Researcher Arieh Eden discusses a recent paper published in Oncotarget entitled, “Empty SV40 capsids increase survival of septic rats by eliciting numerous host signaling networks that participate in a number of systemic functions.”
The Behind the Study series transcribes videos of chosen researchers elaborating on their recent papers published in Oncotarget. Visit the Oncotarget YouTube channel for more insights from outstanding authors.
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Good evening, everyone. My name is Arieh Eden. I’m the Director of the intensive care unit at the Carmel Hospital, and I’m going to talk to you about the research that I’ve been doing in collaboration with the Hebrew University in Jerusalem, the Faculty of Medicine and the Department of Hematology.
We studied the effect of empty SV40 capsids in treatment of septic rats, by eliciting numerous host signaling networks to participate in a number of systemic functions. We have studied empty SV40 capsids increased survival of septic rats, by eliciting numerous host signaling networks that participate in a number of systemic functions.
Our study was based on previous work that we’ve done looking at the effect of those empty capsids in other disease states. It all arised from an attempt to produce a vehicle for the introduction of gene therapy into animals, where we have found that the empty capsids that were a control group in that initial study way, way long ago, had their own medical properties. They’ve induced the survival of cells and of animals, at least as well as, if not better than, the capsids which contained the actual genes that we wanted to deliver.
Sepsis is a major problem. It is one of the greatest health burden of the modern era, and we have combated cardiovascular disease very well over the last half a century, and the same is true for cancer and for trauma by preventing trauma, especially road accidents. But we’ve failed with sepsis. We give treatment for sepsis today, the same as what we did 30, 40, even 50 years ago. Antibiotics, supportive care, and whenever possible, surgically excise out the source of infection.
We’ve, researchers, have looked over the last four decades into numerous ways to treat sepsis on a different level. That is to control and modify the immune response of the septic patient. But without success have been numerous studies, literally. I think over a hundred studies in humans on different ways to modify the immune response. None of them came out with a drug that can be used in septic patients today in the current world of medicine.
We administered the empty cups of the SB 42 animals who were going to have sepsis later as a prophylactic treatment, and have shown, and that’s the main finding of the study, that by pre-administering the empty capsids, we’ve modified, somehow, the immune response of the animals, and animals did not develop sepsis, but recovered.
On day 1, 24 hours after the induction of sepsis, animals that were septic of that were treated with SV40 nanocapsid and those that were not treated with a nanocapsid were very similar. They were very, very, ill. However, those were treated with the capsids, they recovered, and within 75% of them, made full recovery, as you can see by looking at their weight gain, attached figures we have in our paper. On the other end of the animals that were induced with sepsis without pre-treatment with nanocapsids, all died.
We look into the profile of the genes that were involved in the process. We did the RNA-Seq analysis, and we’ve shown that the empty capsids, when given to healthy animals, modify the expression of four genes compared to animals that were not given the empty capsids. That means that their effect is negligible on the healthy animal. However, in the septic animal, first of all, without SV40 capsid treatment, there is an activation and modification of thousands of genes that take part in numerous different pathways. However, septic animals that were pretreated with the capsids, show an activation of a whole different subset of genes and different pathways.
All in all, we could see a difference within 6 hours of the onset of sepsis in thousands of genes and in 24 different pathways that were unique to the animal that had sepsis and were pretreated with the SV40 capsids. These pathways, by looking at the published data, appear to be related to host defense mechanisms, to a hemostasis mechanisms, and to recovery and growth mechanisms, which we think play a role in the response of the animals to the septic events. Strikingly, these animals, these pathways, when we studied them again 24 hours later, were completely modified. And 24 hours after the onset of sepsis, the pathways that were shown in the animals that were pretreated with the capsids, were different to those shown at 6 hours after the onset of sepsis.
I think that this shows that the capsids modify the response of the animal cell of the animal, in a different way during the course of disease. We’ve also shown, but we have not got the full results on that yet, but in other diseases, the response is different. The genetic response, the response of the cell to the disease in the presence of capsids, is different than what we’ve seen in septic animals. And the question is, what do we see, or why does it happen?
We think that, and here I have to go back to my clinical background as a physician who treats patients with sepsis, which is what brought me on board this research, is that animals, humans for that matter, when developed, what did we see is the response as it shows the evolutionary process? The evolutionary process allows us to fight infection when it’s localized, when it’s minor. However, when the infection is severe and systemic, we do not have the power to fight it ourselves, and through natural selections, the animals or the subjects that develop these severe systemic infection would die.
The present process, the virus, which developed alongside us over, I don’t know how many thousands of years, has managed to develop a system, which prevents the cell from responding immunologically, because when a virus attacks a cell, the good or the wanted response of the cell would be to apoptose, to commit suicide, to prevent the virus from going on and infecting the rest of the organism. However, the viral capsid, which is the first thing that interacts with the cell, induces pathways that prevent this response of the cells to induce the immunologic response that would prevent further spread of the virus. But, on the other end, there is no DNA that follows the cups because it’s an empty capsid. It does not carry DNA. So, the virus does not propagate.
Basically, the cell gets the homeostatic effect of the viral capsid without the lethal effect of the viral DNA later on. And in that way, we stipulate that this leads to the ability of the animal to withstand a very aggressive insult, that is a severe sepsis, that would otherwise lead to the demise of the animal.
Our next steps, which we are in the process of trying to achieve now, are to show that this effect is maintained when the drug is administered after the onset of sepsis. That is technically more challenging, but that step will show us that we can treat sepsis using the nanocapsids. And that is where we hope to get to in the near future. The other aspect, of course, is to carry on studying the mechanism of action and the interaction between the viral capsid, on the one hand, and the cellular host on the other, and to see how the local effect on the cellular level create a homeostatic response that leads to recovery of the septic animal.
I thank Oncotarget very much for accepting this publication. I think that the challenge of developing new treatments for sepsis is something that is screaming at us, research community at the medical community, because it is a common disease, very high mortality, and the treatment towards severe sepsis is not drastically modified over the last few decades.
Thank you very much.
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