ORF6 Protein Helps COVID-19 Virus Evade Immune System

A recent study published in the journal Cell has revealed how SARS-CoV-2, the virus responsible for COVID-19, evades the cytotoxic immune response. The research, led by Wilfredo Garcia-Beltran and Julie Boucau of the Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, identified a protein called ORF6 as a significant factor in this mechanism.

The cytotoxic immune response involves T-lymphocytes that eliminate pathogens by recognizing specific antigens on infected cells while sparing uninfected neighboring cells. The study's first authors, Marcella Cardoso, a Brazilian postdoctoral research fellow at Harvard Medical School (HMS) and MGH, and Jordan Hartmann of HMS, were joined by scientists from institutions in Brazil and Germany.

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Cardoso explained, "We discovered that SARS-CoV-2 can evade detection by the immune system by reducing the markers that indicate the presence of the virus in cells. In this process, the virus alters certain proteins on the surface of infected cells to inhibit their interaction with T-lymphocytes."

Role of Natural Killer (NK) Cells in COVID-19 Immune Response

Natural killer (NK) cells, which are crucial for detecting and combating viruses, are part of the innate immune response, the body's first line of defense against infection. NKG2D, a protein expressed on the surface of NK cells, identifies and eliminates infected cells (and cancer cells) by targeting stress-induced ligands such as MIC-A and MIC-B. This recognition is essential for the removal of contaminated cells from the body.

A systematic analysis of SARS-CoV-2 proteins revealed that ORF6, unique to and conserved among mammalian sarbecoviruses, actively participates in the removal of these critical markers from infected cells, facilitating viral proliferation within the host organism. Confirming this evasion mechanism, researchers found that when MIC-A and MIC-B receptors were shielded with the antibody 7C6, NK cells were significantly more effective at locating and destroying infected cells.

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Collaboration and Contributions from Brazilian Researchers

The study's co-authors include four other Brazilian researchers: Maria Cecília Ramiro, a PhD candidate at the State University of Campinas's School of Medical Sciences (FCM-UNICAMP); and Fernanda Orsi, Lício Velloso, and Erich de Paula, professors at FCM-UNICAMP. According to De Paula, UNICAMP's involvement was connected to projects funded by FAPESP during the pandemic. "Our group contributed by discussing strategies and sharing a clinical cohort used to validate the data," he said.

De Paula was the principal investigator for the project "Evaluation of the mechanisms of hemostatic activation in COVID-19 and their modulation by bradykinin inhibitors." Velloso led the project "Clinical trial of bradykinin inhibition in hospitalized adults with severe COVID-19," which provided some of the clinical data and samples.

Cardoso emphasized the importance of collaborative research in addressing pandemics: "Studies of the immune response in severe COVID-19 patients showed that this elimination of proteins also occurred in these cases. Data collected from patients during hospitalization were key to this cross-border research project."

Samples collected at UNICAMP's general and teaching hospital (Hospital de Clínicas) exhibited a greater diversity of clinical outcomes in response to different strains of the virus. "In parallel, we conducted in vitro experiments in which lung tissue cells were infected with the live virus," Cardoso added.

Monoclonal Antibodies and New Research Frontiers

In light of recent preclinical oncological trials demonstrating that the monoclonal antibody 7C6 can prevent the elimination of MIC-A and MIC-B, which stimulate NK cells and T-cells, researchers decided to test its efficacy in curtailing the virus's immune evasion. "We anticipated that this approach would not only promote the elimination of infected cells but also enhance the co-stimulation of CD8+ T cells, thus activating both the innate and adaptive immune systems," Cardoso explained. A series of experiments and in vitro assays were conducted to test these hypotheses.

"Understanding how SARS-CoV-2 and other coronaviruses affect these proteins and how this impacts the immune response helps us better comprehend their interaction with the body. It also identifies potential targets for novel treatments to strengthen the immune system and combat viral infections," Cardoso stated.

The findings open new research avenues in the field of host-directed antiviral therapies, as the role of the antibody 7C6 in enhancing the elimination of SARS-CoV-2-infected cells suggests innovative therapeutic strategies. "Based on these results, we can conduct in vivo trials using transgenic animal models to evaluate the clinical applicability of this strategy. Further stages of research are required, but the results are highly promising," Cardoso concluded.

About the São Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution dedicated to supporting scientific research across all fields of knowledge by awarding scholarships, fellowships, and grants to researchers affiliated with higher education and research institutions in the State of São Paulo, Brazil. Recognizing that the best research is conducted through international collaboration, FAPESP has established partnerships with funding agencies, higher education institutions, private companies, and research organizations worldwide. These collaborations enhance the quality of research and encourage scientists funded by FAPESP to develop further international cooperation. For more information, visit FAPESP and FAPESP News Agency for the latest scientific breakthroughs achieved through its various programs, awards, and research centers.

News Source:- miragenews.com