From Cell to Symptoms: The Role of SARS-CoV-2 Cytopathic Effects in the Pathogenesis of COVID-19 and Long COVID

Abstract

Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection triggers various events from molecular to tissue level, which in turn is given by the intrinsic characteristics of each patient. Given the molecular diversity characteristic of each cellular phenotype, the possible cytopathic, tissue and clinical effects are difficult to predict, which determines the heterogeneity of COVID-19 symptoms. The purpose of this article is to provide a comprehensive review of the cytopathic effects of SARS-CoV-2 on various cell types, focusing on the development of COVID-19, which in turn may lead, in some patients, to a persistence of symptoms after recovery from the disease, a condition known as long COVID. We describe the molecular mechanisms underlying virus-host interactions, including alterations in protein expression, intracellular signaling pathways, and immune responses. In particular, the article highlights the potential impact of these cytopathies on cellular function and clinical outcomes, such as immune dysregulation, neuropsychiatric disorders, and organ damage. The article concludes by discussing future directions for research and implications for the management and treatment of COVID-19 and long COVID.

SARS‐CoV‐2, periodontal pathogens, and host factors: The trinity of oral post‐acute sequelae of COVID‐19

“…For example, SARS-CoV-2 open reading frame6 and 8 proteins specifically downregulate MHC-I molecule expression. [298][299][300][301] As stated above, higher inflammation also induces ACE2 expression in inflamed gingiva to provide a conducive microenvironment for virus adherence and entry, 16 ORF3b and ORF6 inhibit IRF3 translocation to the nucleus. [302][303][304] In addition, a reduction in number through autophagy or apoptosis, exhaustion, or anergic may occur if viral infection persists.…”

“…This manifests as a depressed clearance of virus such as SARS‐COV‐2. For example, SARS‐CoV‐2 open reading frame6 and 8 proteins specifically downregulate MHC‐I molecule expression 298–301 . As stated above, higher inflammation also induces ACE2 expression in inflamed gingiva to provide a conducive microenvironment for virus adherence and entry, 16 which in turn, will amplify inflammatory signals.…”

MULTIMORBIDITY, MORBIDITIES, AND LONG COVID – findings of the Sulcovid longitudinal study

“…One of the most distinguished mechanisms in the literature for the emergence of long COVID is mitochondrial dysfunction, which can have cytopathic effects on the central nervous, respiratory, circulatory, immune, renal, and digestive systems [29]. After infection with SARS-CoV-2, the binding between a viral protein and mitochondrial complexes can lead to mitochondrial dysfunction, which in turn increases oxidative stress and causes immune cells to overreact, this exacerbated reaction leads to in ammation and potentially persistent symptoms of COVID-19 [5,6].…”

Exploring the Pathophysiology of Long COVID: The Central Role of Low-Grade Inflammation and Multisystem Involvement

“…Despite the diversity of their molecular mechanisms, viral invasions tend to follow a limited set of typical infection scenarios, which include parasitization and a range of host responses. Notably, viral infections induce all standard processes and outcomes of cellular stress in the target cells they infect [ 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. Additionally, viral infections are implicated in all major types of general pathological processes, ranging from various forms of inflammation to tumor growth, as seen with oncoviruses.…”