Table 2.

Differences in acute and long-term changes post-MHV-1 coronavirus infection in mice (highlighted items in 12 months post-infection are important changes that were identified in addition to those observed in mice 7 days post-infection)

	Acute changes (7 days post-infection)	Long-term changes (12 months post-infection)	Post-treatment with SPK (both acute and after long-term)
Clinical signs	Stages IV–VI	Stages II–III	No signs of symptoms
Liver enzymes	AST and ALT, 30–90-fold increase; ALP and bilirubin, 1–tenfold increase	AST and ALT, 4–tenfold increase; ALP and bilirubin, 1–fourfold increase	7 days: AST and ALT, 6–30-fold increase; ALP and bilirubin, 1–threefold increase 12 months: AST and ALT, 1–eightfold increase; ALP and bilirubin, 1–twofold increase
Brain	Congested blood vessels Perivascular cavitation Pericellular halos Vacuolation of neuropils Darkly stained nuclei and pyknotic nuclei amid associated vacuolation of the neuropil Acute eosinophilic necrosis	Congested blood vessels Perivascular cavitation Pericellular halos Vacuolation of neuropils Darkly stained nuclei and pyknotic nuclei amid associated vacuolation of the neuropil Acute eosinophilic necrosis A widespread necrotic neurons with fragmented nuclei and vacuolation	7 days: darkly stained nuclei, occasional perivascular cavitation 12 months: infrequent darkly stained nuclei, moderate pericellular halos, as well as perivascular cavitation
Heart	Severe interstitial edema Vascular congestion and dilation Red blood cells infiltrating between degenerative myocardial fibers	Severe interstitial edema Vascular congestion and dilation Red blood cells infiltrating between degenerative myocardial fibers Presence of inflammatory cells and apoptotic bodies in the cardiac tissue Acute myocyte necrosis Hypertrophy Fibrosis	7 day: mild vascular congestion 12 months: mild vascular congestion
Kidney	Tubular epithelial cell degenerative changes Peritubular vessel congestion Proximal and distal tubular necrosis Hemorrhage in interstitial tissue, and vacuolation of renal tubules	Tubular epithelial cell degenerative changes Peritubular vessel congestion Proximal and distal tubular necrosis Hemorrhage in interstitial tissue, and vacuolation of renal tubules Edema and inflammation of the renal parenchyma Severe acute tubular necrosis Infiltration of macrophages and lymphocytes	7 days: mild-moderate peritubular vessel congestion 12 months: mild peritubular vessel congestion and moderate degenerating tubules
Liver	Hepatocyte degeneration Severe periportal hepatocellular necrosis with pyknotic nuclei Hepatic congestion Ballooned hepatocytes Vacuolation and the presence of piecemeal necrosis Ground glass hepatocytes showed voluminous, abundant, granular cytoplasm, Peripheral cytoplasmic clearing and central nuclei Apoptotic (acidophil) bodies Absent hepatocytes replaced by abundant inflammatory cells Condensation and dark staining of the cytoplasm Absence of the nucleus Fatty changes Binucleated hepatocytes Activated Kupffer cells	Hepatic congestion Ballooned hepatocytes Vacuolation and the presence of piecemeal necrosis Occasional ground glass hepatocytes showed voluminous, abundant, granular cytoplasm, Peripheral cytoplasmic clearing and central nuclei Activated Kupffer cells Lymphocyte infiltration in sinusoidal spaces Multifocal hepatic necrosis both in the periportal area and near the terminal hepatic veins Increased number of portal veins associated with luminal severe dilatation Activated Kupffer cells with large cytoplasm containing necrotic debris Eosinophilic bodies Mitotic cells, and balloon-like liver cells Mild inflammation of lobular lymphocytic and portal tract, Mild hydropic degeneration of liver parenchymal cells lipofuscin pigment (indicative of oxidative stress)	7 days: normal appearance 12 months: mild hepatocyte degeneration
Lung	Inflammation (i.e., granular degeneration of cells, and migration of leukocytes into the lungs) Proteinaceous debris filling of the alveolar spaces with fibrillar to granular eosinophilic protein strands Presence of hemosiderin-laden macrophages Peribronchiolar interstitial infiltration Bronchiole epithelial cell necrosis Necrotic cell debris within alveolar lumens Alveolar exudation Hyaline membrane formation Alveolar hemorrhage with red blood cells within the alveolar space Interstitial edema	Inflammation (i.e., granular degeneration of cells, and migration of leukocytes into the lungs) Proteinaceous debris filling of the alveolar spaces with fibrillar to granular eosinophilic protein strands Presence of hemosiderin-laden macrophages Peribronchiolar interstitial infiltration Bronchiole epithelial cell necrosis Necrotic cell debris within alveolar lumens Alveolar exudation Hyaline membrane formation Alveolar hemorrhage with red blood cells within the alveolar space Interstitial edema Bronchioles with thickened airway walls due to fibrotic remodeling (likely due to excessive deposition of collagen bundles) Bronchioles containing a large intra-luminal mucous plug Bronchioles with increased numbers of goblet cells in the epithelial lining Bronchiole walls with increased numbers of inflammatory cells	7 days: Moderate congested blood vessels 12 months: Mild congested blood vessels