Insights from humanized models

The ongoing battle against COVID-19 highlighted the need for effective models to study SARS-CoV-2 infection. Researchers developed humanized mouse models expressing the human ACE2 (the receptor for SARS-CoV-2), which the virus uses to enter cells. These models allowed for the evaluation of vaccine efficacy, antiviral drugs, and immune responses, contributing to a better understanding of the virus’s pathology and aiding in developing countermeasures.

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MISTRG6-hACE2 Humanized Mouse Model and Chronic COVID-19

The MISTRG6-hACE2 humanized mouse model played a critical role in uncovering the mechanisms of chronic COVID-19. This model recapitulates many of the human immune system responses and allows researchers to observe the key features of severe COVID-19, such as persistent inflammation and sustained interferon (IFN) responses, which are otherwise difficult to study in vitro. The MISTRG6-hACE2 mouse model is genetically modified to express human ACE2 in a reconstituted human immune system, including macrophages, which are central to COVID-19 pathology. This model helped a research group at Yale to identify that lung-resident human macrophages, upon infection, activate inflammasomes, leading to the production of pro-inflammatory cytokines like IL-1β and IL-18 and initiating pyroptosis—a form of cell death that exacerbates lung inflammation. The study found that blocking viral replication with remdesivir or inhibiting the IFN response with anti-IFNAR2 antibodies significantly reduced the hyperinflammatory state. Additionally, inhibition of the NLRP3 inflammasome pathway in this mouse model reversed lung pathology. This model further demonstrated that inflammasome activation is essential for the severe inflammation of chronic COVID-19 and highlighted the therapeutic potential of targeting this pathway to alleviate disease symptoms.

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Immune Response to Repeated mRNA Vaccination

Another striking example of SARS-CoV-2 infection research was a study where genetically engineered mice were used to investigate the immune response to repeated mRNA vaccinations. These mouse models revealed that spike-specific IgG4 antibodies increased over time, which led to a reduction in pro-inflammatory immune responses. This switch to IgG4-dominant responses, observed months after the third vaccination, was linked to a diminished capacity for antibody-dependent cellular phagocytosis and complement deposition, key mechanisms in antiviral immunity.

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Mouse Models for Monkeypox Research

In parallel, research on monkeypox (declared a health emergency by WHO in mid-2022) in mouse models has shed light on clade-specific virulence differences. CAST/EiJ mice, a wild-derived inbred strain, have proven to be an exceptional model for studying these differences. Researchers demonstrated that clade I of the monkeypox virus caused more severe disease compared to clades IIa and IIb.1, mimicking the clinical severity observed in humans. This model has been instrumental in understanding how genetic variations among monkeypox virus strains affect virulence and transmission.

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Gut Microbiome Insights from Gnotobiotic Mouse Studies

Finally, new insights into gut microbiome interactions were derived from studies on gnotobiotic mice. Researchers showed that diverse gut microbiota provides robust protection against pathogens like Klebsiella pneumoniae and Salmonella enterica. By using combinations of bacterial species in mice, the studies demonstrated how nutrient competition within the gut can prevent pathogenic colonization, offering potential therapeutic strategies based on microbiome modulation.

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These breakthroughs collectively showcase the pivotal role of mouse models in unraveling complex immune processes, host-virus interactions, microbiome studies, and more, guiding vaccine design and informing treatment strategies for infectious diseases.