One of the key differences between mild and severe COVID-19 is the body’s immune response to the virus. In severe COVID-19, there is a severe immune reaction, called a “cytokine storm,” where the immune system overreacts. Rather than helping fight the virus, this overreaction instead leads to harmful inflammation and tissue damage. We will focus on understanding how the virus that causes COVID-19 disrupts the body’s normal immune response. Specifically, we will examine how the virus prevents the formation of “stress granules,” tiny cellular structures that can help regulate immune activity. By creating a virus mutation that allows stress granules to form again, we will investigate how these structures alter the activation of our immune system and impact lung disease. Overall, this work aims to uncover how stress granules change the immune response during infection, with the goal of supporting new treatments for severe COVID-19.
Update: In the first year of this award, our laboratory made significant progress in defining how stress granules, which form during a viral infection, influence SARS-CoV-2 infection. SARS-CoV-2 is the virus that causes COVID-19. First, we characterized two stress granule–restoring mutant viruses and targeted two specific proteins, NSP3 and nucleocapsid (N). We found that each protein restores stress granules at distinct stages of infection. This demonstrates that the SARS-CoV-2 virus uses multiple mechanisms to weaken the body’s protective response. Second, we found that when restoring stress granules, cells produce lower levels of inflammatory molecules, including cytokines. High levels of cytokines can cause severe lung damage in people with serious cases of COVID-19. These findings suggest that the virus makes disease worse by preventing stress granules from forming. They also identify stress granules as a promising new target for treatments that could reduce inflammation and protect the lungs during severe COVID-19.
