Primate model unlocks clues to long-COVID’s impact on blood sugar, hints at vaccine benefits

In a new study posted on the bioRxiv* preprint server, researchers evaluate the association between glucometabolic disruptions and long coronavirus disease 2019 (COVID-19) symptoms using a non-human primate model.

Study: Immune Correlates of Hyperglycemia and Vaccination in a Non-human Primate Model of Long-COVID. Image Credit: Starshaker / Shutterstock.com

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background 

The rapid outbreak of the highly contagious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in the COVID-19 pandemic. In some cases, SARS-CoV-2 infection is more persistent and causes long-term health complications, collectively referred to as long-COVID or post-acute sequelae of SARS-CoV-2 (PASC). 

Several studies have identified a broad spectrum of long COVID symptoms, including type 2 diabetes (T2D), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), neuropsychiatric sequelae like brain fog, metabolic associated fatty liver disease (MAFLD), cardiovascular diseases (CVD) and thrombosis. About 50% of patients who experienced persistent SARS-CoV-2 infection reported the incidence of elevated T2D.

Pre-existing diabetes leads to severe COVID-19 outcomes and higher mortality rates. Furthermore, acute SARS-CoV-2 infection is also associated with new-onset hyperglycemia and diabetic ketoacidosis.

Disruption in glucose metabolism has been associated with multiple factors, including β-cell dysfunctions due to early pancreatic infection by SARS-CoV-2. Elevated levels of circulating inflammatory molecules, such as cytokines and chemokines, also contribute to impaired glucose homeostasis.

Due to the lack of suitable animal models for metabolic PASC, the mechanisms related to SARS-CoV-2 infection that promote prolonged hyperglycemia are unclear.

About the study

The current study developed a suitable model to investigate the potential mechanism linked to the incidence of hyperglycemia due to long-COVID. The impact of the Pfizer/BioNTech BNT162b2 vaccine during acute SARS-CoV-2 infection on immunometabolic dysregulation was also determined.

A total of 15 African green monkeys (AGMs), which included 13 female and two male monkeys, were exposed to SARS-CoV-2 through the intranasal and intratracheal route. Ten animals were studied during the natural SARS-CoV-2 infection, while five received the BNT162b2 Pfizer/BioNTech vaccine four days after infection.

All test animals were monitored for eighteen weeks. During the study period, complete physical, virologic, and clinical assessments were conducted along with blood chemistry and immunometabolic profiling.

One female monkey, who was 19.32 years of age, was sent for necropsy in the eighth week due to anorexia. Importantly, there was no significant difference in age and weight between the vaccinated and unvaccinated groups.

Study findings

Damages caused by early host antiviral responses against SARS-CoV-2 infection could be the underlying mechanism responsible for the clinical outcomes of acute COVID-19 symptoms. AGMs infected with SARS-CoV-2 exhibited a wide range of immunologic and metabolic changes similar to previously reported symptoms in humans during the acute and post-acute phases of COVID-19.

SARS-CoV-2 infection of AGMs was associated with early-onset hyperglycemia. Several plasma analytes positively and significantly correlated with plasma glucose levels over time, most of which were chemokines and inflammation-related proteins.

Gene-ontology analyses and application of protein-protein interaction tools indicated that the functionally enriched networks associated with these plasma analytes were linked to macrophage proliferation, chemotaxis, leukocyte migration, and viral protein interaction with cytokines.

Among all plasma analytes, C-C motif chemokine ligand 25 (CCL25) and glial-derived neurotrophic factor (GDNF) were significantly increased after one week of SARS-CoV-2 infection in AGMs. These analytes positively correlated with blood glucose levels across all time points.

Increased T-cell hypersensitivity was observed in AGMs during infection. Furthermore, polyfunctional responses to ex-vivo PMA/I stimulation were observed that were positively associated with glucose levels.

A wide range of antibody responses was similar in both vaccinated and unvaccinated groups. Importantly, vaccination aided in a significant lowering of blood glucose levels over the study period.

Increased glycogen levels were detected in the hepatocytes of infected AGMs at necropsy, which was positively associated with blood glucose levels. However, no significant amount of SARS-CoV-2 proteins or nucleic acid was found in the liver or pancreas during the 18th week of analysis. Although elevation of CCL25 could significantly impair insulin secretion from the pancreas, the current study did not find any evidence of long-term pancreatic damage.

As compared to uninfected controls, several differentially regulated chemokines, including CCL8, CCL19, and CCL25, were identified. The infected AGM model exhibited robust interactions between CCL19, CCL8, CCL25, tumor necrosis factor (TNF), and interleukin 18 (IL-18), thereby suggesting a link between chemokine signature, inflammatory responses, and COVID-19-related metabolic diseases.

A protein-protein interaction analysis demonstrated that GDNF interacts with neural cell adhesion molecule 1 (NCAM1) with high confidence, which implies that GDNF acts like a chemotaxis factor essential to maintaining gut wall integrity. Since GDNF levels are inversely correlated with plasma glucose levels in T2D patients, their increased level indicates an adaptive response. More research is required to understand the precise role of GDNF in COVID-19-related pathologies.

Conclusions

The newly developed SARS-CoV-2 infected AGM model exhibited many immunologic, virologic, and metabolic features that are also observed in infected humans. Therefore, this model could be used to study metabolic PASC.

The current study identified CCL25 and GDNF, which significantly and positively correlated with glucose levels over time. The vaccinated group exhibited better glycemic control; however, additional studies are needed to assess the benefits of this vaccination strategy during the acute phase of infection.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.