Pathological Sequelae of SARS-CoV-2: A Review for Clinicians

Abstract

The Coronavirus Disease 2019 (COVID-19) pandemic, driven by the novel coronavirus and its variants, has caused over 518 million infections and 6.25 million deaths globally, leading to a significant health crisis. Beyond its primary respiratory impact, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been implicated in various extra-pulmonary complications. Research studies reveal that the virus affects multiple organs, including the kidneys, liver, pancreas, and central nervous system (CNS), largely due to the widespread expression of Angiotensin Converting Enzyme-2 (ACE-2) receptors. Clinical evidence shows that the virus can induce diabetes by disrupting pancreatic and liver functions as well as cause acute kidney injury. Additionally, neurological complications, including cognitive impairments and neuroinflammation, have been observed in a significant number of COVID-19 patients. This review discusses the mechanisms linking SARS-CoV-2 to acute kidney injury, Type 1 and Type 2 Diabetes Mellitus (T1DM and T2DM), emphasizing its effects on pancreatic beta cells, insulin resistance, and the regulation of gluconeogenesis. We also explore how SARS-CoV-2 induces neurological complications, detailing the intricate pathways of neuro-invasion and the potential to trigger conditions such as Alzheimer's disease (AD). By elucidating the metabolic and neurological manifestations of COVID-19 and the underlying pathogenic mechanisms, this review underscores the imperative for continued research and the development of effective therapeutic interventions to mitigate the long-term and short-term impacts of SARS-CoV-2 infection.

Keywords: Alzheimer’s disease; Hyperglycemia; Neuro-invasion; SARS-CoV-2; Type 1 Diabetes Mellitus; Type 2 Diabetes Mellitus.

Figure 1

SARS-CoV-2 Infection pathway mediated by ACE2 and TMPRSS2 leading to membrane fusion and viral uptake.

Figure 2

Pancreatic beta cell infection results in immediate or inflammatory-mediated cell death. Consequently, this leads to a reduction of insulin secretory granules and hypoinsulinemia. 1. SARS-CoV-2 infects pancreatic beta cells. 2. SARS-CoV-2 infection either results in direct cell death or the release of increased proinflammatory cytokines which also leads to beta cell (2-3) apoptosis. Beta cell death reduces insulin secretory granules, consequently leading to hypoinsulinemia (4-5).

Figure 3

A schematic diagram showing the inhibition of the IRS family proteins by the SARS-CoV-2-induced proinflammatory cytokines. SARS-CoV-2 invades pancreatic beta cells (1). SARS-CoV-2 infection triggers the release of proinflammatory cytokines, primarily TNF-α and IL-6 (2). TNF-α and IL-6 inhibits IRS-1 resulting in insulin resistance (3).

Figure 4

A diagram showing the involvement of GP73 in SARS-CoV-2-induced metabolic disorder. SARS-CoV-2 infection increases the cellular exudation of GP73 via the S and/or N protein. Secreted GP73 moves to the liver to activate gluconeogenesis, leading to hyperglycemia.

Figure 5

Schematic diagram showing multiple routes for SARS-CoV-2 neuro-infection.

Figure 6

SARS-CoV-2 infects the microglial cells inducing ROS. ROS oxidizes the RyR2 channel resulting in calcium leak into the cytoplasm (4-5). The increased Calcium concentration in the brain results in tau hyperphosphorylation by stimulating Calpain (6b-8b). The increased Calcium concentration also results in αβ deposition by stimulating BACE activity (6a-8a). NB: The amyloid precursor protein (APP) is enriched in the brain.