COVID-19 Animal Model

DEVELOPMENTAL-CELL 2024 Nov 27
Microbiota-derived short-chain fatty acids determine stem cell characteristics of gastric chief cells
The gastric mucosa is a highly dynamic tissue that undergoes constant self-renewal through stem cell differentiation. Chief cells maintain a quiescent state in homeostasis but are responsible for regeneration after injury. Although the role of microbiome-host interactions in the intestine is well studied, less is known about these interactions in the stomach. Using the mouse organoid and germ-free mouse models, we show that microbiota-derived short-chain fatty acids (SCFAs) suppress the proliferation of chief cells in mice. This effect is mediated by activation of G-protein-coupled receptor 43. Most importantly, through metabolomics and transplantation studies, we show butyrate-producing Lactobacillus intestinalis modulates the proliferation of chief cells in mice. Our findings identify a mechanism by which the microbiota regulates the cell characteristics of chief cells, providing insight into the complex interplay between the host and its microbial environment and the mechanisms underlying gastric homeostasis, with potential therapeutic implications for gastric diseases.

Scientific Reports 2024 Nov 13
Elimination of olfactory sensory neurons by zinc sulfate inoculation prevents SARS-CoV-2 infection of the brain in K18-hACE2 transgenic mice
Coronavirus disease-2019 (COVID-19), attributed to the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), has posed global health challenges since it first emerged in 2019, and its impact continues to persist. The neurotropic nature of SARS-CoV-2 remains undisclosed, though researchers are proposing hypotheses on how the virus is transmitted to the central nervous system. One of the prevailing hypotheses is that SARS-CoV-2 travels through the olfactory nerve system via the olfactory epithelium (OE). Using a K18-human angiotensin converting-enzyme 2 (hACE2) transgenic mouse model with impaired olfactory sensory neurons (OSNs) induced by zinc sulfate, we examined the role of the olfactory nerve in the brain invasion by SARS-CoV-2. Mice lacking OSNs exhibited reduced levels of viral transmission to the brain, leading to significantly improved outcomes following SARS-CoV-2 infection. Moreover, a positive correlation was observed between viral persistence in the OE and brain infection. These results indicate that early inhibition of the olfactory nerve pathway effectively prevents viral invasion of the brain in K18-hACE2 mice. Our study underscores the significance of the olfactory nerve pathway in the transmission of SARS-CoV-2 to the brain.

BMC Pulmonary Medicine 2024 Nov 12
A novel chronic obstructive pulmonary disease mouse model induced by intubation-mediated intratracheal co-administration of porcine pancreatic elastase and lipopolysaccharide
Chronic obstructive pulmonary disease (COPD) is a significant respiratory disorder in humans characterized by persistent airway constriction or obstruction due to chronic bronchitis and pulmonary emphysema. Various methods of inducing COPD in mouse models are frequently used in COPD research; however, these cannot completely reproduce histopathologic lesions. This study aimed to establish a new COPD mouse model that reproduces histopathological lesions closely resembling clinical COPD within a shorter induction time.

Biochim Biophys Acta Mol Basis Dis 2024 Jul 15
Discovery of a new long COVID mouse model via systemic histopathological comparison of SARS-CoV-2 intranasal and inhalation infection
Intranasal infection is commonly used to establish a SARS-CoV-2 mouse model due to its non-invasive procedures and a minimal effect from the operation itself. However, mice intranasally infected with SARS-CoV-2 have a high mortality rate, which limits the utility of this model for exploring therapeutic strategies and the sequelae of nonfatal COVID-19 cases. To resolve these limitations, an aerosolised viral administration method has been suggested. However, an in-depth pathological analysis comparing the two models is lacking. Here, we show that inhalation and intranasal SARS-CoV-2 (106 PFU) infection models established in K18-hACE2 mice develop unique pathological features in both the respiratory and central nervous systems, which could be directly attributed to the infection method. While the inhalation-infection model exhibited relatively milder pathological parameters, it closely mimicked the prevalent chest CT pattern observed in COVID-19 patients with focal, peripheral lesions and fibrotic scarring in the recuperating lung. We also found the evidence of direct neuroninvasion from the olfactory receptor neurons to the olfactory bulb in the intranasal model and showed the trigeminal nerve as an alternative route of transmission to the brain in inhalation infected mice. Even after viral clearance confirmed at 14 days post-infection, mild lesions were still found in the brain of inhalation-infected mice. These findings suggest that the inhalation-infection model has advantages over the intranasal-infection model in closely mimicking the pathological features of non-fatal symptoms of COVID-19, demonstrating its potential to study the sequelae and possible interventions for long COVID

Immune Network 2024 Feb 02
Immune cells are differentially affected by SARS-CoV-2 viral loads in K18-hACE2 mice
Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019. In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virus infected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105 PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination

EBioMedicine 2023 Dec 19
A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic mice
The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to approximately 500 million cases and 6 million deaths worldwide. Previous investigations into the pathophysiology of SARS-CoV-2 primarily focused on peripheral blood mononuclear cells from patients, lacking detailed mechanistic insights into the virus’s impact on inflamed tissue. Existing animal models, such as hamster and ferret, do not faithfully replicate the severe SARS-CoV-2 infection seen in patients, underscoring the need for more relevant animal system-based research.

Virol J 2023 Dec 1;20(1):285
Development of a neutralization monoclonal antibody with a broad neutralizing effect against SARS-CoV-2 variants.
The selected clones were converted to human IgG, and among them, SKAI-DS84 was selected for further analyses based on its binding affinity with the variant RBDs. Using pseudoviruses, we confirmed that SKAI-DS84 was strongly neutralizing against wild-type, B.1.617.2, B.1.1.529, and subvariants of SARS-CoV-2. We also tested the neutralizing effect of SKAI-DS84 on authentic viruses, in vivo and observed a reduction in viral replication and improved lung pathology. We performed binding and epitope mapping experiments to understand the mechanisms underlying neutralization and identified quaternary epitopes formed by the interaction between RBDs as the target of SKAI-DS84.

Lab Anim Res 2023 April
Carboxylmethyl cellulose produced from wood sawdust for improving.
Cellulose-based materials have shown immense potential for diverse applications because of their attractive properties such as excellent mechanical properties, rich hydroxyl groups for modification, and natural properties with recyclability, nontoxicity, biocompatibility, biodegradability, and environmental friendliness. This study aimed to optimize cellulose extraction from wood sawdust using deep eutectic solution (DES) treatments for the preparation of carboxymethyl cellulose (CMC) and to evaluate the application of CMC in sodium alginate (SA) microgel for dye adsorption.

Nat Commun 2024 Apr 30;15(1):3666
Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection.
Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity.

Lab Anim Res 2022 Jun 28;38(1):17
Laboratory information management system for COVID-19 non-clinical efficacy trial data.
In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface.