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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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Viremia, AST, and body weight of IFNAR-/- mice infected with various Old World arenaviruses.Groups of five animals were inoculated i.v. with 103 FFU (filled squares) or 105 FFU (open squares). Two of them were randomly euthanized at days 9–10 to collect organs. Mean and standard deviation are shown (n ≥ 3). The range of viremia below the detection limit of the immunofocusassay as well as the normal reference range of AST in mice [43] are shaded in grey. The weight curve of the uninfected controls is shown without data points.
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pone-0072290-g001: Viremia, AST, and body weight of IFNAR-/- mice infected with various Old World arenaviruses.Groups of five animals were inoculated i.v. with 103 FFU (filled squares) or 105 FFU (open squares). Two of them were randomly euthanized at days 9–10 to collect organs. Mean and standard deviation are shown (n ≥ 3). The range of viremia below the detection limit of the immunofocusassay as well as the normal reference range of AST in mice [43] are shaded in grey. The weight curve of the uninfected controls is shown without data points.

Mentions: In the first set of experiments, IFNAR-/- mice were infected with various Lassa virus strains of different origin. Strains AV, Nig04-10, and Josiah had been isolated from humans with Lassa fever from Côte d’Ivoire, Nigeria, and Sierra Leone, respectively, while strain BA366 had been isolated from M. natalensis from Guinea [12,38–40]. Groups of 3 to 5 mice were inoculated with Lassa virus via the i.v. route and the level of viremia as well as the disease markers AST and body weight were measured at six time points up to day 21 after inoculation. AST is a classical biochemical marker of human Lassa fever [18,19,23]. In a pilot experiment with Lassa virus AV, low and high inoculation doses (103 and 105 FFU) were tested. Both doses resulted in an acute infection with up to 5.5 log10 FFU/ml of blood, although the peak of viremia was reached earlier with the higher inoculation dose (Figure 1). The elevation of AST was higher after inoculation with the lower dose. Therefore, all other experiments were performed with a dose of 103 FFU per animal. IFNAR-/- mice were susceptible to infection with all Lassa virus strains. The peak of viremia was around day 8 p.i. and ranged from 4.5 to 6 log10 FFU/ml blood (Figure 1). At day 21, the virus was not yet fully cleared with levels of viremia ranging from 2 to 3 log10 units FFU/ml blood. AST elevations were observed in all groups. AST peaks were seen at day 8 p.i. with values ranging from 250 to 650 U/l blood (Figure 1). ALT values were measured for BA366, Nig04-10, and Josiah and peaked at day 8 p.i. with 91 U/l (AST 232 U/l), 163 U/l (AST 620 U/l), and 133 U/l (AST 392 U/l), respectively (the normal reference range for 6 to 20-week old mice is 30–80 U/l for AST and 25–60 U/l for ALT [43]). Thus, like in human Lassa fever the values for AST were higher than for ALT [18,19,23]. All Lassa virus-infected animals lost about 15% of body weight by day 8 p.i. compared to non-infected controls (Figure 1). These data demonstrate that IFNAR-/- mice are susceptible to various Lassa virus strains. Lassa virus infection causes non-lethal acute disease with elevation of AST and ALT and loss of weight.


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)

Viremia, AST, and body weight of IFNAR-/- mice infected with various Old World arenaviruses.Groups of five animals were inoculated i.v. with 103 FFU (filled squares) or 105 FFU (open squares). Two of them were randomly euthanized at days 9–10 to collect organs. Mean and standard deviation are shown (n ≥ 3). The range of viremia below the detection limit of the immunofocusassay as well as the normal reference range of AST in mice [43] are shaded in grey. The weight curve of the uninfected controls is shown without data points.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3750052&req=5

pone-0072290-g001: Viremia, AST, and body weight of IFNAR-/- mice infected with various Old World arenaviruses.Groups of five animals were inoculated i.v. with 103 FFU (filled squares) or 105 FFU (open squares). Two of them were randomly euthanized at days 9–10 to collect organs. Mean and standard deviation are shown (n ≥ 3). The range of viremia below the detection limit of the immunofocusassay as well as the normal reference range of AST in mice [43] are shaded in grey. The weight curve of the uninfected controls is shown without data points.
Mentions: In the first set of experiments, IFNAR-/- mice were infected with various Lassa virus strains of different origin. Strains AV, Nig04-10, and Josiah had been isolated from humans with Lassa fever from Côte d’Ivoire, Nigeria, and Sierra Leone, respectively, while strain BA366 had been isolated from M. natalensis from Guinea [12,38–40]. Groups of 3 to 5 mice were inoculated with Lassa virus via the i.v. route and the level of viremia as well as the disease markers AST and body weight were measured at six time points up to day 21 after inoculation. AST is a classical biochemical marker of human Lassa fever [18,19,23]. In a pilot experiment with Lassa virus AV, low and high inoculation doses (103 and 105 FFU) were tested. Both doses resulted in an acute infection with up to 5.5 log10 FFU/ml of blood, although the peak of viremia was reached earlier with the higher inoculation dose (Figure 1). The elevation of AST was higher after inoculation with the lower dose. Therefore, all other experiments were performed with a dose of 103 FFU per animal. IFNAR-/- mice were susceptible to infection with all Lassa virus strains. The peak of viremia was around day 8 p.i. and ranged from 4.5 to 6 log10 FFU/ml blood (Figure 1). At day 21, the virus was not yet fully cleared with levels of viremia ranging from 2 to 3 log10 units FFU/ml blood. AST elevations were observed in all groups. AST peaks were seen at day 8 p.i. with values ranging from 250 to 650 U/l blood (Figure 1). ALT values were measured for BA366, Nig04-10, and Josiah and peaked at day 8 p.i. with 91 U/l (AST 232 U/l), 163 U/l (AST 620 U/l), and 133 U/l (AST 392 U/l), respectively (the normal reference range for 6 to 20-week old mice is 30–80 U/l for AST and 25–60 U/l for ALT [43]). Thus, like in human Lassa fever the values for AST were higher than for ALT [18,19,23]. All Lassa virus-infected animals lost about 15% of body weight by day 8 p.i. compared to non-infected controls (Figure 1). These data demonstrate that IFNAR-/- mice are susceptible to various Lassa virus strains. Lassa virus infection causes non-lethal acute disease with elevation of AST and ALT and loss of weight.

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