Persistence of SARS-CoV-2 in tissues leads to long COVID
Soon after its emergence at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a devastating wave of infections, hospitalizations, and deaths throughout the world. The SARS-CoV-2 infection causes coronavirus disease 2019 (COVID-19), which is associated with a wide range of clinical features and an unpredictable prognosis.
In a recent iScience journal pre-proof study, the authors present evidence that severe and persistent COVID-19 may share a common underlying immunologic feature. These findings could help identify patients at higher risk for long-term disease.
Study: Immune Response To SARS-Cov-2 In Severe Disease and Long COVID-19. Image Credit: Alexey Boldin / Shutterstock.com
SARS-CoV-2 infects multiple cell types after binding to the angiotensin-converting enzyme 2 (ACE2) receptor to gain cell entry. The ACE2 receptor is found on the surface of human respiratory tract cells, endothelial cells of the brain vasculature, smooth muscle cells of the blood vessel walls, as well as several types of cells within the gastrointestinal tract.
A considerable amount of research has focused on identifying the characteristics of SARS-CoV-2 infection and immune response. Modeling studies, for example, may be useful in predicting features that worsen COVID-19 by disturbing the immunologic environment and/or lead to a chronic illness known as post-acute sequelae of COVID-19 (PASC) or long Covid.
For example, some models have mimicked the spread of SARS-CoV-2 and the ensuing immune response within the lungs. Others have simulated the entry of SARS-CoV-2 and its replication in epithelial cells, followed by its spread through the circulation and the resulting systemic inflammation and clotting abnormalities.
In the current study, researchers examine how SARS-CoV-2 influences immune cells, cytokines, as well as other associated molecules in a network of interactions. The authors also discuss the effect of age-related factors on the severity of COVID-19.
IFN1 and DCs during infection
Type 1 interferon (IFN1) is a potent and early cytokine released by virally infected cells.
Dendritic cells (DCs) are primary immune cells that contribute to innate immunity. DC cells also suffer a loss of function with age, as demonstrated by their reduced ability to migrate and perform phagocytosis. Nevertheless, DCs will remain abundant and possess the same phenotype.
DCs transform into antigen-presenting cells (APCs) as they encounter viral antigens early in the course of infection; thus, DC levels rise rapidly after symptoms appear. APCs move into the local lymph nodes and proliferate, while also inducing naïve CD4 T-cells to differentiate into type 1 T helper cells (Th1) and T follicular helper cells (Tfh).
Prior research has shown a persistent decline in CD1c+ DCs up to seven months from the resolution of COVID-19, irrespective of the initial severity of disease.
Lymph node APCs and Tfh elicit the differentiation and proliferation of naïve B-cells into antibody-producing B-cells. These cells also promote the differentiation of naïve CD8 T-cells into cytotoxic T lymphocytes (CTL) that travel to the infection sites. CTLs kill infected cells, causing the count to dip sharply, while some of the newly produced virions within infected cells degrade at a much slower rate.
The model used in the current study predicted that low APC activity with impaired IFN1 responses were associated with an immediate rise in viral load that peaked two hours from infection. This was accompanied by higher persistent viral loads that were attributable to a rise in infected cells.
IFN1 signaling profoundly affects the suppression of viral replication in infected cells.”
The initial rise in viral load was followed by a decline. After reaching its lowest point, a slow rise to equilibrium occurred. The model also reported that IFN1 production is dysregulated by both SARS-CoV-2 and increasing age.
SARS-CoV-2 can evade antiviral responses triggered by IFN1. Since infected cells increase at a much faster rate than antigen-exposed APCs, IFN1 levels are predicted to decline simultaneously with low APC activity.
Chronic DC fall and PASC
The model also confirmed a decline in DCs over time as compared to healthy donors, thus leading to viral persistence and accompanying DC-induced inflammation. A rapid reduction in DC levels was observed in acute infection, with a subsequent increase to below baseline thereafter. The initial decline was attributed to the persistence of undetectable virus in the host.
In this model, the persistent decrease in DCs during acute infection, as well as after clinical resolution, is associated with chronic inflammation that manifests as PASC.
Similarly, in multisystem inflammatory syndrome in children (MIS-C), DCs appear to decline over time. These patients also exhibit fewer non-classical monocytes and one set of natural killer (NK) cells, thus indicating that this response also plays a role in the ongoing inflammation reported in children with prior SARS-CoV-2 infection.
Aging and COVID-19
With aging, immunologic potency is similarly lost. New infections are more common and latent infections may become active, both tending to worsen disease severity.
Notably, older people are disproportionately more likely to develop severe COVID-19. This could be explained by the presence of increasing IFN1-autoantibodies observed in patients above the age of 70 years, as well as in over one in five patients who succumbed to COVID-19.
The significant reduction in CTLs leads to persistence of infection, which may explain delayed viral clearance, even at moderate viral loads. Such a decline, even by one order of magnitude as seen with advancing age, did not affect the initial viral load.
Taken together, the foregoing findings indicate that all patients that are partially deficient in innate and/or acquired immunity because of inflammation and (immune) disease are also potentially at high risk of severe or even fatal COVID-19.”
With increasingly robust antiviral responses, the likelihood of complete viral clearance is enhanced. When SARS-CoV-2 persists at a steady rate, the risk of PASC increases.
The model suggests that even moderate SARS-CoV-2 loads are not cleared by many, if not most, patients with impaired immunity because their immune system fails to arrest viral replication. The persistence of SARS-CoV-2 over time has been reported in various earlier studies.
Thus, PASC is more likely the result of long-term persistence of SARS-CoV-2 in various tissues, rather than lingering effects from virus- or inflammation-induced tissue injury or thrombotic damage during the acute illness.
The chronic decrease in DCs is attributable to their migration into inflamed sites due to the presence of SARS-CoV-2 in long Covid. This prediction is supported by the accompanying decline in certain other innate immune cells.
In other words, the model suggests that “successful elimination of the virus depends on the capacity of the host immune response which is directly related to viral load.”
Future studies should also identify the infectivity of these patients and better PASC management strategies.