Acquired lymphocytopenia can occur with a number of other disorders…The most common causes include:
- Protein-energy undernutrition
- HIV infection
- Certain other viral infections
- Lymphocytopenia is most often due to AIDS, and recently COVID-19, or undernutrition, but it also may be inherited or caused by various infections, drugs, or autoimmune disorders.
- Patients have recurrent viral, bacterial, fungal, or parasitic infections.
Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.
The hypothesis presented in the introduction states that Betacoronavirus, especially from the phylogenesis of Sarvecovirus, has the potential to cause an Acquired Immune Deficiency Syndrome as the main objective of persistence, potentiated by respiratory disease as a vehicle of rapid propagation and dissemination for its maturation affinity to infect lymphocytes.
As it has been exposed as well in the introduction the objective of this manuscript is to elevate this hypothesis to theory by performing an artificial intelligence-driven assay wrangling the latest full-length sequences reported to GISAID, correlating those genotypes with the protein complexes implied in the clinical scope of immunodeficiency.
However, infecting lymphocytes gives coronaviruses the ability to prolong the period of contagiousness by delaying the immune response, obviously, without causing a sudden fatality, as was the case in 2003 with SARS-CoV.
According to the results of the In-Silico, it is evidenced a natural evolution of the Betacoronavirus genera in order to balance propagation, infectivity and persistence. The main genotypes are evidenced in S/493, S/484, N/120 and N/152. Optimizing S/493 and S/484 means better airborne spread by infecting more the lungs and nasopharyngeal tissue meanwhile N/120 and N/152 genotypes reduce the Immune Response infecting lymphocytes allowing the virus to persist indefinitely, causing an Acquire Immune Deficiency Syndrome and other related syndromes to chronic viremia, especially with viruses that cause respiratory and blood diseases.
SARS-CoV-2 infection alters multiple housekeeping pathways associated with the immune system, infectious diseases, cell cycle, and cellular metabolism. SARS-CoV-2 exposure elicits alterations associated with ‘cellular responses to stress,’ which include changes in proteins involved in translation, mitochondrial metabolism, cytoskeleton remodeling, cellular senescence, and apoptosis.
We hereby demonstrated that CD4 and CD8 T cells from COVID-19 patients are more likely to die by apoptosis…The propensity of CD4 T cells to die is positively correlated with T cell lymphopenia and higher levels of CXCL10, both markers of disease severity…In addition to CD4, we found that CD8 T cells are also dying in severely-affected COVID-19 patients…The death of CD4 T cells may contribute to the greater likelihood of CD8 T cell apoptosis, since help from CD4 is crucial for the development of memory and effector CD8 T cells, given that helpless CD8 T cells are exhausted and shorter-lived cells.
We showed that SARS-CoV-2 infected T lymphocytes, mainly CD4 + T cells, in an ACE2-independent manner. SARS-CoV-2 infection triggered pronounced T-cell death, which potentially contributed to lymphopenia in patients with COVID-19. T-cell infection may also pose profound influences on patients. Infected T lymphocytes not only lost the ability to control viral infection but may also carry viruses to other parts of the body through blood circulation. In addition, this ACE2-independent infection mode may compromise the therapeutic effect of neutralizing antibodies targeting at spike-ACE2 binding. These may synergistically result in more severe infection outcomes in patients with COVID-19.
COVID-19 monocytes switch their gene expression profile from canonical innate immune to pro-thrombotic signatures and are functionally pro-thrombotic, both at baseline and following ex vivo stimulation with SARS-CoV-2. Transcriptionally, COVID-19 monocytes are characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation and clot formation. These results identify a potential mechanism by which monocyte dysfunction may contribute to COVID-19 pathology. [ie, infection causes genetic changes to drive clotting.
The initial inflammatory response mounted upon SARS-CoV-2 infection could potentially drive the changes in monocyte functionality, as inflammation is well known to activate the coagulation system57,58,59.
T-cell differentiation and acquisition of effector function is accomplished via Feed-forward control. In Covid-19, there is nonspecific and possibly bystander cytotoxic CD8+ T-cell activation which may be a double-edged sword, exerting damage to tissues and vital organs like the lung and pancreas (14, 30–32, 52, 53, 60).
Previous studies have reported the dysregulation of T cells during COVID-19 disease (63, 64) which was observed in this study as well. This is particularly important, since lymphopenia is a key feature of COVID-19 disease, and an altered lymphopenia is also observed in convalescent COVID-19 patients (65–67). A sharp decrease in the CD4+ and CD8+ T cell and a delayed T cell response were associated with higher COVID-19 severity…The lymphopenia observed in the COVID-19 patients is also characterized by the abnormal activation and exhaustion of the T cell.
As a bridge between innate immunity and adaptive immunity, DCs have important roles during virus invasion. The impaired function and reduced numbers of DCs are a catastrophe for the immune system during SARS-CoV-2 infection. The deficiency and dysfunction of DCs persist for several months after SARS-CoV-2 infection (113). Seven months after SARS-CoV-2 infection, the function of cDC2, as well as the number and IFNα production in pDCs, remains abnormal (113). This prolonged deficiency and dysfunction of DCs are associated with “post-acute COVID-19 syndrome” (“long-hauler syndrome”) in COVID-19 patients. It is characterized by persistent symptoms and/or delayed or long-term complications of SARS-CoV-2 infection beyond 4 weeks from symptom onset (141, 142). Scholars have reported that SARS-CoV-2 can persist in the intestines 7 months after symptom resolution (143). We postulate that the persistent tissue damage and presence of viral antigens which are hard to eliminate due to the deficiency and dysfunction of DCs may contribute to long-hauler syndrome in COVID-19 patients.
Superantigens have differing effects on immature and mature CD4 and CD8 T-cells (Figure 1). Superantigens can deplete thymocytes or immature T-cells, but can hyperstimulate mature, antigen-experienced CD4s and CD8s . After hyperstimulation by Staphylococcal enterotoxin B (SEB) superantigen, T-cells can enter a state of unresponsiveness known as ‘anergy’ where they fail to respond, and may sometimes subsequently enter apoptosis, or programmed cell death [39,40]. Not limited to only affecting CD4s by virtue of MHC II, superantigens can cause differentiation of naive T-cells and stimulation of CD8 memory cells from bystander activation via cytokines or from similar Vβ gene segments in their TCRs . Antigen-independent activation, or bystander activation of CD8 T-cells, is a well-studied consequence of viral infection [41,42,43].
Chronic exposure to superantigen could continually stimulate T-cells, keeping them in a perpetual state between anergy and hyperstimulation.
The COVID-19 pandemic has placed a huge strain on global healthcare and been a significant cause of increased morbidity and mortality, particularly in at-risk populations. This disease attacks the respiratory systems and causes significant immune dysregulation in affected patients creating a perfect opportunity for the development of invasive fungal disease (IFD). COVID-19 infection can instill a significant, poorly regulated pro-inflammatory response. Clinically induced immunosuppression or pro-inflammatory damage to mucosa facilitate the development of IFD and Aspergillus, Mucorales, and Candida infections have been regularly reported throughout the COVID-19 pandemic.
immune exhaustion likely plays a role and is well documented during COVID-19 infection, and host immunity, post even moderate disease, has been shown not to respond as expected to the presence of fungi. Given the complexity of this picture, a range and combination of factors will likely predispose individual COVID-19 patients to IFD, and a single predisposing profile is highly unlikely.
Here, we show that convalescent immune profiles after COVID-19 are different from those following infection with other coronaviruses…These findings suggest that SARS-CoV-2 infection exerts unique prolonged residual effects on the innate and adaptive immune systems and that this may be driving the symptomology known as LC…Our data indicate an ongoing, sustained inflammatory response following even mild-to-moderate acute COVID-19, which is not found following prevalent coronavirus infection.
This study found persistent changes to the peripheral immune system of SARS-CoV-2 convalescents until at least 6 months post-infection and identified a subset of these changes that were associated with long COVID. These changes to the peripheral immune system could have implications for how individuals recovering from SARS-CoV-2 infection respond to other infections encountered in this period and persistent immune activation may also exacerbate other chronic conditions.
We show evidence of persistent abnormalities in T cell populations following acute SARS-CoV-2 infection that are unrelated to commonly-reported post-COVID symptoms of ill-health. We included the full spectrum of disease, with severity ranging from mild disease managed in the community to requirement for ICU care, in order to capture the complete range of immune recovery. Specifically, we demonstrate an expansion of effector CD8+ T cells, activated CD4+ and CD8+ T cell populations and reduction in naïve CD4+ and CD8+ T cells at ten weeks following acute infection. Further analysis of COVID convalescence found that the expansion of activated CD8+ T lymphocytes is still evident at a median of 101 days following infection. We demonstrate that these changes are more marked in those with more severe initial disease. Equally notable is the recovery post-COVID of myeloid populations to levels similar to healthy controls. While we report persistent expansion of intermediate monocytes at 68 days, all monocyte populations have normalized at 101 days. Given that the myeloid compartment is significantly altered in acute infection, it is reassuring to see resolution of these changes at convalescence. Similarly, routine clinical measures of inflammation and coagulation also return to normal levels. The exception to this is D-dimers, which remain elevated in 18% of patients.
It will be illuminating to follow the prevalence of autoimmune disease in the general population in the post-pandemic era. This is particularly relevant given the concept of bystander T cell activation during viral infection. Bystander T cell recruitment has been described in both hepatitis A and influenza A infection (55, 56). While the activation of such T cells are considered beneficial in the control of acute infection and protective immunity, such non-specific immune activation has been associated with immunopathology, or host damage (57). Indeed, activation of both CD4+ and CD8+ lymphocytes in acute infection has been associated with the development of a wide array of autoimmune conditions (58, 59).
Our data detail lymphocyte alterations in previously hospitalized COVID-19 patients up to 6 months following hospital discharge…We propose that alterations in B and T cell function following hospitalization with COVID-19 could affect longer-term immunity and contribute to some persistent symptoms observed in convalescent COVID-19 patients….Our study therefore identifies lymphocyte changes in convalescent COVID-19 patients, which could have longer-term effects on subsequent anti-pathogen or auto-inflammatory responses.
We found the genes related to metabolism and metabolism products were dysregulated. Additionally, we found that the ROS of B cells in recovered patients was increased, which indicates an increased cell metabolism of B cells in recovered patients. Previous studies reported that metabolite and lipid alterations are shown apparent correlation with the course of disease in these COVID-19 patients, suggesting that the development of COVID-19 affected whole-body metabolism of the patients.
Dendritic cells (DCs) recognize viral infections and trigger innate and adaptive antiviral immunity. COVID-19 severity is greatly influenced by the host immune response and modulation of DC generation and function after SARS-CoV-2 infection could play an important role in this disease. This study identifies a long-lasting reduction of DCs in the blood of COVID-19 patients and a functional impairment of these cells…Depletion and functional impairment of DCs beyond the acute phase of the disease may have consequences for susceptibility to secondary infections and clinical management of COVID-19 patients.
T cells play a vital role in viral clearance, with CD8+ cytotoxic T cells (CTLs) capable of secreting an array of molecules such as perforin, granzymes, and IFN-γ to eradicate viruses from the host (13). At the same time, CD4+ helper T cells (Th) can assist cytotoxic T cells and B cells and enhance their ability to clear pathogen (14). However, persistent stimulation by the virus may induce T cell exhaustion, leading to loss of cytokine production and reduced function (15, 16).
T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer.
Taken together, we conclude that T cells are decreased and exhausted in patients with COVID-19.