SARS-CoV-2-Induced Immunosuppression: A Molecular Mimicry Syndrome

Abstract

Background Contrary to immunological expectations, decay of adaptive responses against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) characterizes recovered patients compared with patients who had a severe disease course or died following SARS-CoV-2 infection. This raises the question of the causes of the virus-induced immune immunosuppression. Searching for molecular link(s) between SARS-CoV-2 immunization and the decay of the adaptive immune responses, SARS-CoV-2 proteome was analyzed for molecular mimicry with human proteins related to immunodeficiency. The aim was to verify the possibility of cross-reactions capable of destroying the adaptive immune response triggered by SARS-CoV-2. Materials and Methods Human immunodeficiency–related proteins were collected from UniProt database and analyzed for sharing of minimal immune determinants with the SARS-CoV-2 proteome. Results Molecular mimicry and consequent potential cross-reactivity exist between SARS-CoV-2 proteome and human immunoregulatory proteins such as nuclear factor kappa B (NFKB), and variable diversity joining V(D)J recombination-activating gene (RAG). Conclusion The data (1) support molecular mimicry and the associated potential cross-reactivity as a mechanism that can underlie self-reactivity against proteins involved in B- and T-cells activation/development, and (2) suggest that the extent of the immunosuppression is dictated by the extent of the immune responses themselves. The higher the titer of the immune responses triggered by SARS-CoV-2 immunization, the more severe can be the cross-reactions against the human immunodeficiency–related proteins, the more severe the immunosuppression. Hence, SARS-CoV-2-induced immunosuppression can be defined as a molecular mimicry syndrome. Clinically, the data imply that booster doses of SARS-CoV-2 vaccines may have opposite results to those expected.

Effect of Glucocorticoids on the Development of COVID-19-Associated Pulmonary Aspergillosis: A Meta-Analysis of 21 Studies and 4972 Patients

“…5,14,15 The direct damage to the respiratory epithelium due to hyperinflammation and an immunosuppressed state due to immune dysregulation together create an optimal opportunity for the occurrence of CAPA in COVID-19 patients who were immunocompetent before SARS-CoV-2 infection and had no GC pretreatment or traditional risk factors such as neutropenia or immunodeficiency. [46][47][48] These pathological features of COVID-19 patients concur with our results of CAPA in patients with no GC therapy treatment. A recent meta-analysis and several research studies reporting CAPA in immunocompetent patients with no underlying risk factors suggest that severe COVID-19 is by itself a risk factor for the development of CAPA.…”

SARS-CoV-2: The Self-Nonself Issue and Diagnostic Tests

“…In closing, it is also worth noting that, in agreement with reports from this laboratory, 8 10 11 42 43 44 Khavinson et al 45 have recently described an intense peptide sharing between almost all the SARS-CoV-2 proteins and human proteins, with hepta- and octamers scattered along the entire length of the SARS-CoV-2 spike protein molecule, thus furtherly supporting the possibility of cross-reactivity and consequent autoimmunity between SARS-CoV-2 and the human host. 7…”

Effect of glucocorticoids on the development of COVID‐19‐associated pulmonary aspergillosis: A meta‐analysis of 21 studies and 5174 patients

“…5,14,15 The direct damage to the respiratory epithelium due to hyperinflammation and an immunosuppressed state due to immune dysregulation together create an optimal opportunity for the occurrence of CAPA in COVID-19 patients who were immunocompetent before SARS-CoV-2 infection and had no GC pretreatment or traditional risk factors such as neutropenia or immunodeficiency. [46][47][48] These pathological features of COVID-19 patients concur with our results of CAPA in patients with no GC therapy treatment. A recent metaanalysis and several research studies reporting CAPA in immunocompetent patients with no underlying risk factors suggest that severe COVID-19 is by itself a risk factor for the development of CAPA.…”

“…SARS‐CoV‐2 infection targets the respiratory system and causes significant immune dysregulation involving hyperinflammation (cytokine storm) and depletion of CD4+ and CD8+ T cells and NK cells 5,14,15 . The direct damage to the respiratory epithelium due to hyperinflammation and an immunosuppressed state due to immune dysregulation together create an optimal opportunity for the occurrence of CAPA in COVID‐19 patients who were immunocompetent before SARS‐CoV‐2 infection and had no GC pretreatment or traditional risk factors such as neutropenia or immunodeficiency 46–48 . These pathological features of COVID‐19 patients concur with our results of CAPA in patients with no GC therapy treatment.…”