BREAKING! COVID-19 News: Study Shows SARS-CoV-2 Does Not Spread And Attack Other Organs Due To Just ACE-2 Alone But Also By Human Proteomes

COVID-19 News: A new study by Spanish researchers explains why certain organs are ‘attacked’ by the SARS-CoV-2 coronavirus while others are not. Previous studies showed that the ACE-2 receptors played a major role in this but the new research reveals that human protein to protein interactions (PPIs)  and also interactions of the SARS-CoV-2 with these PPIs is behind why certain organs are more affected than the rest. These proteins or proteomes are manifested by the various organs and tissues including the lungs.
 
The research findings were published in the journal: Chaos -An Interdisciplinary Journal of Nonlinear Science.
 https://aip.scitation.org/doi/10.1063/5.0015626


An interaction map of the main disease activators for SARS-CoV-2 in the lungs and how they impact proteins in other organs. Image Credit: Ernesto Estrada
 
It has been observed that in severe cases of COVID-19, damage can spread beyond just the lungs and into other organs, including the heart, kidneys, liver, and the brain.
 
The SARS-CoV-2 uses the enzyme angiotensin-converting enzyme 2 (ACE2) to enter and infect human cells.
 
The COVID-19 disease is characterized by important damage at a multi-organ level, partially due to the abundant expression of ACE2 in practically all human tissues.
 
However, not every organ in which ACE2 is abundant is affected by SARS-CoV-2, which suggests the existence of other multi-organ routes for transmitting the perturbations produced by the virus.
 
Researchers from the University of Zaragoza and Agencia Aragonesa para la Investigacion Foundation in Spain propose that diffusive processes through the protein–protein interaction (PPI) network of proteins targeted by SARS-CoV-2 as an alternative route.
 
The study team found a subdiffusive regime that allows the propagation of virus perturbations through the PPI network at a significant rate. By following the main subdiffusive routes across the PPI network, they identified proteins mainly expressed in the heart, cerebral cortex, thymus, testis, lymph node, kidney, among others of the organs reported to be affected by COVID-19.
 
The abundance of ACE-2 on human organs has been claimed as responsible for such multi-organ spread of the virus damages.
 
However, once on circulation, the SARS-CoV-2 coronavirus could spread to practically every organ in the human body as ACE2 is ubiquitous on endothelia and smooth muscle cells of virtually all organs.
 
Contrastingly, SARS-CoV-2 only damages selectively a few organs. Here, the study team developed the hypothesis that the effects of the SARS-CoV-2 virus can be spread through the human protein–protein interaction (PPI) network in a subdiffusive way.
 
They used a time-fractional diffusion model on networks, which allowed them to study this phenomenon. Starting with the diffusion from the SARS-CoV-2 spike protein to the human PPI network, they showed that the perturbations can spread across the whole network in a very few steps.Consequently, t hey discovered a few potential routes of propagation of these perturbations from proteins mainly expressed in the lungs to proteins mainly expressed in other different tissues, such as the heart, cerebral cortex, thymus, lymph node, testis, prostate, liver, small intestine, duodenum, kidney, among others already reported as damaged by COVID-19.
 
Professor Dr Ernesto Estradaa from the Department of biomolecular studies at University of Zaragoza says that that for two proteins to find each other and establish an interaction complex, they need to move inside the cell in a subdiffusive way, which is likened to a drunkard walking on a crowded street wherein the crowd gives challenges to the stunting displacement and making it harder for him to his destination.
 
Also, proteins in a cell are faced with many challenges they need to surpass to interact. Some of the proteins also exist within the same cell or organ, but others do not. Because of the complexity of these mechanisms, Estrada developed a mathematical model that follow 59 proteins within the lungs, which work as major activators that affect other human organs. This triggers a chain of interactions, starting with this set, stimulating changes in proteins along the way until eventually affecting their health.
 
Dr Estrada explained,"Targeting some of these proteins in the lungs with existing drugs will prevent the perturbation of the proteins expressed in organs other than the lungs, avoiding multi-organ failure, which, in many cases, conduces the death of the patient."
 
The study team also found that there are potential routes of propagation of the perturbations from proteins in the lungs, to proteins expressed in other tissues, including the heart, thymus, cerebral cortex, lymph node, prostate, testes, liver, duodenum, small intestine, kidney, among others that have been reported as damaged by COVID-19.
 
Significantly, the study team found that the so-called Spike protein (S-protein) of the SARS-CoV-2 interacts with only two proteins in the human hosts, namely, ZDHHC5 and GOLGA7.
 
The first protein, ZDHHC5, is not in the main connected component of the PPI network of SARS-CoV-2 targets.
 
Perturbation produced by the interaction of the virus S-protein with GOLGA7 is propagated through the whole PPI network of SARS-CoV-2 targets.
 
Based on the model platform created by the team with regards to diffusion (refer to study) the protein GOLGA7 has degree one in this network, and its diffusion is mainly to close neighbors, namely, to proteins separated by two to three edges. When starting the diffusion process at the protein GOLGA7, the main increase in the probability of perturbing another protein is reached for the protein GOLGA3, which increases its probability up to 0.15 at t=0.2t=0.2, followed by PRKAR2A, with a small increase in its probability, 0.0081. Then, the process switch and restarts at GOLGA3, which mainly triggers the probability of the protein PRKAR2A, a major hub of the network.
 
The moment the diffusion process at PRKAR2A is initiated, practically, the whole network is perturbed with probabilities larger than 0.1 for 19 proteins apart from GOLGA3. These proteins are in decreasing order of their probability of being perturbed: AKAP8, PRKAR2B, CEP350, MIB1, CDK5RAP2, CEP135, AKAP9, CEP250, PCNT, CEP43, PDE4DIP, PRKACA, TUB6CP3, TUB6CP2, CEP68, CLIP4, CNTRL, PLEKHA5, and NINL. Notice that the number of proteins perturbed is significantly larger than the degree of the activator, indicating that not only nearest neighbors are activated.
 
Significantly an important criterion for revealing the important role of the protein PRKAR2A as a main propagator in the network of proteins targeted by SARS-CoV-2 is its average diffusion path length. This is the average number of steps that a diffusive process starting at this protein needs to perturb all the proteins in the network. We have calculated this number to be 3.6250, which is only slightly larger than the average (topological) path length, which is 3.5673. That is, in less than four steps, the whole network of proteins is activated by a diffusive process starting at PRKAR2A. Also remarkable that the average shortest diffusive path length is almost identical to the shortest (topological) one. This means that this protein mainly uses shortest (topological) paths in perturbing other proteins in the PPI. In other words, it is highly efficient in conducting such perturbations. (in simple terms the protein PRKAR2A is able to connect to more other proteins in the PPI network in the shortest time and help the virus and its proteins spread to other other organs and tissues in the shortest possible time.)
 
The study team noted that further studies are still needed to determine how the impacted proteins travel between organs.
 
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