Effect of obesity on the acute response to SARS-CoV-2 infection and development of [PASC] in nonhuman primates, 2025, Sauter et al.

[SNT Gatchaman]

Effect of obesity on the acute response to SARS-CoV-2 infection and development of post-acute sequelae of COVID-19 PASC in nonhuman primates

Spoiler: Authors

Kristin A. Sauter; Gabriela M. Webb; Lindsay Bader; Craig N. Kreklywich; Diana L. Takahashi; Cicely Zaro; Casey M. McGuire; Anne D. Lewis; Lois M. A. Colgin; Melissa A. Kirigiti; Hannah Blomenkamp; Cleiton Pessoa; Matthew Humkey; Jesse Hulahan; Madeleine Sleeman; Robert C. Zweig; Sarah Thomas; Archana Thomas; Lina Gao; Alec J. Hirsch; Maayan Levy; Sara Cherry; Steven E. Kahn; Mark K. Slifka; Daniel N. Streblow; Jonah B. Sacha; Paul Kievit; Charles T. Roberts

Long-term adverse consequences of SARS-CoV-2 infection, termed “long COVID” or post-acute sequelae of COVID (PASC), are a major component of overall COVID-19 disease burden. Prior obesity and metabolic disease increase the severity of acute disease, but SARS-CoV-2 infection also contributes to the development of new-onset metabolic disease. Since the COVID pandemic occurred in the context of the global obesity epidemic, an important question is the extent to which pre-existing obesity modifies long-term responses to SARS-CoV-2 infection.

We utilized a nonhuman primate model to compare the effects of infection with the SARS-CoV-2 delta variant in lean and obese/insulin-resistant adult male rhesus macaques over a 6-month time course.

While some longitudinal responses to SARS-CoV-2 infection, including overall viral dynamics, SARS-CoV-2-specific IgG induction, cytokine profiles, and tissue persistence of viral RNA, did not appreciably differ between lean and obese animals, other responses, including neutralizing Ab dynamics, lung pathology, body weight, degree of insulin sensitivity, adipocytokine profiles, body temperature, and nighttime activity levels were significantly different in lean versus obese animals.

Furthermore, several parameters in lean animals were altered following SARS-CoV-2 infection to resemble those in obese animals. Notably, persistent changes in multiple parameters were present in most animals, suggesting that PASC may be more prevalent than estimated from self-reported symptoms in human studies.

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[SNT Gatchaman]

Another important finding of this study was the progressive decline in circulating adiponectin in conjunction with a minimal change in circulating leptin, such that the ALR in the lean group was decreased to the level characteristic of the obese group by 4 months PI. This finding suggests that SARS-CoV-2 infection preferentially alters the levels of surrogate biomarkers of long-term cardiometabolic risk in lean animals. Previous human studies have reported the association of low adiponectin levels or a decreased ALR with severe acute COVID-19 disease and mortality, but ours is the first study, to our knowledge, that analyzed the time course of adiponectin and leptin levels after the acute phase of infection.

It is also notable that circulating adiponectin levels declined at the same time that insulin sensitivity increased; thus, the discordance between adiponectin levels and insulin sensitivity suggests altered metabolic homeostasis following recovery from acute SARS-CoV-2 infection.

In addition to the long-term decrease in the ALR that was unique to the lean group, two other parameters that were persistently altered preferentially in lean vs obese animals were [body temperature and activity.

Lean animals exhibited a significant increase in nighttime activity that was particularly evident towards the end of the study period, while obese animals were somewhat less active at baseline and exhibited a smaller increase in nocturnal activity by the end of the study period. These findings are consistent with recent reports of insomnia and sleep disturbances in long COVID.

The development of specific aspects of PASC in lean animals, including those associated with metabolic dysfunction such as a decreased ALR, and increased nighttime activity, suggests that, while preexisting obesity can increase the risk for some components of PASC such as long-term lung pathology, other aspects of PASC can develop in the absence of pre-infection obesity.

For logistical and budgetary reasons, it was not possible to include females, although future studies using females are clearly warranted based on the reported sex differences in multiple components of PASC]. Indeed, the scope and magnitude of the effects we report here may well be greater in females in light of the greater extent of PASC in women.