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Mouse-passaged severe acute respiratory syndrome-associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in adult but not young mice.

ABSTRACT: Advanced age is a risk factor of severe acute respiratory syndrome (SARS) in humans. To understand its pathogenesis, we developed an animal model using BALB/c mice and the mouse-passaged Frankfurt 1 isolate of SARS coronavirus (SARS-CoV). We examined the immune responses to SARS-CoV in both young and adult mice. SARS-CoV induced severe respiratory illness in all adult, but not young, mice on day 2 after inoculation with a mortality rate of 30 to 50%. Moribund adult mice showed severe pulmonary edema and diffuse alveolar damage accompanied by virus replication. Adult murine lungs, which had significantly higher interleukin (IL)-4 and lower IL-10 and IL-13 levels before infection than young murine lungs, rapidly produced high levels of proinflammatory chemokines and cytokines known to induce macrophage and neutrophil infiltration and activation (eg, tumor necrosis factor-alpha). On day 2 after inoculation, young murine lungs produced not only proinflammatory cytokines but also IL-2, interferon-gamma, IL-10, and IL-13. Adult mice showed early and acute excessive proinflammatory responses (ie, cytokine storm) in the lungs after SARS-CoV infection, which led to severe pulmonary edema and diffuse alveolar damage. Intravenous injection with anti-tumor necrosis factor-alpha antibody 3 hours after infection had no effect on SARS-CoV infection. However, intraperitoneal interferon-gamma injection protected adult mice from the lethal respiratory illness. The experimental model described here may be useful for elucidating the pathophysiology of SARS and for evaluating therapies to treat SARS-CoV infection.

SUBMITTER: Nagata N

PROVIDER: S-EPMC2408422 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Mouse-passaged severe acute respiratory syndrome-associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in adult but not young mice.

Nagata Noriyo N Iwata Naoko N Hasegawa Hideki H Fukushi Shuetsu S Harashima Ayako A Sato Yuko Y Saijo Masayuki M Taguchi Fumihiro F Morikawa Shigeru S Sata Tetsutaro T

The American journal of pathology 20080508 6

Advanced age is a risk factor of severe acute respiratory syndrome (SARS) in humans. To understand its pathogenesis, we developed an animal model using BALB/c mice and the mouse-passaged Frankfurt 1 isolate of SARS coronavirus (SARS-CoV). We examined the immune responses to SARS-CoV in both young and adult mice. SARS-CoV induced severe respiratory illness in all adult, but not young, mice on day 2 after inoculation with a mortality rate of 30 to 50%. Moribund adult mice showed severe pulmonary e ...[more]

PMID: 18467696

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Project description:Background: Two notable findings of clinically healthy feedlot cattle suggest they may have pulmonary hydrostatic edema during the finishing phase of production: increased pulmonary arterial wedge pressures and pulmonary venous hypertrophy. The goal of this study was to determine if increased pulmonary arterial wedge pressure (PAWP) in a Holstein calf could lead to diffuse alveolar damage consistent with the early, exudative phase of acute interstitial pneumonia of feedlot cattle. Methods: Six male Holstein dairy calves were given daily subcutaneous injections of the nonspecific ß-adrenergic agonist isoprenaline (10 mg/kg/d), to induce left ventricular diastolic dysfunction, or sterile water for 14 days. On Day 14, pulmonary arterial pressures and wedge pressures were measured, echocardiography performed, and the ratio of mitral valve flow velocity (E) to septal lengthening velocity (e') calculated. Calves were euthanized on Day 15 and lung lesions semi-quantitatively scored. Results: Mean PAWP was 12 ± 1 mm Hg in calves that received isoprenaline and 7 ± 1 mm Hg in controls ( P = 0.01). Calves that received isoprenaline tended to have greater relative wall thickness than control calves ( P = 0.15) and greater E/e' ratios ( P = 0.16), suggestive of concentric hypertrophy and diastolic dysfunction, respectively. Calves that received isoprenaline also tended to have a left ventricle and interventricular septum that was 29 ± 10 g heavier than control calves ( P = 0.10) when controlling for body mass. Hyaline membranes, the hallmark feature of diffuse alveolar damage, were evident in lung sections from all calves that received isoprenaline but none of the controls. Conclusions: Consistent with prior pathological and physiological studies of feedlot cattle, this study provides preliminary evidence that cattle presenting with clinical signs and pathology consistent with early stage acute interstitial pneumonia could be attributable to hydrostatic edema associated with left ventricular failure.

Project description:BackgroundLung damage in severe COVID-19 is highly heterogeneous however studies with dedicated spatial distinction of discrete temporal phases of diffuse alveolar damage (DAD) and alternate lung injury patterns are lacking. Existing studies have also not accounted for progressive airspace obliteration in cellularity estimates. We used an imaging mass cytometry (IMC) analysis with an airspace correction step to more accurately identify the cellular immune response that underpins the heterogeneity of severe COVID-19 lung disease.MethodsLung tissue was obtained at post-mortem from severe COVID-19 deaths. Pathologist-selected regions of interest (ROIs) were chosen by light microscopy representing the patho-evolutionary spectrum of DAD and alternate disease phenotypes were selected for comparison. Architecturally normal SARS-CoV-2-positive lung tissue and tissue from SARS-CoV-2-negative donors served as controls. ROIs were stained for 40 cellular protein markers and ablated using IMC before segmented cells were classified. Cell populations corrected by ROI airspace and their spatial relationships were compared across lung injury patterns.FindingsForty patients (32M:8F, age: 22-98), 345 ROIs and >900k single cells were analysed. DAD progression was marked by airspace obliteration and significant increases in mononuclear phagocytes (MnPs), T and B lymphocytes and significant decreases in alveolar epithelial and endothelial cells. Neutrophil populations proved stable overall although several interferon-responding subsets demonstrated expansion. Spatial analysis revealed immune cell interactions occur prior to microscopically appreciable tissue injury.InterpretationThe immunopathogenesis of severe DAD in COVID-19 lung disease is characterised by sustained increases in MnPs and lymphocytes with key interactions occurring even prior to lung injury is established.FundingUK Research and Innovation/Medical Research Council through the UK Coronavirus Immunology Consortium, Barbour Foundation, General Sir John Monash Foundation, Newcastle University, JGW Patterson Foundation, Wellcome Trust.

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Mouse-passaged severe acute respiratory syndrome-associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in adult but not young mice.

Publications

Mouse-passaged severe acute respiratory syndrome-associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in adult but not young mice.

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