Frontiers | Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms

Hoffmann et al., 2020). Viral cell entry additionally requires priming of the spike protein by cellular serine proteases such as TMPRSS2 and TMPRSS4nHighlight:SARS-CoV-2 employs a number of mechanisms to disable and evade the host immune responsenHighlight:These include the ability to replicate within double-membrane vesicles that are not detected by host pathogen pattern recognition receptors (Taefehshokr et al., 2020). SARS-CoV-2 also dysregulates the host interferon response (Ribero et al., 2020). Interferons are cytokines secreted by host cells in response to viral infection. They bind to cell surface receptors and act as transcription factors, regulating the expression of hundreds of genes whose protein products target viruses at many levelsnHighlight:better survive by rendering the host innate immune response inefficient.nHighlight:hyperinflammation, and in some cases, a cytokine storm syndromenHighlight:Severe COVID-19 can also result in functional exhaustion and decreased numbers of T lymphocytes, (particularly CD4+ T cells, CD8+ T cells) and natural killer cellsnHighlight:Impaired T cell responses can result from deficient interferon production driven by SARS-CoV-2, as interferons promote the survival and effector functions of T cells.nHighlight:thromboinflammation, dysregulation of the renin–angiotensin–aldosterone system, and endothelial cell damagenHighlight:SARS-CoV-2 may drive chronic symptoms by persisting in certain body sites or tissue reservoirs after acute infection.nHighlight:some patients infected with SARS-CoV-2 do not successfully clear the virus over long periods of time (Liotti et al., 2020; Sun et al., 2020; Vibholm et al., 2021)nHighlight:Vibholm et al. (2021nHighlight:PCR positive group displayed SARS-CoV-2-specific CD8 T-cell responses of significantly increased breadth and magnitude, leading the team to suggest that such subjects might still harbor replicating virus.nHighlight:identified SARS-CoV-2 RNA and protein in 7 of 14 of the biopsy samples obtained from asymptomatic COVID-19 patients with negative nasal-swab PCR, at an average of 4 months after acute infection.nHighlight:Immunosuppression may facilitate SARS-CoV-2 persistencenHighlight:in some patients, SARS-CoV-2 may be able to evade the immune response in a manner that allows it to drive persistent symptoms.nHighlight:some recent COVID-19 variants have spike protein mutations that allow for increased immune evasion, including resistance to neutralizing antibodies or escape from HLA-restricted cellular immunitynHighlight:Persistence of SARS-CoV-2 in some patients with PASC symptoms is not unexpected. The literature is replete with examples of single-stranded RNA virus persistence, spanning decades of research on samples obtained from living human patients, autopsy studies, and animal studiesnHighlight:hepatitis C virus (HCV)nHighlight:Dozens of studies show coronaviruses capable of persistence, with some coronaviruses tied to chronic disease development nHighlight:influenza virus AnHighlight:enterovirusesnHighlight:Zika virusnHighlight:EbolanHighlight:no firm consensus on whether patients harboring SARS-CoV-2 RNA or protein for long periods of time remain contagious. Very preliminary data suggest that such patients do not infect others.nHighlight:virus may dysregulate the host immune response during acute COVID-19 in a manner that allows previously harbored pathogens to reactivate, infect new body sites, and drive new chronic symptomsnSticky notes:Key to reactivation argumentnHighlight:humans accumulate persistent viruses over the course of a lifetime. These viruses generally persist in dormant, latent, or non-cytolytic forms, but may reactivate under conditions of stress or immunosuppressionnHighlight:Epstein-Barr virus (EBV), herpes simplex virus (HSV-1), varicella zoster virus (VZV), cytomegalovirus (CMV), human herpes virus 6-A/B (HHV6-A/B), human herpes virus 7 (HHV-7), hepatitis C virus (HCV), human papilloma virus (HPV), adeno-associated virus and RNA viruses including respiratory syncytial virus (RSV), and parainfluenza virus 3. Human coronavirus 229-E was identifiednHighlight:This suggests that persistent viruses are normally kept “in check” by the host immune system.nSticky notes:ImmunoeditingnHighlight:if the immune response is weakened, challenged, or dysregulated, the same viruses may change their gene expression or protein production to drive a range of persistent symptoms.nSticky notes:Cancer and viruses here behaving very similarly—immunoeditingnHighlight:reported VZV and HSV-1 reactivation in a patient with severe COVIDnSticky notes:ReactivationnHighlight:reactivation of HHV-6, HHV-7, and EBV in patients with acute COVID-19nSticky notes:ReactivationnHighlight:EBV, CMV, and Kaposi’s sarcoma-associated herpesvirus (KSHV) are recognized as cancer-causing or oncogenic virusesnHighlight:These and related viruses such as hepatitis B virus (HBV), HCV, and papillomavirus can drive diseases like cancer by expressing proteins that directly modulate human gene expression, the human immune response, host cell metabolism, and even the host epigenetic environment to promote a range of pathological processesnSticky notes:Viral reactivation drives oncogenesisnHighlight:all viruses, and many bacterial and fungal pathogens, hijack the metabolism of the cells they infect in order to gain amino acids, lipids, and other substrates required for their own replication and survivalnHighlight:dysregulate oxidative phosphorylation levels and even regulation of cell death.nHighlight:under conditions of immunosuppression, they can move out of blood, saliva, or tissue and deeper into the CNS.nSticky notes:IFN 1 suppression and T cell exhaustionnHighlight:HHV-6 was shown to accelerate neuroinflammationnHighlight:life-long need to control the virulence of such pathogens places a significant burden on the human immune systemn]]>