The study, ‘Topoisomerase 1 inhibition suppresses the transcriptional activation of innate immune responses and protects against inflammation-induced death’, shows both in the laboratory and in animal models that small doses of am inhibitor of Topoisomerasa I (Top I) can diminish the acute inflammatory response that is produced in certain infections, allowing at the same time a normal immune response in the organism to confront the disease. The new treatment could benefit millions of people that are affected by infections and pandemics.

Luis Martínez-Gil, current Juan de la Cierva research at the Universitat de València and co-author of the work, explains: ‘the development of a new approximation was key to find an alternative use to the inhibitors of Top1 and our work shows the value of a cutting-edge and risky research’.  The researcher, that participated in the study during his postdoctoral stay at the Icahn School of Medicine at Mount Sinai and concluded it in the Universitat de València, details that is ‘the first specific treatment of the uncontrolled inflammatory response that is produced against infections with certain pathogenics’

The responsible researcher of the published work, Ivan Marazzi, professor of the Department of Microbiology of the Icahn School of Medicine explains that the treatment could control not only sepsis -result of hospital infections in patients with a weak immune system- but also new attacks to the immune system from new varieties of flu or pandemics such as Ebola. ‘Our results suggest that a therapy based on an inhibitor of the Top 1 could save millions of people affected by sepsis, pandemics and congenital deficiencies associated with acute inflammation episodes, which is known as a inflammatory storm’ These storms take place when the body does not know how to adjust the inflammation level appropriated, on one side, to contain the infection but also to not to damage the own organism’. 

The sepsis is caused by an excessive response of the host to an infection, which causes a multiple organ failure and, afterwards, death. With a mortality rate of between 20 and 50%, sepsis is the tenth cause of death in the United States and causes more deaths than the AIDS virus and breast cancer. 

‘Until now there wasn’t any specific treatment against sepsis beyond the treatment of the infection that causes the inflammatory storm’ points out the doctor Marazzi. ‘This treatment is desperately needed’. For instance, sepsis is one of the first causes of death of neonates and children. ‘The septic shock and the destruction of lung tissue can occur when a child is suffering a pneumonia caused by the co-infection of a virus and a bacterium, even when antibiotic therapy is used.’ Elderly people are also specially vulnerable to sepsis.’

Following the challenge opened by the National Institutes of Health of the United States to find new usages for existent medication, the research team in which Luis Martínez-Gil took part, now researcher of the Universitat de València, used a cellular assay to find candidates that could diminish the inflammatory response. What they found out is that medicines against cancer from the inhibitors of the Top 1 -four of them have already been approved for their usage in diverse types of cancer-  are able to block a group of inflammatory genes that are activated in immune cells when fighting the infection.

Doses 50 times below the used in chemotherapy
The research team found out that the usage of an inhibitor of Top1 in a dose 50 times less than the used in chemotherapy was enough to recover the 70-90% of mice from a lethal inflammatory storm caused by a bacterial infection, liver failure or a co-infection virus-bacteria. The treatment, apparently, did not have any secondary effects. It was also proved that the treatment in infected cells with influenza, Ebola and other microbial infections (virus and bacteria) that over-stimulate the immune system to find that the compound is able to modulate the dangerous inflammatory response. 

This study, which has resulted in the work published in the Science journal, has been funded by the National Institutes of Health of the United States and the Department of Defence. 

Researcher at the Universitat
The research of Luis Martínez-Gil is focused on the study of the interactions between virus and hosts, and its application in the development and improvement of antivirals and vaccines. During his doctoral thesis, at the Universitat de València, he was under the direction of Ismael Mingarro, full university professor of Molecular Biology and Biochemistry.  Currently, he is working in the identification of protein-protein interactions between the Nipah virus and its host (human cells) with the aim of identifying new bullseyes for the antivirals design. 

The co-authors of the article are Alex Rialdi, Laura Campisi, Nan Zhao, Arvin Cesar Lagda, Luis Martinez-Gil, Megan Edwards, Giorgi Metreveli, Nicole Bouvier, Chris Basler, Adolfo García-Sastre, Zuleyma Peralta, Romain Fenouil, Stefan Jordan, Harm vanBakel, Miriam Merad and Jian Jin (from the Icahn School of Medicine at Mount Sinai). Colette Pietzsch and Alex Bukreyev from University of Texas Medical Branch, Galveston; Jessica Sook Yuin Ho from the Institute of Molecular and Cell Biology, Singapore; Xiaoting Chen and Matthew Weirauch from the Cincinnati Children’s Hospital Medical Center; Cesar Munoz-Fontela from the Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Sven Heinz from the University of California, San Diego; and Chris Benner from the Salk Institute for Biological Studies, La Jolla, CA. 

Article: 
Topoisomerase 1 inhibition suppresses the transcriptional activation of innate immune responses and protects against inflammation-induced death. A. Rialdi et al., Science 10.1126/science.aad7993 (2016)