As we know well by now, long covid patients present a multitude of symptoms that expand from respiratory and musculoskeletal to neuropsychiatric for more than four weeks after diagnosis, even lasting many months in a lot of cases. However, what is triggering this variety of symptoms and why?
Can we say that all of it is due to the virus, or do the health and genetic background of these patients play a part as well? In an attempt to answer these questions and to explain the idea of having molecular subtypes of Long Covid, we need to go back a bit to the basics of immunology.
A brief summary of an immunological response
There are three lines of defence when our body encounters a pathogen. The first and second lines of defence are non-specific. In the first, the skin, the secretion of acid and mucus work as barriers to keep pathogens out or to kill them. In the second, an inflammatory response evolves, caused by the reaction of certain cells of the immune system against the pathogen. Such cells are phagocytes, macrophages and dendritic cells, which engulf the pathogen, and natural killer cells (NK), which, as the name suggests, kill abnormal cells. These lines of defence are our innate immunity. The inflammatory process is provoked by a release of histamine that will increase the permeability of capillaries (thin blood vessels), which in turn enhance migration of phagocytes and rapid delivery of blood-clotting chemicals.
If this defence is not sufficient, the specific cell response is triggered. This involves T cells and B cells, and they proliferate in the presence of the pathogen to promote an efficient response. This defence is known as adaptive immunity. T cells have specific complementary receptors to antigens (molecules on the surface of pathogens) and therefore they are able to present antigens to B cells, which will then produce specific antibodies against the pathogen.
How does one cell talk to another? It does so by releasing cell-signalling proteins called cytokines. These attract other immune cells to the site of inflammation/invasion.
Sars-CoV-2’s role in our innate immunity
One: Plasmacytoid dendritic cells (pDCs), which recognise the virus via a receptor known as Toll-like receptor 7 (TLR7) along with other cells, which recognise the virus via TLR3 and TLR8 receptors. Alveolar macrophages survey the lumen of the respiratory tract and also provide the first line of defence.
Two: RNA is detected by sensors in the cell, such as RIG-I-like receptors (RLRs). Once these receptors – TLRs and RLRs – are engaged in the surface of the cells, signalling occurs inside the cell, which activates inflammatory cytokines such as interferons (IFNs) and nuclear factor kB (NF-kB)-dependent pro-inflammatory cytokines and chemokines.
Sars-CoV-2 manages to escape this line of defence by producing viral proteins that block these signalling pathways that lead to the production of interferon and IFN-stimulated genes (ISGs). The virus also induces low levels of sentinel cells, including pDCs and conventional DCs (cDCs), in the blood and lungs. NK cells from patients with a severe form of Covid-19 do not function properly due to high levels of transforming growth factor-b (TGFb). TGFb has an immunomodulatory role in the immune system as an immunosuppressive agent. It inhibits proliferation, differentiation, and function of various cells, including NK cells.
Sars-CoV-2’s role in our adaptive immunity
Antibodies neutralise the virus by impairing the binding of the viral spike (S) protein to the angiotensin-converting enzyme 2 (ACE2) receptor, and promote effector function by binding to the complement and Fc receptors. ACE2 plays a role in the cardiovascular and renal function and fertility. Complement is a cascade of proteins that interact with one another under a strict regulated process to complement the lytic function of antibodies. Lytic function is the destruction of pathogens by lysis, which creates holes in the cell wall. Fc receptors bind to invariable regions of the antibody – Fc portions – that are responsible for the effector function of the antibody.
The quality and quantity of the antibody response depends on the amount of antigen and the duration of the collaboration between proliferating antigen-specific B cells, T follicular helper cells, and the specialised follicular dendritic cells. This T-dependent humoral immunity is responsible for the high-affinity antibody-secreting plasma cells and memory B cells that ensure sustained immune protection and rapid-recall responses against previously encountered foreign antigens. We know that the different variants of concern (VOCs) have mutations in specific parts of the S protein that collaborate with the neutralising antibodies not recognising the S protein anymore.
T cells are subdivided into two sets: CD4+ and CD8+. Both sets recognise structural and non-structural proteins of the virus. A study in rhesus macaques showed that depletion of CD8+ cells partially abrogated the protective efficacy of natural immunity against re-infection with the virus, indicating that cellular immune responses may contribute to protection if antibody responses are suboptimal.
Influence of immune response and pathology developed
During the infection with Sars-CoV-2, There is a first viral phase that is characterised by replication of the virus, which then induces tissue damage. The extent of this damage will determine the pathogenesis of the second phase, which is characterised by the recruitment of immune effector cells, causing a local and systemic inflammatory response that persists even after viral clearance.
Pulmonary disease develops because of vascular permeability excess that leads to the deposition of microthrombi (very small blood clots). The other pathogenesis observed in the intestine, heart, liver, and kidneys seem to be multifactorial because of direct viral injury to tissues, vessels, or neurons as well as cytokine release, auto-antibodies-induced tissue damage, or gut dysbiosis (imbalance of bacteria) in the case of gastrointestinal symptoms.
The molecular subtypes of Long Covid and the different pathologies
It is worthwhile to mention, first of all, that there are multiple early biological factors that anticipate Long Covid. The post-acute Covid sequelae is associated with autoantibodies, Epstein-Barr Virus (EBV) viremia, Sars-CoV-2 RNAemia, reactivation of latent viruses in the onset of the disease, and other comorbidities. All of these can explain the chronically elevated IFNs and cytokines and they all should be used as good biomarkers for not only pre-diagnosis but also for the treatment of Long Covid.
The idea of molecular subtypes of Long Covid comes from the fact that dysregulation of monocyte/macrophage-related cytokines (pro-inflammatory and pro-fibrotic) is marked by Monocyte Chemoattractant Protein-1 (MCP-1: plays a fundamental role in the migration and infiltration of monocytes/macrophages), interleukin-8 (IL-8: attracts and activates neutrophils, which contain granule enzymes) and persistence of high levels of interleukin-5 (IL-5: role in the maturation of eosinophils that degranulate to kill extra-cellular parasites) and interleukin-17F (IL-17F: inflammatory cytokine involved in the recruitment of other cytokines). However, these factors are not correlated to the presence or levels of Sars-CoV-2 spike protein (S1). This suggests that an independent subset of Long Covid patients may exist.
These cytokines are all pro-fibrotic in lung, liver, and heart, and might explain the lasting of tissue damage in Long Covid patients. S1 levels in these patients seem to correlate only with antibodies against the virus.
The figure below, based on a review article by Mehandru et. al., summarises the roles of the different possible immunological responses in the development of the different pathologies and how all of these could shed a light on future treatments.
Above: Possible mechanisms for the development of the different forms of Covid-19 and strategies for future therapy. Protein expression: genetic information in DNA is passed to RNA, which then codes for the different proteins of an organism. Immune Tolerance: regulated unresponsiveness of the immune system to self antigens or against determined antigens.
Once again, if research funds are directed into targeted therapy, and data collection from Long Covid patient groups based on their symptoms is allowed in the UK, a huge step forward towards treatment would be achieved.
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