Long COVID: A proposed hypothesis-driven model of viral persistence for the pathophysiology of the syndrome

Abstract

Background: Long COVID (coronavirus disease 2019) syndrome includes a group of patients who, after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibit lingering mild-to-moderate symptoms and develop medical complications that can have lasting health problems. In this report, we propose a model for the pathophysiology of the long COVID presentation based on increased proinflammatory cytokine production that results from the persistence of the SARS-CoV-2 virus or one of its molecular components. Associated with this hyperproduction of inflammatory cytokines is a heightened activity of nuclear factor κ B (NF-κB) and p38 mitogen-activated protein kinase signaling pathways that regulate cytokine production. Objective: The purpose of the present report was to review the causes of long COVID syndrome and suggest ways that can provide a basis for a better understanding of the clinical symptomatology for the of improved diagnostic and therapeutic procedures for the condition. Methods: Extensive research was conducted in medical literature data bases by applying terms such as "long COVID" associated with "persistence of the SARS-CoV-2 virus" "spike protein' "COVID-19" and "biologic therapies." Results and Conclusions: In this model of the long COVID syndrome, the persistence of SARS-CoV-2 is hypothesized to trigger a dysregulated immune system with subsequent heightened release of proinflammatory cytokines that lead to chronic low-grade inflammation and multiorgan symptomatology. The condition seems to have a genetic basis, which predisposes individuals to have a diminished immunologic capacity to completely clear the virus, with residual parts of the virus persisting. This persistence of virus and resultant hyperproduction of proinflammatory cytokines are proposed to form the basis of the syndrome.

Figure 1.

Schematic representation of the total immune capability of the host based on efficiency of elimination of foreign matter. Reproduced with permission from Ref. .

Figure 2.

Schematic representation of the innate and adaptive immune responses after the encounter of a nonimmune host with a chronic microbial pathogen, showing evasion of the immune response and the persistence of the bacterial pathogen with immunopathology. Reproduced and modified with permission from Ref. .

Figure 3.

Schematic representation of the NF-κB signaling pathway during healthy and COVID-19 conditions in association with the production of proinflammatory factors. (A) The NF-κB signaling pathway during usual conditions, showing the sequential effects of phosphorylation and the usual production of proinflammatory cytokines. (B) The NF-κB signaling pathway during COVID-19 infection, showing the effects of blockage by inhibitors that block the phosphorylation of IKK-β and inhibit production of proinflammatory cytokines. NF-κB = nuclear factor κ B; COVID-19 = coronavirus disease 2019; IKK-β = IκB kinase-β. Reproduced with permission from Ref. .

Figure 4.

Schematic representation of the yin and yang inflammatory response carried out by the NF-κB signaling pathway. Intranuclear signal transduction can proceed via two pathways; pathway NF-κB can progress to enhance and perpetuate the inflammatory response by triggering the expression of proinflammatory cytokines, and pathway nuclear factor-erythroid factor 2–related factor 2 (Nrf2) activation through oxidation of Kelch-like ECH-associated protein 1 (Keap1) by peroxidases and other anti-inflammatory proteins can dampens proinflammatory signaling. NF-κB = nuclear factor κ B. Reproduced with permission from Ref. .