Long COVID: Molecular Mechanism Involving Abnormally Hard M and a Viral Reservoir Within Phagocytes

Abstract

Highlights What are the main findings? A structural disorder analysis of the abnormally hard outer shell (M) seen in SARS-CoV-2 with comparison to the M disorder and structures of SARS-CoV-1 and NL63 reveals molecular characteristics that can explain the differences in clinical manifestations of all three viruses. The 3D mechanism of the abnormally hard M and its resistance to digestive enzymes upon phagocytosis suggests a viral reservoir among phagocytes, which can account for the multitude of long COVID clinical manifestations that include immune damage, cardiovascular outcomes, brain fog and the presence of NETs and microclots found in the blood of long COVID patients. What are the implications of the main findings? An understanding of mechanism of rigidity of SARS-CoV-2 M can provide us with insights into the underlying molecular cause of long COVID and the nature of the viral reservoir. The knowledge of how a viral reservoir is formed among phagocytes can lead to more targeted treatments that involve the search for drugs that interact and penetrate phagocytes more efficiently. Abstract: It has been previously suggested that long COVID arises from the abnormally hard outer shell, M, and phagocytes are the viral reservoir because attempts to engulf and subsequent digestion upon phagocytosis. When the phagocyte fails to digest the virus as the result of the hard M, the virus would then dwell in the phagocyte. In this paper, a structural disorder analysis is conducted with comparison among the M proteins of SARS-CoV-1/2 and HCoV-NL63. The study highlights the mechanism of rigidity in SARS-CoV-2 M, not found in SARS-CoV-1 and NL63 M. The proposed mechanism provides insight into the way SARS-CoV-2 M prevents destructive enzymes and water from entering the pore-like structure. SARS-CoV-1 and NL63 M disorder and structures are found, using two inherently different AI tools, to be qualitatively and quantitatively different from SARSCoV-2. These could account for the various clinical manifestations of the three viruses including the presence of a viral reservoir within phagocytes especially among long COVID patients and the difference between long COVID and long SARS. It can also account for the formation of neutrophil extracellular traps (NETs) and microclots in the bloodstream of long COVID patients. A viral reservoir within phagocytes can also explain the reason for many other long COVID manifestations such the weakened immune system, brain fog and cardiovascular damages as professional and non-professional phagocytes encompass a large variety of cells.