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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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Influence of CD4+ and CD8+ T cells on susceptibility of IFNAR-/- mice to apathogenic arenaviruses.CD8+ and/or CD4+ T cell populations were depleted by intraperitoneal administration of anti-CD8 and/or anti-CD4 on day -3 and day -1 of infection. Groups of three animals were inoculated i.v. with 103 FFU of the indicated viruses. Mean and standard deviation are shown (n = 3). For AST measurement, blood of the three animals was pooled. 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.
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pone-0072290-g005: Influence of CD4+ and CD8+ T cells on susceptibility of IFNAR-/- mice to apathogenic arenaviruses.CD8+ and/or CD4+ T cell populations were depleted by intraperitoneal administration of anti-CD8 and/or anti-CD4 on day -3 and day -1 of infection. Groups of three animals were inoculated i.v. with 103 FFU of the indicated viruses. Mean and standard deviation are shown (n = 3). For AST measurement, blood of the three animals was pooled. 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.

Mentions: The above experiments demonstrated that Mopeia, Morogoro, and Mobala virus hardly replicate in mice despite the absence of a functional type I interferon system, while Lassa virus is able to grow to high titers. Therefore, we wondered whether T cells might play a role in restricting the growth of the apathogenic viruses. To test this, IFNAR-/- mice were depleted of CD8+ T cells or of CD4+ T cells or were depleted of both cell populations using anti-CD4 and anti-CD8 antibodies. Subsequently, the animals were inoculated with 103 FFU Mopeia, Morogoro, or Mobala virus and observed for 30 days. Depletion of CD8+ T cells led to higher viremia of Mopeia and Morogoro virus, while no major change was seen for Mobala virus (Figure 5, top left). Virus was cleared during the observation period, though with slightly delayed kinetics compared to non-depleted mice. Depletion of CD4+ T cells led to enhanced replication of all three viruses (Figure 5, top right). However, the growth kinetics for Mopeia and Morogoro virus was slower than in non-depleted mice and both viruses were not cleared; the titer at the end of the 30-days observation period was still around 4 log10 FFU/ml. Similarly, one of three mice infected with Mobala virus did not clear the virus. Combined depletion of CD4+ and CD8+ T cells clearly enhanced growth of all three viruses with peak viremia of 4–5 log10 FFU/ml around day 20 (Figure 5, bottom). Virus was not cleared and still ranged between 3 and 4 log10 FFU/ml at the end of the experiment. While some biochemical evidence of disease was observed after single depletion, the level of AST was not elevated after double depletion. Taken together, depletion of CD4+ and CD8+ T cells enhanced susceptibility of IFNAR-/- mice to Mopeia, Morogoro, and Mobala virus infection.


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)

Influence of CD4+ and CD8+ T cells on susceptibility of IFNAR-/- mice to apathogenic arenaviruses.CD8+ and/or CD4+ T cell populations were depleted by intraperitoneal administration of anti-CD8 and/or anti-CD4 on day -3 and day -1 of infection. Groups of three animals were inoculated i.v. with 103 FFU of the indicated viruses. Mean and standard deviation are shown (n = 3). For AST measurement, blood of the three animals was pooled. 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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750052&req=5

pone-0072290-g005: Influence of CD4+ and CD8+ T cells on susceptibility of IFNAR-/- mice to apathogenic arenaviruses.CD8+ and/or CD4+ T cell populations were depleted by intraperitoneal administration of anti-CD8 and/or anti-CD4 on day -3 and day -1 of infection. Groups of three animals were inoculated i.v. with 103 FFU of the indicated viruses. Mean and standard deviation are shown (n = 3). For AST measurement, blood of the three animals was pooled. 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.
Mentions: The above experiments demonstrated that Mopeia, Morogoro, and Mobala virus hardly replicate in mice despite the absence of a functional type I interferon system, while Lassa virus is able to grow to high titers. Therefore, we wondered whether T cells might play a role in restricting the growth of the apathogenic viruses. To test this, IFNAR-/- mice were depleted of CD8+ T cells or of CD4+ T cells or were depleted of both cell populations using anti-CD4 and anti-CD8 antibodies. Subsequently, the animals were inoculated with 103 FFU Mopeia, Morogoro, or Mobala virus and observed for 30 days. Depletion of CD8+ T cells led to higher viremia of Mopeia and Morogoro virus, while no major change was seen for Mobala virus (Figure 5, top left). Virus was cleared during the observation period, though with slightly delayed kinetics compared to non-depleted mice. Depletion of CD4+ T cells led to enhanced replication of all three viruses (Figure 5, top right). However, the growth kinetics for Mopeia and Morogoro virus was slower than in non-depleted mice and both viruses were not cleared; the titer at the end of the 30-days observation period was still around 4 log10 FFU/ml. Similarly, one of three mice infected with Mobala virus did not clear the virus. Combined depletion of CD4+ and CD8+ T cells clearly enhanced growth of all three viruses with peak viremia of 4–5 log10 FFU/ml around day 20 (Figure 5, bottom). Virus was not cleared and still ranged between 3 and 4 log10 FFU/ml at the end of the experiment. While some biochemical evidence of disease was observed after single depletion, the level of AST was not elevated after double depletion. Taken together, depletion of CD4+ and CD8+ T cells enhanced susceptibility of IFNAR-/- mice to Mopeia, Morogoro, and Mobala virus infection.

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