral antigen was absent.


Infection of type I interferon receptor-deficient mice with various old world arenaviruses: a model for studying virulence and host species barriers.

Rieger T, Merkler D, Günther S - PLoS ONE (2013)

H/E-stained sections of liver and lung of infected IFNAR-/- mice.Animals were inoculated i.v. with 103 FFU of the indicated viruses and euthanized at day 9–10 p.i. to collect the organs.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3750052&req=5

pone-0072290-g003: H/E-stained sections of liver and lung of infected IFNAR-/- mice.Animals were inoculated i.v. with 103 FFU of the indicated viruses and euthanized at day 9–10 p.i. to collect the organs.
Mentions: Collected organs (lung, kidney, heart, spleen, brain, and liver) of infected mice were assessed on H/E-stained sections and viral distribution in situ was assessed by immunostaining for NP at days 9–10 p.i. Pathological findings were largely identical for the Lassa virus strains and the apathogenic viruses, respectively. Therefore, they are described collectively for each group. Liver: Infection with Lassa virus was associated with acute hepatitis, as evidenced by periportal mononuclear inflammatory cell infiltrate disrupting the limiting plate of hepatocytes, and focal necrosis (Figure 3). The architecture of Iba-1-positive hepatic monocytes/macrophages (Kupffer cells) was disturbed (Figure 4). The cells were enlarged, rounded up, disorganized, and often accumulated in clusters (under physiological conditions, these cells form a flat layer along liver sinusoids). In addition, iNOS-expressing monocytes/macrophages, which are not present in normal liver, were detectable (Figure 4). These alterations are suggestive for monocyte/macrophage activation. T cells were scattered at moderate density throughout the liver parenchyma and in periportal inflammatory nodules. Lassa virus antigen was readily detected in a large fraction of hepatocytes and Kupffer cells (Figure 4). In contrast, Mobala, Mopeia, and Morogoro virus-infected animals were largely devoid of inflammatory infiltrates nor was viral antigen detectable (Figure 3). Lung: Lung tissue showed variable degree of interstitial pneumonia in Lassa virus-infected mice, but not in Mopeia, Morogoro, and Mobala virus-infected animals (Figure 3). Similar to the liver, the lung of Lassa virus-infected animals contained dense infiltrations of Iba-1-positive monocyte/macrophage lineage cells, iNOS-expressing monocytes/macrophages and accumulations of T cells (Figure 4). A large fraction of cells expressed Lassa virus antigen, consistent with the high virus titer in lung tissue. Spleen: Mice infected with Lassa virus showed pronounced alterations of follicular cytoarchitecture as evidenced by disturbed segregation of white and red pulpa. Immunostaining revealed widespread and numerous NP-positive cells in the parenchyma. In contrast, mice infected with Mobala, Mopeia, or Morogoro virus had a largely preserved follicular cytoarchitecture and infected cells were sparse or absent. Kidney, heart, and brain: In Lassa virus-infected mice, viral antigen could be detected in the endothelial cells of vasa recta (straight arterioles), in some glomeruli, and some interstitial cells of the kidney. Lassa virus antigen was sparsely present in the heart tissue with only few and focal spots of NP-positive endothelial cells, few macrophages, and isolated myocardiocytes. There were no signs of endo- or myocarditis. Brain samples showed focal Lassa virus NP-positive cells restricted to the brain coverings (ependymal cells and meninges) and some perivascular spots (most likely within astrocytes). In these perivascular areas, some activated microglial cells and isolated microglial nodules were noted that were associated with sparse lymphocytic infiltrates. Kidney, heart, and brain of Mobala, Mopeia, and Morogoro-virus infected mice showed no pathology and viral antigen was absent.

Bottom Line: Lassa fever-like pathology included acute hepatitis, interstitial pneumonia, and pronounced disturbance of splenic cytoarchitecture.Infiltrations of activated monocytes/macrophages expressing inducible nitric oxide synthase and T cells were found in liver and lung.In addition to the type I interferon system, T cells seem to regulate whether or not an arenavirus can productively infect non-host rodent species.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.

ABSTRACT
Lassa virus causes hemorrhagic Lassa fever in humans, while the related Old World arenaviruses Mopeia, Morogoro, and Mobala are supposedly apathogenic to humans and cause only inapparent infection in non-human primates. Here, we studied whether the virulence of Old World arenaviruses in humans and non-human primates is reflected in type I interferon receptor deficient (IFNAR(-/-)) mice by testing several strains of Lassa virus vs. the apathogenic viruses Mopeia, Morogoro, and Mobala. All Lassa virus strains tested-Josiah, AV, BA366, and Nig04-10-replicated to high titers in blood, lung, kidney, heart, spleen, brain, and liver and caused disease as evidenced by weight loss and elevation of aspartate and alanine aminotransferase (AST and ALT) levels with a high AST/ALT ratio. Lassa fever-like pathology included acute hepatitis, interstitial pneumonia, and pronounced disturbance of splenic cytoarchitecture. Infiltrations of activated monocytes/macrophages expressing inducible nitric oxide synthase and T cells were found in liver and lung. In contrast, Mopeia, Morogoro, and Mobala virus replicated poorly in the animals and acute inflammatory alterations were not noted. Depletion of CD4(+) and CD8(+) T cells strongly enhanced susceptibility of IFNAR(-/-) mice to the apathogenic viruses. In conclusion, the virulence of Old World arenaviruses in IFNAR(-/-) mice correlates with their virulence in humans and non-human primates. In addition to the type I interferon system, T cells seem to regulate whether or not an arenavirus can productively infect non-host rodent species. The observation that Lassa virus overcomes the species barrier without artificial depletion of T cells suggests it is able to impair T cell functionality in a way that corresponds to depletion.

Show MeSH
Related in: MedlinePlus