Humanized mouse models reveal insight into our understanding of protective immune responses to SARS-CoV-2
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Abstract
In 2020 the world faced a global pandemic that was unparalleled to anything seen in the past century. It created economic, social and health impacts that are persisting today. This pandemic was triggered by the emergence of a novel coronavirus referred to as severe acute respiratory coronavirus 2 (SARS-CoV-2). This novel virus causes a respiratory disease known as coronavirus disease 19 (COVID-19), which can be potentially fatal. While the pandemic provided an opportunity to enrich our understanding of immune mechanisms that lead to severe viral respiratory diseases, our understanding of immune mechanisms driving protection from severe COVID-19 have remained mostly elusive. Such a knowledge gap mostly stems from the inability to access human pulmonary tissues from patients who resolved infection, and the lack of suitable preclinical small animal models able to recapitulate human immune responses to SARS-CoV-2. Here, we present a panel of tissue-humanized mouse models that have allowed us to capture mechanisms of immune protection that prevent the development of severe COVID-19 disease. First, we developed a novel myeloid enhanced human immune system mouse model engrafted with human fetal lung tissue (HNFL mice). HNFL mice demonstrate a superior ability to rapidly control SARS-CoV-2 infection in fetal lung xenograft (fLX) compared to mice lacking an immune system (NRGL). Along with rapid clearance of SARS-CoV-2 infection, fLX of HNFL mice are effectively protected from the severe histopathological features associated with severe COVID-19 and observed in NRGL’s fLX. Notably, HNFL mice protection from acute replication and severe histopathological disease is associated with increased macrophage infiltration and balanced macrophage polarization. A key finding of HNFL mice was the upregulation of a distinct set of 11 genes associated with a protective response. Notably, this gene signature was macrophage-enriched, mainly enriched in type I IFN genes and included the upregulation of negative regulators of drivers of severe inflammation in COVID-19 patients, emphasizing the role of balanced macrophage activation and polarization in mitigating the impact of SARS-CoV-2.
In parallel, we utilized a previously reported multi-tissue humanized mouse model, BLT-L mice, co-engrafted with a human thymus, liver, fLX and human hematopoietic stem cells. Critically, BLT-L mice elicit significant susceptibility to acute viral replication prior to an effective, yet delayed viral clearance compared to HNFL mice, permitting us to identify novel immunological mechanisms driving protection from COVID-19. Using this model, we found that there is an increase in the human myeloid compartment within fLX during acute infection. This coincides with transcriptional reprograming of the monocyte and macrophage lineages. Notably, infection resulted in a CD163+ inflammatory monocyte subset that was specific to acute infection and was absent after infection resolution. These CD163+ inflammatory monocytes, displayed robust antiviral responses and high levels of viral RNA. Interestingly, systemic depletion of CD4+ abrogates viral clearance, resulting in persistent SARS-CoV-2 infection. CD4+ cell depletion correlated with a loss of CD163+ cells in fLX during persistent infection. This research underscores the potential role of CD163+ extravascular monocytes during SARS-CoV-2 virus infection resolution and opens avenues for a better understanding of this subset in the control of viral respiratory infection. Together, these studies provide valuable insight into the cellular and molecular mechanisms of SARS-CoV-2 infection resolution and underscore the significance of using tissue-humanized mouse models to understand the immunological features of emerging infectious diseases.
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2025