Key to the development of successful and effective vaccines to SARS-CoV-2 infections and treatments for COVID-19 patients is to understand SARS-CoV-2 infectivity and pathogenesis. The fundamental mechanism underlying the SARS-CoV-2 entry remains poorly understood. Previous studies show that the spike (S) proteins of SARS-CoV-1 (SARS-CoV-S [4, 30]) and SARS-CoV-2 (SARS-CoV-2-S [31–35]) bind to human angiotensin-converting enzyme 2 (hACE2), a well-recognized, functional receptor for SARS-CoV-1 and SARS-CoV-2, to mediate viral entry. A hACE2 transgenic (Tg) mouse model is being widely used [36–39], which is clearly invaluable but with some limits (e.g., low expression of hACE2 in human lung, heart, and immune cells). Other models for studying SARS-CoV-2 infection in mice that are currently being optimized include models that utilize mouse-adapted virus derivations [40, 41], immunocompromised or obese mice that lack interferon receptors , or utilize different animals entirely [42, 43]. However, while these models have recapitulated some aspects of the COVID-19 disease course in infected mice, such as lung inflammation , cytokine storm , viral neuroinvasion , and impaired lung function , they fail to explain other aspects of COVID-19 such as increased thrombosis risk for affected individuals, increased risk for COVID-19 in diabetic patients , hemodynamic instability, and why stroke and immunosuppression may be predisposing risk factors and clinical sequelae of COVID-19 [49–51].
One of most outstanding features of coronaviruses is the diversity of receptor usage, which includes the newly proposed human CD147 (hCD147) as a receptor for SARS-CoV-2. CD147 is a transmembrane glycoprotein with multiple functions in normal lung, immune cells, and diseased tissues . The role of CD147 in normal lung remains obscure. The role of CD147 in immune cells is important for T cell activation and proliferation, as well as cell migration, adhesion, and invasion . CD147 is expressed on different cell types (e.g., hematopoietic, epithelial, and endothelial cells) at varying levels . Normal epithelial and fetal tissues have low expression of CD147, when measured by immunohistochemical analysis . However, CD147 is significantly upregulated in aggressive and chronic disease states, such as in cancers [55, 56], atherosclerosis , diabetes , ischemic stroke , and chronic lung obstruction diseases . Intriguingly, recent studies show that CD147 plays a functional role in facilitating SARS-CoV-1 and SARS-CoV-2 entry [22, 61], and antibody against CD147 blocks the infection of SARS-CoV-2 . A humanized anti-CD147 antibody (Meplazumab) efficiently improves the recovery of COVID-19 patients with pneumonia with a favorable safety profile . However, the majority of studies related to CD147 and SARS-CoV-2 are focused on cell line-based in vitro assays and protein binding experiments and have yet-to-be verified in vivo [63, 64].
Our hCD147Tg model offers several strengths to the scientific community as it will better capture other nuances of the COVID-19 disease. (1) This model will allow researchers to study hemodynamic instability and increased thrombosis risk following COVID-19 infection as the hCD147 protein is expressed in circulating erythrocytes. (2) The NSG background will allow scientists to study how adoptive transfer of any immune cell subset can either dampen or initiate the COVID-19-induced cytokine storm that is often seen in affected individuals. Additionally, as the NSG background has been used to study diabetes , our model will allow further studies into the role of diabetes and COVID-19. (3) This model can be crossed with other mouse models to determine whether a combination of human CD147 and other viral entry-related receptors (e.g., ACE2, TMPRSS2, CD26) can exacerbate clinical disease. (4) As the human CD147 protein is expressed at physiological levels in these mice, this model will better recapitulate true physiological conditions and expression patterns normally observed in mice and humans. Even if CD147 is later determined to play a relatively minor role compared to ACE2 in SARS-CoV-2 viral entry, this mouse model may prove to be invaluable for understanding how the virus globally impacts CD147-positive cells and tissues in the in vivo setting and how therapies may modulate COVID-19 disease via this receptor. (5) This model can be used to test the infectivity and pathogenesis of the emergence of variants of SARS-CoV-2, such as B.1.1.7, B.1.351, and P.1 (20J501Y.V3), given the recently reported studies showing extension of host range to BALB/c and C57BL/6 mice . In conclusion, the newly generated hCD147Tg-NSG mouse model can be used as a platform where direct clinical implications for vaccine and therapeutic strategies can be evaluated.