Potential anti-tumor immune response mechanisms of SARS-CoV-2 in lymphomas: can the devil be converted into a boon? (preprint)

Recently, two cases of complete remission of classical Hodgkin lymphoma (cHL) and follicular lymphoma (FL) after SARS-CoV-2 infection were reported. However, the precise molecular mechanism of this rare event is yet to be understood. Here, we hypothesize a potential anti-tumor immune response of SARS-CoV-2 and based on computational approach show that (i) SARS-CoV-2 Spike-RBD may bind to extracellular domains of CD15, CD27, CD45, and CD152 receptors of cHL or FL, (ii) upon internalization, SARS-CoV-2 membrane (M) protein and Orf3a may bind to gamma-tubulin complex component 3 (GCP3) at its tubulin gamma-1 chain (TUBG1) binding site, (iii) M protein may also interact with TUBG1 blocking its binding to GCP3, (iv) both M and Orf3a may render the GCP2-GCP3 lateral binding where M possibly interacts with GCP2 at its GCP3 binding site and Orf3a to GCP3 at its GCP2 interacting residues, (v) interactions of M and Orf3a with these gamma-tubulin ring complex components potentially block the initial process of microtubule nucleation, leading to cell cycle arrest and apoptosis, (vi) Spike-RBD may also interact with and block PD-1 signaling similar to pembrolizumab and nivolumab like monoclonal antibodies and may induce B-cell apoptosis and remission, (vii) finally, the TRADD interacting PVQLSY motif of Epstein-Barr virus LMP-1, that is responsible for NF-kB mediated oncogenesis, potentially interacts with SARS-CoV-2 Mpro, nsp7, nsp10, and Spike proteins and may regulate the LMP-1 mediated cell proliferation. Taken together, our results suggest a possible therapeutic potential of SARS-CoV-2 in proliferative disorders.

Computational, Experimental, and Clinical Evidence for a Specific but Peculiar Evolutionary Nature of (COVID-19) SARS-CoV-2 (preprint)

SARS-CoV-2 was empirically and computationally found to be of a specific but peculiar evolution. Shell disorder models found that the outer shell (M protein) of SARS-CoV-2 to be among the hardest in its CoV family. The hard outer shell (low M percentage of disorder (PID)) is likely to be related to the SARS-CoV-2 resistance to the antimicrobial enzymes in saliva and mucus, and be responsible for the high-level of viral shedding which has been observed clinically. Experimental studies have also shown that SARS-CoV-2 is more resilient in the environment than many other CoVs, including SARS-CoV-1. Another aspect of the shell disorder models predicts that SARS-CoV-1 is more virulent than SARS-CoV-2 because of higher inner shell disorder (N PID) that helps SARS-CoV-1 replicate faster in vital organs despite being of lesser viral loads in the saliva and mucus, unlike SARS-CoV-2. This has been reaffirmed experimentally, where higher levels (50 folds) of infectious particles were detected in the SARS-CoV-1 samples in comparison with those of SARS-CoV-2. The hard outer shell of SARS-CoV-2 has been found to be associated with burrowing animals, particularly pangolins, which are often in contact with buried feces. For these reasons, the M protein is highly conserved among close relatives of SARS-CoV-2. The phylogenetic tree using M, unlike the genome-wide one, shows that pangolin-CoVs are more closely related to SARS-CoV-2 than bat-RaTG13. Previous phylogenetic studies may have been confused by recombinations that are usually poorly handled. According to the shell disorder models based on the N PID, an attenuated COVID-19 strain is likely to have entered humans via pangolins in 2017 or before, which provides the virus enough time to adapt to humans. This could explain why the SARS-CoV-2 S protein is highly adapted to the human ACE-2. The specific but peculiar evolution has a wide range of clinical, immunological, and epidemiological implications.

Understanding Structural Malleability of the SARS-CoV-2 Proteins and their Relation to the Comorbidities (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of the coronavirus disease (CoVID-19), is a part of the β-coronaviridae family. In comparison with two other members of this family of coronaviruses infecting humans (SARS-CoV and Middle East Respiratory Syndrome (MERS) CoV), SARS-CoV-2 showed the most severe effects on the entire Earth population causing world-wide CoVID-19 pandemic. SARS-CoV-2 contains five major protein classes, such as four structural proteins (Nucleocapsid (N), Membrane (M), Envelop (E), and Spike Glycoprotein (S)) and Replicase polyproteins (R), which are synthesized as two polyproteins (ORF1a and ORF1ab) that are subsequently processed into 12 nonstructural proteins by three viral proteases. All these proteins share high sequence similarity with their SARS-CoV counterparts. Due to the severity of the current situation, most of the SARS-CoV-2-related research is focused on finding therapeutic solutions and the analysis of comorbidities during infection. However, studies on the peculiarities of the amino acid sequences of viral protein classes and their structure space analysis throughout the evolutionary time-frame are limited. At the same time, due to their structural malleability, viral proteins can be directly or indirectly associated with the dysfunctionality of the host cell proteins, which may lead to comorbidities during the infection and at the post infection stage. To fill these gaps, we conducted the evolutionary sequence-structure analysis of the viral protein classes to evaluate the rate of their evolutionary malleability. We also looked at the intrinsic disorder propensities of these viral proteins and confirmed that although they typically do not have long intrinsically disordered regions (IDRs), all of them have at least some levels of intrinsic disorder. Furthermore, short IDRs found in viral proteins are extremely effective and prioritize the proteins for host cell interactions, which may lead to host cell dysfunction. Next, the associations of viral proteins with the host cell proteins were studied, and a list of diseases which are associated with such host cell proteins was developed. Other than the usual set of diseases, we have identified some maladies, which may happen after the recovery from the infections. Comparison of the expression rates of the host cell proteins during the diseases suggested the existence of two distinct classes. First class includes proteins, which are directly associated with certain sets of diseases, where they have shared similar activities. Second class is related to the cytokine storm-mediated pro-inflammation (already known for its role in acute respiratory distress syndrome, ARDS), and neuroinflammation may trigger some of the neurological malignancies and neurodegenerative and neuropsychiatric diseases. Finally, since the transmembrane serine protease 2 (TMPRSS2), which is one of the leading proteins associated with the viral uptake, is an androgen-mediated protein, our study suggested that males and postmenopausal females can be more susceptible to the SARS-CoV-2 infection.

A Novel Strategy for the Development of Vaccines for SARS-CoV-2 (COVID-19) and Other Viruses Using AI and Viral Shell Disorder (preprint)

A model that predicts levels of coronavirus (CoV) respiratory/fecal-oral transmission potentials based on the outer shell hardness has been built using neural network (artificial intelligence, AI) analysis of the percentage of disorder (PID) in the nucleocapsid, N, and membrane, M, proteins of the inner and outer viral shells, respectively. Based mainly on the PID of N, SARS-CoV-2 is categorized as having intermediate levels of both respiratory and fecal oral transmission potential. Related to this, other studies have found strong positive correlations between virulence and inner shell disorder among numerous viruses, including Nipah, Ebola, and Dengue viruses. There is some evidence that this is also true for SARS-CoV-2 and SARS-CoV, which have N PIDs of 48% and 50%, and are characterized by case-fatality rates of 7.1% and 10.9%, respectively. The link between levels of respiratory transmission and virulence lies in viral load of body fluids and organ respectively. A virus can be infectious via respiratory modes only if the viral loads in saliva and mucus exceed certain minima. Likewise, a person may die, if the viral load is too high especially in viral organs. Inner shell proteins of viruses play important roles in the replication of viruses, and structural disorder enhances these roles by providing greater efficiency in protein-protein/DNA/RNA/lipid binding. This paper outlines a novel strategy in attenuating viruses involving comparison of disorder patterns of inner shells of related viruses to identify residues and regions that could be ideal for mutation. The M protein of SARS-CoV-2 has one of the lowest M PID values (6%) in its family, and therefore this virus has one of the hardest outer shells, which makes it resistant to antimicrobial enzymes in body fluid. While this is likely responsible for its contagiousness, the risks of creating an attenuated virus with a more disordered M are discussed.