The relationship between chronic immune response and neurodegenerative damage in long COVID-19

Abstract

In the past two years, the world has faced the pandemic caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2), which by August of 2022 has infected around 619 million people and caused the death of 6.55 million individuals globally. Although SARS-CoV-2 mainly affects the respiratory tract level, there are several reports, indicating that other organs such as the heart, kidney, pancreas, and brain can also be damaged. A characteristic observed in blood serum samples of patients suffering COVID-19 disease in moderate and severe stages, is a significant increase in proinflammatory cytokines such as interferon-α (IFN-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6) and interleukin-18 (IL-18), as well as the presence of autoantibodies against interferon-α (IFN-α), interferon-λ (IFN-λ), C-C motif chemokine ligand 26 (CCL26), CXC motif chemokine ligand 12 (CXCL12), family with sequence similarity 19 (chemokine (C-C motif)-like) member A4 (FAM19A4), and C-C motif chemokine ligand 1 (CCL1). Interestingly, it has been described that the chronic cytokinemia is related to alterations of blood-brain barrier (BBB) permeability and induction of neurotoxicity. Furthermore, the generation of autoantibodies affects processes such as neurogenesis, neuronal repair, chemotaxis and the optimal microglia function. These observations support the notion that COVID-19 patients who survived the disease present neurological sequelae and neuropsychiatric disorders. The goal of this review is to explore the relationship between inflammatory and humoral immune markers and the major neurological damage manifested in post-COVID-19 patients.

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

“…As we have already discussed in this review article, long COVID could be induced by different mechanisms, including viral persistence that leads to chronic activation of the immune system and reactivation of latent viruses, the release of superantigens that over-activate the immune system, alteration in the gut microbiota, and damage to the gut and blood–brain barriers which collectively may result in autoimmunity and polyautoimmunity, including neuroautoimmunity [ 43 , 44 , 93 , 95 , 213 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 ].…”

COVID-19 as a polymorphic inflammatory spectrum of diseases: a review with focus on the brain

“…The neuroinflammatory basis of brain fog in COVID survivors has been compared to that of cancer-therapy induced cognitive impairment, with white matter microglial reactivity and consequent neural dysregulation (Fernández-Castañeda et al ., 2022). Chronic cytokinemia affecting BBB permeability, inducing neurotoxicity, plus the generation of autoantibodies resulting in the interference with neurogenesis, neuronal repair, chemotaxis and microglia function naturally would result in cognitive impairment (Elizalde-Díaz et al ., 2022).…”

What Role Does Microthrombosis Play in Long COVID?

“…67 Chronic cytokinemia and inflammation can alter BBB permeability and induce neurotoxicity, and autoantibodies generated can alter neurogenesis, neuronal repair, and the function of microglia. 68 Meanwhile, others showed that the spike protein could damage the endothelium and BBB, which leads to perivascular inflammation. 69 However, a large cohort study reported that the vaccination with the mRNA COVID-19 vaccine was not associated with thrombotic events, hemorrhage, thrombocytopenia, or brain injury.…”