Studies on the pathogenesis of influenza virus pneumonia in mice

Hers, J.; Mulder, J.; Masurel, N.; Kuip, L.Van Der; Tyrrell, D. A. J.

doi:10.1002/path.1700830123

Cited by 65 publications

(24 citation statements)

References 23 publications

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“…Thus, ribavirin may have inhibited this lung damage via antiviral mech anisms sufficiently to prevent the usual SaCL decline but not enough to prevent visible con solidation from occurring. Lung consolida tion in animals generally infected with in fluenza virus has been attributed to a combi nation of viral damage to alveolar cells which causes necrosis of the capillary walls leading to lung hemorrhage as well as to later occur ring vascular phenomena resulting from im mune response to the infection [21][22][23][24]. As indicated earlier, however, the lung lesions seen in the present study were more likely due to viral toxic effects than to the normally seen influenza infection factors.…”

Section: Discussioncontrasting

confidence: 51%

In vitro and in vivo Sensitivity of a Non-Mouse-Adapted Influenza A (Beijing) Virus Infection to Amantadine and Ribavirin

Sidwell¹,

Bailey²,

Wong³

et al. 1995

Chemotherapy

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A clinically isolated non-mouse-adapted influenza A/Beijing/32/92 virus was assayed for sensitivity to amantadine and ribavirin in vitro and in mice. When multiple concentrations of each drug were assayed for ability to inhibit the virus-induced cytopathic effect in MDCK cells, the 50% effective (virus-inhibitory) concentration was 0.12 μg/ml for amantadine and 1.9 μg/ml for ribavirin. The 50% cytotoxic concentrations were 25 and 100 μg/ml, respectively. It is known that intranasal challenge of mice with high concentrations of non-mouse-adapted influenza virus will induce a toxic pneumonitis in the absence of significant viral replication in the lung. Treatment of such virus-infected mice with ∼1,250, ∼625 and ∼313 mg/kg/day of amantadine in the drinking water resulted in significant inhibition of lung scores and weights and a lessened decline in arterial oxygen saturation (SaO₂) in the mice, but virus was in low titer or not recoverable from drug- or placebo-treated animals. Intraperitoneal treatment with 75, 37.5 and 18.8 mg/kg/day of ribavirin given twice daily for 5 days was effective only in preventing SaO₂ decline, which contrasts with strong inhibition of infections induced by mouse-adapted viruses seen in other studies. These in vivo data indicate that when non-mouse-adapted influenza virus infections are used to evaluate potential antiviral drugs, false-negative results may be obtained.

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Section: Discussioncontrasting

confidence: 51%

In vitro and in vivo Sensitivity of a Non-Mouse-Adapted Influenza A (Beijing) Virus Infection to Amantadine and Ribavirin

Sidwell¹,

Bailey²,

Wong³

et al. 1995

Chemotherapy

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“…Mice infected with Sendai virus develop desquamative lesions of the bronchial epithelium and consolidation in the lung parenchyma (3)(4)(5). This Received for publication 2 October 1975 and in revised form 9 February 1976. pathology resembles closely that induced by influenza virus infection in man (6).…”

Section: Introductionmentioning

confidence: 55%

Defect in intracellular killing of Staphylococcus aureus within alveolar macrophages in Sendai virus-infected murine lungs.

Jakab¹,

Green²

1976

J. Clin. Invest.

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A B S T R A C T Bacterial multiplication associated with virus infections is related to defects in in situ bactericidal (phagocytic) mechanisms of the lung. To determine whether the phagocytic defect was in bacterial ingestion and/or intracellular digestion, mice were infected with a sublethal dose of aerosolized Sendai virus and challenged 7 days later with a finely dispersed aerosol of Staphylococcuts aureus. Groups of uninfected and virus-infected mice were sacrificed at 0, 6, 12, and 24 h after challenge, the lungs were perfused with formalin in situ, and the intra-or extracellular location of the bacteria was determined histologically. At 0 h, 49% and 51% of the staphylococci had an intracellular location in virus and nonvirus-infected lungs, respectively. With time, decreasing numbers of staphylococci were observed within the phagocytic cells of nonvirus-infected lungs, mostly as single organisms or in small clusters of less than four. Ill contrast, in focal area of virus-infected lungs, increasing numbers of phagocytic cells showed clumps of more than 25 bacteria/cell. These data demonstrate that virus-infected suppression of pulmonary antibacterial activity against S. aureus is related primarily to defects in intracellular processing mechanisms.

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“…Such mutants possess an increased ability to infect alveolar cells, thereby initiating alveolitis, and can cause lethal pneumonitis (34,54). In addition, all epithelial cells of the bronchi and alveoli are susceptible to infection with fully adapted strains (14,26). The lung pathology induced by the mouse-adapted viruses shows considerable similarities to that of human influenzal pneumonia (45); thus, the changes that occur in the virus during mouse adaptation may provide insight into factors that affect the development of lung infection in humans.…”

mentioning

confidence: 99%

Adaptation of Pandemic H1N1 Influenza Viruses in Mice

Ilyushina

Khalenkov

Seiler

et al. 2010

J Virol

195

204

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The molecular mechanism by which pandemic 2009 influenza A viruses were able to sufficiently adapt to humans is largely unknown. Subsequent human infections with novel H1N1 influenza viruses prompted an investigation of the molecular determinants of the host range and pathogenicity of pandemic influenza viruses in mammals. To address this problem, we assessed the genetic basis for increased virulence of A/CA/04/09 (H1N1) and A/TN/1-560/09 (H1N1) isolates, which are not lethal for mice, in a new mammalian host by promoting their mouse adaptation. The resulting mouse lung-adapted variants showed significantly enhanced growth characteristics in eggs, extended extrapulmonary tissue tropism, and pathogenicity in mice. All mouseadapted viruses except A/TN/1-560/09-MA2 grew faster and to higher titers in cells than the original strains. We found that 10 amino acid changes in the ribonucleoprotein (RNP) complex (PB2 E158G/A, PA L295P, NP D101G, and NP H289Y) and hemagglutinin (HA) glycoprotein (K119N, G155E, S183P, R221K, and D222G) controlled enhanced mouse virulence of pandemic isolates. HA mutations acquired during adaptation affected viral receptor specificity by enhancing binding to ␣2,3 together with decreasing binding to ␣2,6 sialyl receptors. PB2 E158G/A and PA L295P amino acid substitutions were responsible for the significant enhancement of transcription and replication activity of the mouse-adapted H1N1 variants. Taken together, our findings suggest that changes optimizing receptor specificity and interaction of viral polymerase components with host cellular factors are the major mechanisms that contribute to the optimal competitive advantage of pandemic influenza viruses in mice. These modulators of virulence, therefore, may have been the driving components of early evolution, which paved the way for novel 2009 viruses in mammals.

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Studies on the pathogenesis of influenza virus pneumonia in mice

Cited by 65 publications

References 23 publications

In vitro and in vivo Sensitivity of a Non-Mouse-Adapted Influenza A (Beijing) Virus Infection to Amantadine and Ribavirin

In vitro and in vivo Sensitivity of a Non-Mouse-Adapted Influenza A (Beijing) Virus Infection to Amantadine and Ribavirin

Defect in intracellular killing of Staphylococcus aureus within alveolar macrophages in Sendai virus-infected murine lungs.

Adaptation of Pandemic H1N1 Influenza Viruses in Mice

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