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Background:Cardiovascular diseases (CVDs) and diabetes mellitus (DM) are top two chronic comorbidities that increase the severity and mortality of COVID- 19. However, how SARS- CoV- 2 alters the progression of chronic diseases remain unclear. Methods:We used adenovirus to deliver h- ACE2 to lung to enable SARS- CoV- 2 infection in mice. SARS- CoV- 2's impacts on pathogenesis of chronic diseases were studied through histopathological, virologic and molecular biology analysis.Results:Pre- existing CVDs resulted in viral invasion, ROS elevation and activation of apoptosis pathways contribute myocardial injury during SARS- CoV- 2 infection. Viral infection increased fasting blood glucose and reduced insulin response in DM model. Bone mineral density decreased shortly after infection, which associated with im-paired PI3K/AKT/mTOR signaling. Conclusion:We established mouse models mimicked the complex pathological symp-toms of COVID- 19 patients with chronic diseases. Pre- existing diseases could impair the inflammatory responses to SARS- CoV- 2 infection, which further aggravated the pre- existing diseases. This work provided valuable information to better understand the interplay between the primary diseases and SARS- CoV- 2 infection.