Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of coronavirus disease 2019 (COVID‐19), the most consequential pandemic of this century, threatening human health and public safety. SARS‐CoV‐2 has been continuously evolving through mutation of its genome and variants of concern have emerged. The World Health Organization R&D Blueprint plan convened a range of expert groups to develop animal models for COVID‐19, a core requirement for the prevention and control of SARS‐CoV‐2 pandemic. The animal model construction techniques developed during the SARS‐CoV and MERS‐CoV pandemics were rapidly deployed and applied in the establishment of COVID‐19 animal models. To date, a large number of animal models for COVID‐19, including mice, hamsters, minks and nonhuman primates, have been established. Infectious diseases produce unique manifestations according to the characteristics of the pathogen and modes of infection. Here we classified animal model resources around the infection route of SARS‐CoV‐2, and summarized the characteristics of the animal models constructed via transnasal, localized, and simulated transmission routes of infection.

Characteristics of animal models for COVID‐19

Tuberculosis (TB) is a zoonotic infectious disease caused by Mycobacterium tuberculosis (Mtb). Apoptosis and necrosis caused by the interaction between the host and the pathogen, as well as the host's inflammatory response, play an important role in the pathogenesis of TB. Dual-specificity phosphatase 1 (DUSP1) plays a vital role in regulating the host immune responses. However, the role of DUSP1 in the regulation of THP-1 macrophage apoptosis induced by attenuated Mycobacterium bovis Bacillus Calmette-Guérin (BCG) infection remains unclear. In the present study, we report that infection with BCG significantly induces macrophage apoptosis and induces the production of DUSP1, TNF-α and IL-1β. DUSP1 knockdown significantly inhibited BCG-induced macrophage apoptosis and activation of MAPKs/NF-κB signaling pathway. In addition, DUSP1 knockdown suppressed BCG-induced inflammation in vivo. Taken together, this study demonstrates that DUSP1, as a regulator of MAPKs/NF-κB signaling pathway, plays a novel role in BCG-induced macrophage apoptosis and inflammatory response. 

/pdf/dusp1-mediates-bcg-induced-apoptosis-and-inflammatory-16sfevnl.pdf

DUSP1 mediates BCG induced apoptosis and inflammatory response in THP-1 cells via MAPKs/NF-κB signaling pathway

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a positive-sense-single stranded RNA virus and the cause of the coronavirus disease 2019 (COVID-19). The World Health Organisation has confirmed over 250 million cases with over 5.1 million deaths as a result of this pandemic since December 2019. A global outbreak of such intensity and perseverance is due to the novelty of SARS-CoV2 virus, meaning humans lack any pre-existing immunity to the virus. Humanised animal models, from rodents to primates, simulating SARS-CoV2 transmission, cell entry and immune defence in humans have already been crucial to boost understanding of its molecular mechanisms of infection, reveal at-risk populations, and study the pathophysiology in vivo. Focus is now turning towards using this knowledge to create effective vaccines and therapeutic agents, as well as optimise their safety for translatable use in humans. SARS-CoV2 possesses remarkable adaptability and rapid mutagenic capabilities thus exploiting innovative animal models will be pivotal to outmanoeuvre it during this pandemic. In this review, we summarise all generated SARS-CoV2-related animal models to date, evaluate their suitability for COVID-19 research, and address the current and future state of the importance of animal models in this field.

Advances in Modelling COVID-19 in Animals

Silicosis is an irreversible chronic pulmonary disease caused by long-term inhalation and deposition of silica particles, which is currently incurable. The exhaustion of airway epithelial stem cells plays a pathogenetic role in silicosis. In present study, we investigated therapeutic effects and potential mechanism of human embryonic stem cell (hESC)-derived MSC-likes immune and matrix regulatory cells (IMRCs) (hESC-MSC-IMRCs), a type of manufacturable MSCs for clinical application in silicosis mice. Our results showed that the transplantation of hESC-MSC-IMRCs led the alleviation of silica-induced silicosis in mice, accompanied by inhibiting epithelia-mesenchymal transition (EMT), activating B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) signaling and airway epithelial cell regeneration. In consistence, the secretome of hESC-MSC-IMRC exhibited abilities to restore the potency and plasticity of primary human bronchial epithelial cells (HBECs) proliferation and differentiation following the SiO2 -induced HBECs injury. Mechanistically, the secretome resolved the SiO2 -induced HBECs injury through the activation of BMI1 signaling and restoration of airway basal cell proliferation and differentiation. Moreover, the activation of BMI1 significantly enhanced the capacity of HBEC proliferation and differentiation to multiple airway epithelial cell types in organoids. Cytokine array revealed that DKK1, VEGF, uPAR, IL-8, Serpin E1, MCP-1 and Tsp-1 were the main factors in the hESC-MSC-IMRC secretome. These results demonstrated a potential therapeutic effect of hESC-MSC-IMRCs and their secretome for silicosis, in part through a mechanism by activating Bmi1 signaling to revert the exhaustion of airway epithelial stem cells, subsequentially enhance the potency and plasticity of lung epithelial stem cells.

Human embryonic stem cell-derived mesenchymal stem cell secretome reverts silica-induced airway epithelial cell injury by regulating Bmi1 signaling.

Development and assessment of a predictive model for early diagnosis of rheumatoid arthritis in southwest China: A new nomogram

Bmi1 signaling maintains the plasticity of airway epithelial progenitors in response to persistent silica exposures.

The clinical features of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (RA-ILD) usually manifest to an advanced stage of lung disease, which leads the challenge of early diagnosis and the difficulty in guiding treatments for patients with RA-ILD in clinical settings. The aim of this study was to construct a nomogram for identifying ILD in RA patients. Through the incorporation of the level of matrix metalloproteinase-3 (MMP-3) in plasma, demographics, clinical feature, and laboratory parameters of 223 RA patients (85 RA-ILD) which were grouped as training cohorts and validation cohorts, an identifying nomogram of RA-ILD was built. Candidate variables for the nomogram were screened using univariable analysis and multivariable logistic regression analysis. The accuracy of the diagnostic nomogram was measured via concordance index (C-index), calibration plots, and decision curve analysis (DCA). Results showed that plasma MMP-3 protein was elevated in RA-ILD patients compared with non-ILD RA patients in both training cohorts (p = 0.0475) and validation cohorts (p = 0.0006). Following a final regression analysis, the gender of male, current smoking state, levels of circulating rheumatoid factor (RF), C-reactive protein (CRP), and MMP-3 were identified as risk factors for the construction of the nomogram. The calibration plots further showed a favorable consistency between the identifying nomogram and actual clinical findings. In consistence, the C-index (0.826 for both training cohorts and validation cohorts) indicated the satisfactory discriminative ability of the nomogram. Although the incorporation of MMP-3 failed to significantly improve identified outcomes of the nomogram as determined by DCA, including the level of circulating MMP-3 increased the diagnostic accuracy of the nomogram for ILD in RA patients. Thus, our proposed model can serve as a non-invasive tool to identify ILD in RA patients, which may assist physicians to make treatment decisions for RA patients.

/pdf/development-of-a-risk-nomogram-model-for-identifying-29gwo4co.pdf

Development of a Risk Nomogram Model for Identifying Interstitial Lung Disease in Patients With Rheumatoid Arthritis

A graph model of combination therapies.

Abstract Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis. 

/pdf/the-effects-of-atir-blocker-on-the-severity-of-covid-19-in-274wb8mo.pdf

The Effects of ATIR Blocker on the Severity of COVID-19 in Hypertensive Inpatients and Virulence of SARS-CoV-2 in Hypertensive hACE2 Transgenic Mice

Oxidative stress and inflammation are major drivers in the pathogenesis and progression of pulmonary fibrosis (PF). The mesenchymal stem cell (MSC) secretome has regenerative potential and immunomodulatory functions. Human embryonic stem cell (hESC)-derived MSC-like immune and matrix regulatory cells (IMRCs) are manufacturable with large-scale good manufacturing practice (GMP) preparation. In the present study, the antioxidative and anti-inflammatory properties and the therapeutic effect of the secretome of hESC-MSC-IMRC-derived conditioned culture medium (CM) (hESC-MSC-IMRC-CM) were investigated. Results revealed the capacities of hESC-MSC-IMRC-CM to reduce bleomycin (BLM)-induced reactive oxygen species (ROS), extracellular matrix (ECM) deposition, and epithelial–mesenchymal transition (EMT) in A549 cells. The administration of concentrated hESC-MSC-IMRC-CM significantly alleviated the pathogenesis of PF in lungs of BLM-injured mice, as accessed by pathohistological changes and the expression of ECM and EMT. A mechanistic study further demonstrated that the hESC-MSC-IMRC-CM was able to inhibit BLM-induced ROS and pro-inflammatory cytokines, accompanied by a reduced expression of Nox4, Nrf2, Ho-1, and components of the Tlr4/MyD88 signaling cascade. These results provide a proof of concept for the hESC-MSC-IMRC-derived secretome treatment of PF, in part mediated by their antioxidative and anti-inflammatory effects. This study thus reinforces the development of ready-to-use, cell-free hESC-MSC-IMRC secretome biomedicine for the treatment of PF in clinical settings.

/pdf/secretome-of-hesc-derived-msc-like-immune-and-matrix-3pm6k33x.pdf

Shuang Wu

Papers

Bmi1 signaling maintains the plasticity of airway epithelial progenitors in response to persistent silica exposures.

Development of a Risk Nomogram Model for Identifying Interstitial Lung Disease in Patients With Rheumatoid Arthritis

A graph model of combination therapies.

The Effects of ATIR Blocker on the Severity of COVID-19 in Hypertensive Inpatients and Virulence of SARS-CoV-2 in Hypertensive hACE2 Transgenic Mice

Secretome of hESC-Derived MSC-like Immune and Matrix Regulatory Cells Mitigate Pulmonary Fibrosis through Antioxidant and Anti-Inflammatory Effects