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The Coronavirus disease 2019 (COVID-19) pandemic disproportionately affects immunocompetent and immunocompromised individuals, with the latter group being more vulnerable to severe disease and death. However, the differential pathogenesis of SARS-CoV-2 in the context of a specific immunological niche remains unknown. Similarly, systematic analysis of disease pathology in various extrapulmonary organs in immunocompetent and immunocompromised hosts during SARS-CoV-2 infection is not fully understood. We used a hamster model of SARS-CoV-2 infection, which recapitulates the pathophysiology of patients with mild-to-moderate COVID-19, to determine the dynamics of SARS-CoV-2 replication and histopathology at organ-level niches and map how COVID-19 symptoms vary in different immune contexts. Hamsters were intranasally infected with low (LD) or high (HD) inoculums of SARS-CoV-2, and the kinetics of disease pathology and viral load in multiple organs, antibody response, inflammatory cytokine expression, and genome-wide lung transcriptome by RNAseq analysis were determined and compared against corresponding responses from chemically induced immunocompromised hamsters. We observed transient body weight loss proportional to the SARS-CoV-2 infectious dose in immunocompetent hamsters. The kinetics of viral replication and peak viral loads were similar between LD and HD groups, although the latter developed more severe disease pathology in organs. Both groups generated a robust serum antibody response. In contrast, infected immunocompromised animals showed more prolonged body …