Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)

Abstract

COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein–Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.

SARS-CoV-2 neurotropism-induced anxiety/depression-like behaviors require Microglia activation

“…The number of dendritic spines was analyzed using plug-in SpineJ as described (32), with modifications. Spines were examined on dendrites of amygdala neurons that satisfied the following criteria: (1) presence of untruncated dendrites, (2) dark and consistent Golgi staining throughout all dendrites, and (3) visual separability from neighboring neurons. We counted the number of dendritic spines along the second dendritic branch at distances from 50 to 100 µm from the soma, in images obtained at 630× magnification.…”

“…This condition is commonly referred to as “long COVID,” also known as post-acute sequelae of SARS-CoV-2 infection (PASC) (1). While PASC initially attracted attention for its severe impact on older adults and those with underlying health concerns, it has since been clear that it may also occur in otherwise healthy young people, and it can develop after even a modest initial infection (2, 3). These long-lasting symptoms may persist for weeks or even months, posing challenges for healthcare providers and necessitating further research and support to address the long-term health consequences of the disease.…”

“…Among the enduring symptoms of PASC, neurological manifestations stand out prominently. Symptoms include cognitive difficulties, autonomic dysfunction, extreme fatigue, sleep disturbances, and mental health complications such as anxiety and depression (2, 3). The exact cause of these syndromes remains uncertain and is constantly being studied.…”

Intrinsic factors behind long‐COVID: I. Prevalence of the extracellular vesicles

“…However, persistence of such viral reservoirs may be also extended to the reactivation of latent pathogens, such as Epstein-Barr and herpes viruses in COVID-19 immune-deregulated tissue environment, SARS-CoV-2 interactions with the host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. 37,[56][57][58] On the other hand, prolonged post-COVID-19 symptoms, at least in some patients, may not be due to the persistent systemic immune inflammation 59 but may also occur due to the persistence of the viral antigens (e.g., Spike protein) 60 released from the active viral reservoirs that could cause postacute sequelae of COVID-19 (PASC) symptoms. 54 This possibility raised a question: why was the spike protein only detected in such PASC patients?.…”

Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

“…Encapsulated under the umbrella term "post-acute sequelae of SARS-CoV-2", the presence of new or ongoing symptoms more than 12 weeks after the acute infection is most commonly known as long COVID. [1][2][3] The spectrum of disease is extensive and variable.…”