Investigating the strategy used by SARS-CoV-2 to escape cytotoxic immunity – mediated by cells known as lymphocytes – led a group of researchers to identify an important protein in this mechanism, ORF6, describes an article published in the journal cell.
O workled by Wilfredo Garcia-Beltran and Julie Boucau, from Ragon Institute of Mass General, MIT and Harvard (United States), was first authored by Marcella Cardoso, a Brazilian postdoctoral researcher at Harvard Medical School – Massachusetts General Hospital, together with Jordan Hartmann, from the same institution. Scientists from institutions in Brazil and Germany also participated.
“We discovered that SARS-CoV-2 can avoid detection by the immune system when it reduces the traces that point to the presence of the virus inside cells. This process is carried out by the action of the virus, which disrupts certain proteins on the surface of infected cells and reduces the interaction of lymphocytes with them”, explains Cardoso.
The defense cells known as natural killers (NK or natural killers) are essential for detecting and fighting viruses and are part of the innate immune response – the first barrier against infection. NKG2D recognize stress ligands – such as MIC-A/B – released by infection and this recognition is essential for contaminated cells to be removed from the body.
By systematically analyzing the SARS-CoV-2 proteins, the research identified that ORF6 – unique and conserved among mammalian sarbecoviruses (subgenus of the Coronaviridae family to which the Covid-19 virus belongs) – actively participates in the removal of these important signals. of infected cells, making it easier for the virus to remain.
To confirm this evasion mechanism, when MIC-A/B receptors were protected using a “shield” (an antibody called 7C6), NK cells were much more successful in finding and destroying infected cells.
The study includes four other Brazilian researchers: doctoral student Maria Cecília Ramiro and professors Fernanda Orsi, Lício Velloso and Erich de Paula, from the Faculty of Medical Sciences at the State University of Campinas (FCM-Unicamp).
De Paula highlights that Unicamp’s participation in the study is an offshoot of projects financed by FAPESP during the pandemic.
“Our group collaborated by discussing strategies and sharing a clinical cohort that was used to validate the data”, says Paula, project coordinator “Assessment of the mechanisms of hemostasis activation in Covid-19 and its modulation by bradykinin inhibitors ”.
Velloso, in turn, was in charge of the assistance “Clinical Trial of Bradykinin Inhibition in Adults Hospitalized With Severe Covid-19 ”, from which part of the clinical data and samples was obtained.
“Studies on the immune response in patients who developed the severe form of Covid-19 revealed that this elimination of proteins also occurred. The data collected from patients during hospitalization were essential for this international research and show the importance of the role of research in conjunction with hospitals in containing pandemics in real time”, highlights Cardoso.
The researchers say that the samples collected at the Unicamp Hospital de Clínicas showed a greater diversity of clinical outcomes due to the action of different strains of the virus. “In parallel we also work with everyone in vitrocarrying out experiments in which we infected lung tissue cells using the live virus”, says Cardoso.
Monoclonal antibody and new research fronts
Based on recent preclinical oncological studies demonstrating that the 7C6 monoclonal antibody is capable of preventing the elimination of MIC-A/B – the one that alerts the infection –, the article assessed whether it could also be effective in containing the strategy of coronavirus immune evasion.
“In our view, this approach would not only stimulate the elimination of infected cells but also increase the co-stimulation of lymphocytes of the adaptive immune system [T CD8+], summoning both the innate and adaptive immune systems”, says Cardoso. From then on, they developed a series of experiments and tests in vitro to prove the hypotheses.
“Understanding how SARS-CoV-2 and other coronaviruses affect these proteins and how this influences the immune response helps us better understand how the virus interacts with the body. It also helps identify possible targets for new treatments, strengthening the immune system and fighting viral infection,” says Cardoso.
The research opens new fronts of investigation in the field of host-directed antiviral therapies, as the discovery of the role of the 7C6 antibody in the ability to eliminate cells infected with SARS-CoV-2 is also a revelation that sheds light on possible innovative therapeutic strategies.
“Based on the results obtained, the possibility of testing in vivo, in transgenic animal models, which allow the clinical applicability of the strategy to be assessed”, says Cardoso. “Although further research steps are still necessary, the results are potentially very promising”, he concludes.
The article Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses can be read at: www.sciencedirect.com/science/article/pii/S0092867424003179 .
Source: CNN Brasil
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