Diet induced obesity and type 2 diabetes drives exacerbated sex-associated disease profiles in K18-hACE2-mice challenged with SARS-CoV-2

Abstract

SARS-CoV-2 infection results in wide-ranging disease manifestation from asymptomatic to potentially lethal. Infection poses an increased threat of severity to at-risk populations including those with hypertension, diabetes, and obesity. Type 2 Diabetes (T2DM), is characterized, in part, by insulin insensitivity and impaired glucose regulation. T2DM patients have increased disease severity and poorer outcomes with COVID-19. We utilized the diet-induced obesity (DIO) model of Type 2 Diabetes in SARS-CoV-2-susceptible K18-hACE2 transgenic mice to better understand the obesity co-morbidity. Female DIO, but not male DIO mice challenged with SARS-CoV-2 were observed to have shortened time to morbidity compared to normal diet mice. Increase in susceptibility to SARS-CoV2 in female DIO was associated with increased total viral RNA burden compared to male mice. RNAseq analysis was performed on the lungs of non-challenged, challenged, females, males, of either normal diet or DIO cohorts to determine the disease specific transcriptional profiles. DIO female mice had more total activated genes than normal diet mice after challenge; however, male mice experienced a decrease. GO term analysis revealed the DIO condition increased interferon response signatures and interferon gamma production following challenge. Male challenged mice had robust expression of antibody-related genes suggesting antibody producing cell localization in the lung. DIO reduced antibody gene expression in challenged males. Collectively this study establishes a preclinical T2DM/obesity co-morbidity model of COVID-19 in mice where we observed sex and diet specific responses that begin to explain the effects of obesity and diabetes on COVID-19 disease.

Reduced SARS-CoV-2 mRNA vaccine immunogenicity and protection in mice with diet-induced obesity and insulin resistance

“…4B). Lastly, to define immune correlates of protection, we assessed humans, establishing this model as a viable option for studying the relationship between metabolic disease and SARS-CoV-2 vaccine response [19][20][21] . Here, we developed a mouse model of metabolic disease by feeding mice a HFD, which led to obesity, hyperinsulinemia, and glucose intolerance.…”

“…Further, DIO mice mounted impaired immune responses following immunization with subunit or inactivated-virus influenza vaccines, including decreased antibody (Ab) titers relative to controls, lower CD8 + T cell levels, impaired protection from live viral challenge, and greater waning in humoral immunity [15][16][17][18] . Additionally, studies of MERS-CoV and SARS-CoV-2 infection have found that DIO mice exhibit increased lung titers and/or greater morbidity and mortality following live-virus challenge relative to controls [19][20][21] . However, little is known regarding the effects of obesity and hyperglycemia on SARS-CoV-2 vaccine responses.…”

Obesity fosters severe disease outcomes in a mouse model of coronavirus infection associated with transcriptomic abnormalities

“…Obesity has been identified as an independent risk factor for severe COVID‐19 14–18 and has been associated with chronic systemic inflammation 19,20 . However, most of these inferences are correlative and are based either on data from epidemiological studies 7,8,11,15,17 or from studies performed in nonnatural hosts of SARS‐CoV‐2 21,22 . Therefore, a relevant model of coronavirus infection, which mimics SARS‐CoV‐2 infection in humans, is needed to study the impact of obesity on coronavirus disease outcome.…”

“…19,20 However, most of these inferences are correlative and are based either on data from epidemiological studies 7,8,11,15,17 or from studies performed in nonnatural hosts of SARS-CoV-2. 21,22 Therefore, a relevant model of coronavirus infection, which mimics SARS-CoV-2 infection in humans, is needed to study the impact of obesity on coronavirus disease outcome. We hypothesized that this model would be useful for identifying biomarkers associated with disease severity in COVID-19 patients, which could have prognostic value for risk stratification of patients with COVID-19.…”

Obesity fosters severe disease outcomes in a mouse model of coronavirus infection associated with transcriptomic abnormalities

“…Obesity has been identified as an independent risk factor for severe COVID-19 [14][15][16][17][18] and has been associated with chronic systemic inflammation 19,20 . However, most of these inferences are correlative and are based either on data from epidemiological studies 7,8,11,15,17 or from studies performed in non-natural hosts of SARS-CoV-2 21,22 . Therefore, a relevant model of coronavirus infection, which mimics SARS-CoV-2 infection in humans, is needed to study the impact of obesity on coronavirus disease outcome.…”