Pangolin Footprints: Infectivity, Virulence and Long COVID

This review focuses on three closely related models that use protein intrinsic disorder to link the N and M to infectivity, virulence and, potentially, long COVID. While the models, Shell Disorder Models (SDMs), were initially created using computational and empirical molecular techniques based on protein intrinsic disorder, experimental and clinical data were continuously used for refinement and checked for reproducibility and reliability of SDMs. Interestingly, SDMs are uniquely able to link the potentially major cause of infectivity, virulence and long COVID under one coherent concept of protein intrinsic disorder. An example of this is SDMs' ability to provide a novel and coherent explanation for the differences in the virulence and infectivity of Omicron, SARS-CoV-1 and non-Omicron SARS-CoV-2. SARS-CoV-2 has been clinically shown to induce much greater shedding of infectious particles in patients. Curiously, all known SARS-CoV-2-related viruses, excluding SARS-CoV-1, have an abnormally hard outer shell (low M disorder), which is associated with burrowing animals, such as rabbits and pangolins. Evidence of a unique molecular and evolutionary relationship (“pangolin footprints”) between pangolins and COVID-19 is examined. SDMs suggest that this hard outer shell is responsible for the high infectivity of COVID-19 and , potentially, long COVID, as the hard M provides resistance to the antimicrobial enzymes found in the immune and respiratory systems. The implications could provide clues towards further research involving long COVID and infectivity, including possible reservoirs among macrophages. This also explains clinical observations of the persistence of the virus throughout the body months after infection. In the case of virulence, greater disorder in N contributes to more rapid replication by providing more efficient protein-protein binding. As a results, N disorder correlates with viral titer and therefore virulence and, to some extent, infectivity.