All Phenotypes Tg(K18-ACE2)2Prlmn MGI Mouse

increased susceptibility to viral infection induced morbidity/mortality ( J:296067 )

• mice intranasally inoculated with influenza A virus (A/HKx31 [X31, H3N2]) followed by SARS-CoV-2 (strain hCoV-19/England/Liverpool_REMRQ0001/2020) that does not contain the deletion or mutations of the furin cleavage site in the S protein show more rapid mortality as compared with mice infected with either virus alone

increased susceptibility to Coronaviridae infection induced morbidity/mortality ( J:294084 , J:300960 )

• all high dose SARS-CoV-2 challenged females and 80% of males succumb to the disease (J:294084)

• low dose SARS-CoV-2 challenged females show 40% mortality while 100% of males succumb to the disease (J:294084)

• all mice infected with SARS-CoV-2, USA-WA1/2020 strain, succumb to infection by 6 days post infection (dpi) (J:300960)

blood vessel inflammation ( J:300960 )

• lungs of SARS-CoV-2-infected mice exhibit vasculitis by 2 dpi

increased leukocyte cell number ( J:294084 )

• SARS-CoV-2-infected mice show an increase in CD45+ and CD3+ cells in infected lungs, indicative of infiltrating leukocytes including T-cells

increased neutrophil cell number ( J:294084 , J:300960 , J:302313 )

• SARS-CoV-2-infected mice show neutrophilia (J:294084)

• SARS-CoV-2-infected mice show increasing neutrophils in the brain with progression of infection (J:300960)

• SARS-CoV-2-infected mice exhibit neutrophilic rhinitis by 4 dpi (J:300960)

• SARS-CoV-2 inoculated mice show an infiltration of neutrophils to the lungs (J:302313)

increased lymphocyte cell number ( J:302313 )

• SARS-CoV-2 inoculated mice show an infiltration of lymphocytes to the lungs

increased T cell number ( J:300960 )

• SARS-CoV-2-infected lungs show a modest migration of CD3+ T cells at 2 dpi

• however, histocytes and neutrophils do not accumulate in the lung over time with SARS-CoV2-infection

• SARS-CoV-2-infected mice show increasing CD3+ T cells in the brain with progression of infection

increased macrophage cell number ( J:294084 , J:302313 )

• SARS-CoV-2-infected mice show an increase in the presence of CD68+ macrophages (J:294084)

• SARS-CoV-2 inoculated mice show an infiltration of macrophages to the lungs (J:302313)

microgliosis ( J:294084 )

• SARS-CoV-2-infected mice show increased number of microglia expanding outward from the perivascular neuropil and in the neuropil surrounding affected vessels

increased IgG level ( J:302313 )

• SARS-CoV-2 inoculated mice show spike-specific IgG in sera at 7 dpi

increased IgM level ( J:302313 )

• SARS-CoV-2 inoculated mice show spike-specific IgM in sera at 7 dpi

abnormal cytokine level ( J:294084 , J:302313 )

• SARS-CoV-2-infected mice show an increase in IL-6, IFN-gamma receptor-1, and chemokines Ccl2, Ccl5, Ccl9, and Cxcl10 transcripts and a decrease in IFNA1, IFNB1, and IFNG, and IL-9 and IL-2 transcripts (J:294084)

• high dose SARS-CoV-2 inoculated mice show a rapid systemic upregulation of proinflammatory cytokines and chemokines in the lung and brain, including an increase in Th1-mediated cytokines INF-gamma and TNF-alpha, chemoattractant granulocyte-macrophage colony-stimulating factor (GM-CSF) and monocyte chemoattractant protein-1 (MCP-1) at 7 dpi (J:302313)

abnormal circulating cytokine level ( J:302313 )

• serum GM-CSF, CXCL-1, and monocyte chemoattractant protein-1 (MCP-1) are increased at 7 dpi with SARS-CoV-2

abnormal circulating chemokine level ( J:294084 )

• SARS-CoV-2-infected mice show higher serum levels of CCL2 and CCL7

increased circulating CXCL10 level ( J:302313 )

• serum IFN-gamma-induced protein-10 (CXCL10) levels are increased at 7 dpi with SARS-CoV-2 in high dose mice

abnormal chemokine level ( J:302313 )

• CXCL-1 is increased on 7 dpi, more in high dose than low dose mice in both brain and lungs

increased CXCL10 level ( J:300960 )

• mice show an increase in CXCL10 level in the lungs, the spleen, nasal turbinate and in the brain by 2 dpi for the lungs, spleen, and nasal turbinate and by 4 dpi with SARS-CoV-2 in the brain

abnormal interferon level ( J:300960 , J:302313 )

• IFN-alpha is seen in the brain by 6 dpi with SARS-CoV-2 (J:300960)

• IFN-gamma and IFN-lambda are lower in the brain of SARS-CoV-2-infected mice compared to infected wild-type mice, except for 6 dpi where IFN-gamma is higher (J:300960)

• high dose SARS-CoV-2 inoculated mice show an increase in IFN-gamma in the lungs and brain (J:302313)

• IFN-gamma levels in the brain are higher in high dose mice than the low dose (J:302313)

increased circulating interferon-gamma level ( J:302313 )

• serum IFN-gamma levels are increased at 7 dpi with SARS-CoV-2 in high dose mice

abnormal interleukin level ( J:300960 , J:302313 )

• SARS-CoV-2-infected mice show increased IL-12, IL-17, IL-27, IL-4, and IL-10 levels in the lungs at 2 dpi (J:300960)

• high SARS-COV-2 dose mice show increased IL-6 levels in the brain at 7 dpi (J:302313)

increased circulating interleukin-10 level ( J:294084 , J:302313 )

• SARS-CoV-2-infected mice exhibit higher serum levels of IL-10 (J:294084)

• IL-10 serum levels are increased at 7 dpi with SARS-CoV-2 (J:302313)

increased circulating interleukin-6 level ( J:294084 )

• SARS-CoV-2-infected mice exhibit higher serum levels of IL-6

abnormal tumor necrosis factor level ( J:300960 , J:302313 )

• SARS-CoV-2-infected mice show increased TNF levels in the lungs at 2 dpi (J:300960)

• high dose SARS-CoV-2 inoculated mice show an increase in TNF-alpha levels in the lungs and brain (J:302313)

• TNF-alpha levels in the brain are higher in high dose mice than the low dose (J:302313)

increased circulating tumor necrosis factor level ( J:294084 )

• SARS-CoV-2-infected mice exhibit higher serum levels of TNF-alpha

enhanced humoral immune response ( J:302313 )

• SARS-CoV-2 inoculated mice show a rapid humoral immune response

cytokine storm ( J:300960 )

• infection with SARS-CoV-2 triggers both a local (lung) and systemic (spleen) chemokine response and a local cytokine storm

• by 2 dpi with SARS-CoV-2, a chemokine storm is seen in the lungs, with an increase in MIP-2/CXCL2, MCP-1/CCL2, MIP-1alpha/CCL3, MIP-1beta/CCL4, RANTES/CCL5, and IP-10/CXCL10 levels in the lungs; by 4 dpi several chemokines decrease but are still elevated compared to levels in wild-type infected mice

• chemokine levels of MIP-2/CXCL2, MIP-1alpha/CCL3, MIP-1beta/CCL4, and IP-10/CXCL10 are increased in the spleen at 2 dpi with SARS-CoV-2, and only MIP-1alpha/CCL3 and MIP-1beta/CCL4 maintained an increase at 4 dpi

• nasal turbinate shows transient high levels of MCP-1/CCL2, MIP-1alpha/CCL3, RANTES/CCL5, and IP-10/CXCL10 at 2 dpi with SARS-CoV-2

• brain shows increased levels of MIP-2/CXCL2, IP-10/CXCL10, and MIP-1alpha/CCL3 at 4 and 6 dpi with SARS-CoV-2

• levels of IP-10/CXCL10 in the lungs at 2 dpi with SARS-CoV-2 are significantly higher in females than in males, all other chemokine levels are similar in males and females

• at 2 dpi with SARS-CoV-2, lungs show a mixed inflammatory (TNF, IL-6, IFN-alpha, and IFN-gamma), TH1 (IL-12, IFN-lambda), TH17 (IL-17, IL-27), and TH2 (IL-4, IL-10) profile

• the cytokine storm in response to SARS-CoV-2 resolves by 4 dpi with the exception of TNF and type I and III IFNs, which remain increased

• reduction of chemokines and cytokines occurs despite detectable viral loads and extensive weight loss

• the cytokine storm is absent in the spleen, nasal turbinate, and trachea of SARS-CoV-2-ifnected mice, except for an increase in TNF at 2 dpi in the spleen and a moderate increase in IL-10 in the nasal turbinate at 2 dpi

• brain shows a delay in the cytokine storm, with an increase in some TH1 and TH17 cytokines at 4 dpi with SARS-CoV-2

• males show higher TH1 and TH17 cytokine responses at 4 dpi with SARS-CoV-2 than females

• females show higher TH2 responses at 4 dpi with SARS-CoV-2 than males

brain inflammation ( J:294084 )

• brains of SARS-CoV-2-infected mice show neuroinflammation

meningitis ( J:294084 , J:302313 )

• a subset of SARS-CoV-2-infected mice exhibit meningitis that is associated with infiltration of mononuclear leukocytes (mostly lymphocytes) (J:294084)

• SARS-CoV-2 infected mice show meningeal inflammation at 7 dpi (J:302313)

meningoencephalitis ( J:296067 , J:300960 )

• mild or moderate non-suppurative meningoencephalitis mainly affecting the midbrain and brainstem is seen in 3 of 4 single SARS-CoV-2 infected mice at 7 dpi (J:296067)

• more severe non-suppurative meningoencephalitis mainly affecting the midbrain and brainstem is seen in 2 of 4 double influenza A and SARS-CoV-2 infected mice compared to that seen in single SARS-CoV-2 infected mice, where perivascular infiltrates contain degenerate leukocytes and are associated with focal loss of endothelial cell layer integrity (J:296067)

• by 4 dpi with SARS-CoV-2, mice show cerebral pathology, including mild meningoencephalitis with vasculitis (J:300960)

conjunctivitis ( J:294084 )

• SARS-CoV-2-infected mice show conjunctivitis starting on 5 dpi

liver inflammation ( J:300960 )

• SARS-CoV-2-infected mice show evidence of liver inflammation, although mixed inflammatory aggregates are minimal with variable amounts of individual hepatocellular necrosis and gut-associated lymphoid tissue with prominent centers

lung inflammation ( J:294084 , J:302313 )

• SARS-CoV-2-infected mice show inflammation of alveolar septa (J:294084)

• lungs develop inflammation by 3 dpi with SARS-CoV-2 characterized by perivascular lymphocytes and alveolar septal thickened by neutrophils, macrophages, and edema (J:302313)

bronchiolitis ( J:302313 )

• at 7 dpi with SARS-CoV2, 2 of 7 low dose mice develop inflammation or necrosis of the bronchioles, whereas 8 of 8 high dose mice are affected

interstitial pneumonia ( J:300960 , J:302313 )

• SARS-CoV-2-infected mice develop interstitial pneumonia associated with alveolar histiocytosis admixed neutrophils and lymphocytes, mild type II pneumocyte hyperplasia, bronchiolar syncytia, endothelial cell hyperplasia and vasculitis by 2 dpi (J:300960)

• by 4 dpi with SARS-CoV-2, majority of mice have 25% or greater lung involvement indicative of pneumonia, with affected areas showing inflammatory cellular accumulations and hemorrhage in alveolar spaces and interstitium, intra-alveolar fibrin admixed cellular debris, vasculitis, edema, and neutrophilic rhinitis (J:300960)

• by 7 dpi with SARS-CoV-2, mice exhibit multifocal, and often peripheral, pulmonary pathology consistent with interstitial pneumonia characterized by type II pneumocyte hyperplasia, septal, alveolar, and perivascular inflammation comprised of lymphocytes, macrophages, and neutrophils, variable amounts of alveolar fibrin and edema, frequent syncytial cells and single cell necrosis, and terminal bronchioles similarly affected (J:302313)

rhinitis ( J:300960 )

• SARS-CoV-2-infected mice exhibit neutrophilic rhinitis by 4 dpi

increased susceptibility to viral infection ( J:296067 )

• mice infected with influenza A virus and then SARS-CoV-2 exhibit 10,000-fold higher levels of SARS-CoV-2 viral load at day 6 post influenza infection (3 dpi with SARS-CoV-2) than at day 10 post influenza infection (7 dpi with SARS-CoV-2) indicating that peak viral SARS-CoV-2 replication occurs before the onset of symptoms at 4 dpi

• mice infected with SARS-CoV-2 alone show higher levels of viral RNA at 3 days post infection than mice coinfected with influenza A and SARS-CoV2

• however, by day 10, the coinfected and singly infected mice show nearly identical levels of SARS-CoV-2 RNA

• mice coinfected with influenza A virus and SARS-CoV-2 show influenza A virus antigen distributed similarly to that seen in influenza A virus infection alone while SARS-CoV-2 antigen expression is less intense than in SARS-CoV-2-only infected mice

increased susceptibility to viral infection induced morbidity/mortality ( J:296067 )

• mice intranasally inoculated with influenza A virus (A/HKx31 [X31, H3N2]) followed by SARS-CoV-2 (strain hCoV-19/England/Liverpool_REMRQ0001/2020) that does not contain the deletion or mutations of the furin cleavage site in the S protein show more rapid mortality as compared with mice infected with either virus alone

increased susceptibility to Coronaviridae infection induced morbidity/mortality ( J:294084 , J:300960 )

• all high dose SARS-CoV-2 challenged females and 80% of males succumb to the disease (J:294084)

• low dose SARS-CoV-2 challenged females show 40% mortality while 100% of males succumb to the disease (J:294084)

• all mice infected with SARS-CoV-2, USA-WA1/2020 strain, succumb to infection by 6 days post infection (dpi) (J:300960)

increased susceptibility to Coronaviridae infection ( J:294084 , J:296067 , J:300960 , J:302313 )

• mice infected intranasally with SARS-CoV-2 strain WA-1/2020 that has been propagated by two passages in Vero76 cells develop acute disease including weight loss, lung injury, brain infection and lethality (J:294084)

• SARS-CoV-2 infected mice show high levels of virus in lung homogenates on day 3 of infection (J:294084)

• the majority of SARS-CoV-2-infected mice show viral RNA in the nasal cavity and rarely in the eyes localized to the retina and mice succumbing to disease (5-7 dpi) show virus throughout the olfactory bulb, including within neurons (J:294084)

• SARS-CoV-2-infected mice show virus in the brain at 5-11 dpi but not at 3 dpi; virus is seen throughout the brain, highest levels in regions of the thalamus, hypothalamus, amygdala, cerebral cortex, medulla, pons and midbrain, however vessel walls and perivascular spaces infiltrated by mononuclear inflammatory cells in the brain are negative for viral RNA (J:294084)

• mice infected with SARS-CoV-2 (strain hCoV-19/England/Liverpool_REMRQ0001/2020) alone show a 100-fold higher sgRNA (measuring active virus infection) at day 3 dpi SARS-CoV-2 than 7 dpi (J:296067)

• 6 days post SARS-CoV2 infection, viral antigen is detected in multifocal patches of individual to large groups of alveoli, randomly throughout the parenchyma, and in type I and type II pneumocytes and in endothelial cells in capillaries and small vessels in septa but not within bronchiolar epithelial cells (J:296067)

• 7 days post only SARS-CoV-2 infection, mice show multifocal areas with distinct type II pneumocyte activation and syncytial cell formation with mild mononuclear infiltration and mild to moderate lymphocyte-dominated vasculitis and perivascular infiltration, a few areas of mild desquamative pneumonia with intra-alveolar macrophages/type II pneumocytes, edema, and fibrin deposition (J:296067)

• mice are susceptible to infection with SARS-CoV-2 USA-WA1/2020 strain, losing over 20% of their initial body weight, are lethargic with rough fur and hunched appearance, immobile and do not eat or drink and succumb to infection (J:300960)

• by 2 dpi with SARS-CoV-2, mice show presence of virus in nasal turbinate and in lungs; viral titers at the nasal turbinates are maintained, but decrease in the lung by 4 dpi (J:300960)

• by 4 dpi with SARS-CoV-2, virus is detected in the brain, with levels increasing at 6 dpi (J:300960)

• mice intranasally inoculated with SARS-CoV-2 strain nCov-WA1-2020 show weight loss, lethargy, ruffled fur, hunched posture and labored breathing throughout course of infection and high dose mice reach euthanasia by 7 dpi while 5 of 6 low dose mice reach euthanasia 5-9 dpi (J:302313)

• mice intranasally inoculated with SARS-CoV-2 show viral RNA in nasal, oropharyngeal and rectal swabs indicating respiratory tract and rectal viral shedding (J:302313)

• viral genomic RNA is detected in almost all tissues of mice intranasally inoculated with SARS-CoV-2, with highest load in lung tissue and in the brain by 7 dpi, however, no viremia is seen (J:302313)

• SARS-CoV-2 viral antigen is seen in both type I and type II pneumocytes at 3 and 7 dpi with SARS-CoV-2, in ciliated and non-ciliated respiratory epithelial cells at 3 dpi, and in neurons of the cerebral cortex and hippocampus (J:302313)

• mice depleted for NK cells (NK1.1) or neutrophils (Ly6C/Ly6G; Gr-1) and then intranasally inoculated with SARS-CoV-2 survive and show no or minimal signs of disease (J:302313)

increased susceptibility to Orthomyxoviridae infection ( J:296067 )

• 6 days post influenza A virus (A/HKx31 [X31, H3N2]) infection, influenza A virus antigen is detected in epithelial cells in bronchi and bronchioles, in type I and II pneumocyte in affected alveoli, and in a few randomly distributed type II pneumocytes

• 10 days post only influenza A virus infection, infection is almost entirely resolved although the lungs show changes of regenerative process (mild to moderate lymphocyte dominated perivascular infiltration)

increased susceptibility to weight loss ( J:294084 , J:296067 , J:300960 , J:302313 )

• mice exposed to SARS-CoV-2 intranasally with two different doses of virus begin to lose weight 4 days post infection (dpi), which is more pronounced in females than males, and is not seen in wild-type mice (J:294084)

• females lose more than 20% weight while males lose more than 12% weight (J:294084)

• mice intranasally inoculated with influenza A virus (A/HKx31 [X31, H3N2]) show weight loss, reaching a nadir at 7 days post infection (dpi) before starting recovery (J:296067)

• mice intranasally inoculated with SARS-CoV-2 (strain hCoV-19/England/Liverpool_REMRQ0001/2020) start to lose weight at 4 dpi and lose weight up to day 10 (J:296067)

• mice infected with influenza A virus and then SARS-CoV-2 show accelerated weight loss compared to influenza A virus infected mice from day 4 which is most severe at day 6, followed by a recovery to day 8 before losing weight again (J:296067)

• mice infected with SARS-CoV-2 lose over 20% of initial body weight (J:300960)

• males infected with SARS-CoV-2 lose weight starting at 1 dpi, at the rate of approximately 5% per day (J:300960)

• females infected with SARS-CoV-2 start to lose weight starting at 3 dpi (J:300960)

• mice infected with a low or high dose of SARS-CoV-2 start to lose weight at 2 days post inoculation (dpi), with greater weight loss in the high dose group (J:302313)

pulmonary alveolar hemorrhage ( J:300960 )

• SARS-CoV-2-infected mice exhibit hemorrhage in alveolar spaces and interstitium by 4 dpi

increased lung apoptosis ( J:294084 )

• SARS-CoV-2-infected mice show elevated TUNEL+ cell numbers in lungs, indicating increased cell death

lung inflammation ( J:294084 , J:302313 )

• SARS-CoV-2-infected mice show inflammation of alveolar septa (J:294084)

• lungs develop inflammation by 3 dpi with SARS-CoV-2 characterized by perivascular lymphocytes and alveolar septal thickened by neutrophils, macrophages, and edema (J:302313)

bronchiolitis ( J:302313 )

• at 7 dpi with SARS-CoV2, 2 of 7 low dose mice develop inflammation or necrosis of the bronchioles, whereas 8 of 8 high dose mice are affected

interstitial pneumonia ( J:300960 , J:302313 )

• SARS-CoV-2-infected mice develop interstitial pneumonia associated with alveolar histiocytosis admixed neutrophils and lymphocytes, mild type II pneumocyte hyperplasia, bronchiolar syncytia, endothelial cell hyperplasia and vasculitis by 2 dpi (J:300960)

• by 4 dpi with SARS-CoV-2, majority of mice have 25% or greater lung involvement indicative of pneumonia, with affected areas showing inflammatory cellular accumulations and hemorrhage in alveolar spaces and interstitium, intra-alveolar fibrin admixed cellular debris, vasculitis, edema, and neutrophilic rhinitis (J:300960)

• by 7 dpi with SARS-CoV-2, mice exhibit multifocal, and often peripheral, pulmonary pathology consistent with interstitial pneumonia characterized by type II pneumocyte hyperplasia, septal, alveolar, and perivascular inflammation comprised of lymphocytes, macrophages, and neutrophils, variable amounts of alveolar fibrin and edema, frequent syncytial cells and single cell necrosis, and terminal bronchioles similarly affected (J:302313)

rhinitis ( J:300960 )

• SARS-CoV-2-infected mice exhibit neutrophilic rhinitis by 4 dpi

abnormal lung morphology ( J:296067 )

• SARS-CoV-2 infected mice show mild pulmonary changes at 6 days post infection, with a mild increase in interstitial cellularity, type II pneumocyte activation, occasional desquamated alveolar macrophages/type II pneumocytes and single erythrocytes in alveolar lumina, and a multifocal, predominantly perivascular mononuclear infiltration with recruitment of leukocytes into vascular walls

• mice infected with influenza A virus and then SARS-CoV-2 show histological changes almost identical to those induced by influenza A virus alone at 6 days after influenza A infection and 3 days after SARS-CoV-2 infection, although slightly more extensive

• 7 days post only SARS-CoV-2 infection, mice show multifocal areas with distinct type II pneumocyte activation and syncytial cell formation with mild mononuclear infiltration and mild to moderate lymphocyte-dominated vasculitis and perivascular infiltration, a few areas of mild desquamative pneumonia with intra-alveolar macrophages/type II pneumocytes, edema, and fibrin deposition

• mice infected with influenza A virus and then SARS-CoV-2 show more pronounced lung changes than seen in single SARS-CoV-2-infected mice at 7 dpi SARS-CoV-2, alongside equally pronounced regenerative changes seen in single influenza A infected mice

pulmonary edema ( J:300960 )

• SARS-CoV-2-infected mice exhibit edema by 4 dpi

abnormal bronchiole epithelium morphology ( J:296067 )

• 6 days post influenza A infection, mice exhibit epithelial cell degeneration and necrosis in several bronchioles, occasional small focal peribronchial areas where alveoli exhibit necrotic cells

increased type II pneumocyte number ( J:294084 , J:300960 , J:302313 )

• less than half of SARS-CoV-2-infected mice show type II pneumocyte hyperplasia (J:294084)

• SARS-CoV-2-infected mice exhibit mild type II pneumocyte hyperplasia at 2 dpi (J:300960)

• mice show type II pneumocyte hyperplasia by 7 dpi with SARS-CoV-2 (J:302313)

abnormal pulmonary interalveolar septum morphology ( J:294084 )

• SARS-CoV-2-infected mice show expansion of alveolar septa with fibrin

• in areas of septal inflammation, most mice show exudation of fibrin and edema into alveolar lumina from damaged septal capillaries

pulmonary parenchymal consolidation ( J:294084 )

• varying levels of lung injury including area of lung consolidation characterized by inflammation/expansion of alveolar septa with fibrin, edema and mononuclear leukocytes and infiltration of vessel walls by mononuclear leukocytes

abnormal alveolar macrophage physiology ( J:294084 )

• SARS-CoV-2-infected mice show increased cellular proliferation in lungs, most likely of alveolar macrophages

abnormal respiration ( J:296067 )

• mice infected with influenza A virus and then SARS-CoV-2 exhibit more severe respiratory symptoms than singly infected mice or controls

respiratory distress ( J:294084 , J:302313 )

• mice intranasally infected with SARS-CoV-2 show signs of respiratory disease starting on 5 dpi, including labored breathing (J:294084)

• mice infected with a low or high dose of SARS-CoV-2 exhibit labored breathing throughout course of infection (J:302313)

pulmonary alveolar hemorrhage ( J:300960 )

• SARS-CoV-2-infected mice exhibit hemorrhage in alveolar spaces and interstitium by 4 dpi

cerebellum hemorrhage ( J:300960 )

• by 4 dpi with SARS-CoV-2, mice show cerebral pathology, including perivascular hemorrhage

vascular inflammation ( J:294084 , J:296067 )

• approximately 95% of SARS-CoV-2-infected mice exhibit vasculitis, encompassing small and intermediate caliber vessels, characterized by mononuclear inflammatory cell infiltration and containing small amounts of fibrin and occasional necrotic debris (J:294084)

• SARS-CoV-2-infected mice show vasculitis in the thalamus/hypothalamus at 5-11 dpi, characterized by endothelial hypertrophy and increases in mononuclear leukocytes within the vessel wall and/or filling the perivascular space and the presence of increased number of microglia within the adjacent neuropil (J:294084)

• 6 days post influenza A infection, vessels show lymphocyte recruitment, vasculitis and perivascular lymphocyte infiltration (J:296067)

• 6 days post SARS-CoV-2 infection, mice show perivascular mononuclear infiltration with recruitment of leukocytes into vascular walls indicating vasculitis (J:296067)

• 7 days post SARS-CoV-2 infection, mice show mild to moderate lymphocyte-dominated vasculitis and perivascular infiltration (J:296067)

blood vessel inflammation ( J:300960 )

• lungs of SARS-CoV-2-infected mice exhibit vasculitis by 2 dpi

increased leukocyte cell number ( J:294084 )

• SARS-CoV-2-infected mice show an increase in CD45+ and CD3+ cells in infected lungs, indicative of infiltrating leukocytes including T-cells

increased neutrophil cell number ( J:294084 , J:300960 , J:302313 )

• SARS-CoV-2-infected mice show neutrophilia (J:294084)

• SARS-CoV-2-infected mice show increasing neutrophils in the brain with progression of infection (J:300960)

• SARS-CoV-2-infected mice exhibit neutrophilic rhinitis by 4 dpi (J:300960)

• SARS-CoV-2 inoculated mice show an infiltration of neutrophils to the lungs (J:302313)

increased lymphocyte cell number ( J:302313 )

• SARS-CoV-2 inoculated mice show an infiltration of lymphocytes to the lungs

increased T cell number ( J:300960 )

• SARS-CoV-2-infected lungs show a modest migration of CD3+ T cells at 2 dpi

• however, histocytes and neutrophils do not accumulate in the lung over time with SARS-CoV2-infection

• SARS-CoV-2-infected mice show increasing CD3+ T cells in the brain with progression of infection

increased macrophage cell number ( J:294084 , J:302313 )

• SARS-CoV-2-infected mice show an increase in the presence of CD68+ macrophages (J:294084)

• SARS-CoV-2 inoculated mice show an infiltration of macrophages to the lungs (J:302313)

microgliosis ( J:294084 )

• SARS-CoV-2-infected mice show increased number of microglia expanding outward from the perivascular neuropil and in the neuropil surrounding affected vessels

increased IgG level ( J:302313 )

• SARS-CoV-2 inoculated mice show spike-specific IgG in sera at 7 dpi

increased IgM level ( J:302313 )

• SARS-CoV-2 inoculated mice show spike-specific IgM in sera at 7 dpi

abnormal brain thrombosis ( J:294084 )

• a few SARS-CoV-2-infected mice show occlusive fibrin thrombi in the thalamus

cerebral edema ( J:302313 )

• SARS-CoV-2 infected mice show edema in the brain at 7 dpi

pulmonary edema ( J:300960 )

• SARS-CoV-2-infected mice exhibit edema by 4 dpi

abnormal cytokine level ( J:294084 , J:302313 )

• SARS-CoV-2-infected mice show an increase in IL-6, IFN-gamma receptor-1, and chemokines Ccl2, Ccl5, Ccl9, and Cxcl10 transcripts and a decrease in IFNA1, IFNB1, and IFNG, and IL-9 and IL-2 transcripts (J:294084)

• high dose SARS-CoV-2 inoculated mice show a rapid systemic upregulation of proinflammatory cytokines and chemokines in the lung and brain, including an increase in Th1-mediated cytokines INF-gamma and TNF-alpha, chemoattractant granulocyte-macrophage colony-stimulating factor (GM-CSF) and monocyte chemoattractant protein-1 (MCP-1) at 7 dpi (J:302313)

abnormal circulating cytokine level ( J:302313 )

• serum GM-CSF, CXCL-1, and monocyte chemoattractant protein-1 (MCP-1) are increased at 7 dpi with SARS-CoV-2

abnormal circulating chemokine level ( J:294084 )

• SARS-CoV-2-infected mice show higher serum levels of CCL2 and CCL7

increased circulating CXCL10 level ( J:302313 )

• serum IFN-gamma-induced protein-10 (CXCL10) levels are increased at 7 dpi with SARS-CoV-2 in high dose mice

abnormal chemokine level ( J:302313 )

• CXCL-1 is increased on 7 dpi, more in high dose than low dose mice in both brain and lungs

increased CXCL10 level ( J:300960 )

• mice show an increase in CXCL10 level in the lungs, the spleen, nasal turbinate and in the brain by 2 dpi for the lungs, spleen, and nasal turbinate and by 4 dpi with SARS-CoV-2 in the brain

abnormal interferon level ( J:300960 , J:302313 )

• IFN-alpha is seen in the brain by 6 dpi with SARS-CoV-2 (J:300960)

• IFN-gamma and IFN-lambda are lower in the brain of SARS-CoV-2-infected mice compared to infected wild-type mice, except for 6 dpi where IFN-gamma is higher (J:300960)

• high dose SARS-CoV-2 inoculated mice show an increase in IFN-gamma in the lungs and brain (J:302313)

• IFN-gamma levels in the brain are higher in high dose mice than the low dose (J:302313)

increased circulating interferon-gamma level ( J:302313 )

• serum IFN-gamma levels are increased at 7 dpi with SARS-CoV-2 in high dose mice

abnormal interleukin level ( J:300960 , J:302313 )

• SARS-CoV-2-infected mice show increased IL-12, IL-17, IL-27, IL-4, and IL-10 levels in the lungs at 2 dpi (J:300960)

• high SARS-COV-2 dose mice show increased IL-6 levels in the brain at 7 dpi (J:302313)

increased circulating interleukin-10 level ( J:294084 , J:302313 )

• SARS-CoV-2-infected mice exhibit higher serum levels of IL-10 (J:294084)

• IL-10 serum levels are increased at 7 dpi with SARS-CoV-2 (J:302313)

increased circulating interleukin-6 level ( J:294084 )

• SARS-CoV-2-infected mice exhibit higher serum levels of IL-6

abnormal tumor necrosis factor level ( J:300960 , J:302313 )

• SARS-CoV-2-infected mice show increased TNF levels in the lungs at 2 dpi (J:300960)

• high dose SARS-CoV-2 inoculated mice show an increase in TNF-alpha levels in the lungs and brain (J:302313)

• TNF-alpha levels in the brain are higher in high dose mice than the low dose (J:302313)

increased circulating tumor necrosis factor level ( J:294084 )

• SARS-CoV-2-infected mice exhibit higher serum levels of TNF-alpha

cerebellum hemorrhage ( J:300960 )

• by 4 dpi with SARS-CoV-2, mice show cerebral pathology, including perivascular hemorrhage

cerebral edema ( J:302313 )

• SARS-CoV-2 infected mice show edema in the brain at 7 dpi

brain inflammation ( J:294084 )

• brains of SARS-CoV-2-infected mice show neuroinflammation

meningitis ( J:294084 , J:302313 )

• a subset of SARS-CoV-2-infected mice exhibit meningitis that is associated with infiltration of mononuclear leukocytes (mostly lymphocytes) (J:294084)

• SARS-CoV-2 infected mice show meningeal inflammation at 7 dpi (J:302313)

meningoencephalitis ( J:296067 , J:300960 )

• mild or moderate non-suppurative meningoencephalitis mainly affecting the midbrain and brainstem is seen in 3 of 4 single SARS-CoV-2 infected mice at 7 dpi (J:296067)

• more severe non-suppurative meningoencephalitis mainly affecting the midbrain and brainstem is seen in 2 of 4 double influenza A and SARS-CoV-2 infected mice compared to that seen in single SARS-CoV-2 infected mice, where perivascular infiltrates contain degenerate leukocytes and are associated with focal loss of endothelial cell layer integrity (J:296067)

• by 4 dpi with SARS-CoV-2, mice show cerebral pathology, including mild meningoencephalitis with vasculitis (J:300960)

brain lesion ( J:294084 , J:302313 )

• some SARS-CoV-2-infected mice show necrosis in the brain, most prominent within the periventricular region of the hypothalamus and in the amygdala; necrotic lesion is characterized by shrunken, angular cells with hypereosinophilic cytoplasm, pyknotic nuclei and surrounded by a clear halo (J:294084)

• SARS-CoV-2 infected mice exhibit lesions in the brain that range from minimal to moderate and include lymphocytic perivascular cuffing, gliosis, meningeal and perivascular inflammation, edema, and rare cerebral microthrombi at 7 dpi; high dose mice show a greater phenotype than low dose mice (J:302313)

gliosis ( J:302313 )

• SARS-CoV-2 infected mice show gliosis at 7 dpi

microgliosis ( J:294084 )

• SARS-CoV-2-infected mice show increased number of microglia expanding outward from the perivascular neuropil and in the neuropil surrounding affected vessels

conjunctivitis ( J:294084 )

• SARS-CoV-2-infected mice show conjunctivitis starting on 5 dpi

increased lung apoptosis ( J:294084 )

• SARS-CoV-2-infected mice show elevated TUNEL+ cell numbers in lungs, indicating increased cell death

behavior/neurological phenotype ( J:294084 )

N	• SARS-CoV-2-infected mice do not show hind limb paralysis, head tilting or tremors

lethargy ( J:300960 , J:302313 )

• SARS-CoV-2-infected mice become lethargic by 6 dpi (J:300960)

• mice infected with a low or high dose of SARS-CoV-2 exhibit lethargy (J:302313)

decreased fluid intake ( J:300960 )

• by 6 dpi with SARS-CoV-2, mice do not drink

decreased food intake ( J:300960 )

• by 6 dpi with SARS-CoV-2, mice do not eat

hunched posture ( J:300960 )

• by 6 dpi with SARS-CoV-2, mice have a hunched appearance

liver inflammation ( J:300960 )

• SARS-CoV-2-infected mice show evidence of liver inflammation, although mixed inflammatory aggregates are minimal with variable amounts of individual hepatocellular necrosis and gut-associated lymphoid tissue with prominent centers

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
COVID-19		DOID:0080600		J:294084 , J:296067 , J:300960 , J:302313

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
severe acute respiratory syndrome		DOID:2945		J:283648

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