SARS-CoV-2 Gamma Variant In Vivo Model Demonstrates Severe Pathogenicity and Unique Transcriptomic Signatures Compared to Alpha, Delta, and Omicron Variants

Since 2019, SARS-CoV-2 variants of concern (VOCs), Alpha, Gamma, Delta, and Omicron, have exhibited distinct transmissibility and severity profiles. In Brazil, Gamma caused high mortality pre-vaccination, yet its underlying pathological mechanisms remain poorly understood. We evaluated VOC pathogenesis in K18-hACE2 transgenic mice (n = 8/group) by integrating clinical monitoring, lung histopathology, immunohistochemistry (F4/80, Ly-6G, CD4, CD8, Spike), and transcriptomics. Alpha, Gamma, and Delta induced severe weight loss, high clinical scores, and 100% mortality within seven days, whereas Omicron caused milder outcomes and survival despite similar pulmonary viral loads (107–108 copies/µL). Histopathology showed intense inflammation and hyperemia across all VOCs, with hierarchical clustering revealing a unique profile for Gamma. Transcriptomics identified 117 core upregulated genes, but Alpha and Gamma modulated a broader gene set. Gamma upregulated components of the alternative complement pathway (Cfb), heightened inflammatory mediators, and downregulated tissue adhesion genes. These results demonstrate that the Gamma variant phenotype is driven by extensive transcriptomic remodeling, whereas Omicron elicits an attenuated response, providing key insights into variant-specific mechanisms.