DHM COVID-19 Clinical DispatchBite-sized, weekly clinical updates Issue #4: SARS-CoV2 and the Inflammatory ResponseThis week we bring you all the way back to our immunology days as we take a look at the cellular mechanisms of SARS-CoV2 infection and its impact on the host immune response. We start with the basic mechanisms of viral entry and replication in the respiratory epithelium, including a new term to us - pyroptosis! - A severely inflammatory cell death. We then introduce the hypothesized, hyper-inflammatory state of COVID-19 and discuss the mechanisms by which the host response to SARS-CoV2 causes severe disease. Our Big Take-away for the week? Also, be sure to check out "What We're Reading," our weekly literature round-up at the end. Happy Thursday! - The COVID Clinical Working Group Getting Basic - Cellular Mechanisms of COVIDFigure 1. SARS-CoV-2 infects cells of the respiratory tract that express the ACE2 receptor. Viral replication triggers cell death through pyroptosis, leading to activation of inflammatory pathways. Figure adapted from: Tay, et al. Nature Reviews Immunology Unlike common coronaviruses that only infect the upper respiratory tract, SARS-CoV-2 (as well as SARS-CoV and MERS) is capable of infecting the lower respiratory tract. SARS-CoV-2 enters cells via the ACE2 receptor, which is expressed on multiple cells throughout the body, and multiple types of cells found in airway. Specifically, this viral entry into target cells is mediated by the Spike (S) protein. Two ongoing areas of therapeutic investigation are focused on targeting the ACE2 receptor or the viral S protein. Some hypothesize that cell death of SARS-CoV2 infected cells is mediated by a specific pathway called pyroptosis. In contrast to apoptosis, which is generally non-inflammatory, pyroptosis is pro-inflammatory and was first described in Salmonella-infected cells in 2001. Among cytokines induced in this pathway is interleukin-1ẞ, high levels of which have been found in patients with COVID infection. It’s 2AM: Do You Know Where Your T-Cells Are?In a recent Nature Reviews Immunology article, Tay et al describe what is hypothesized about the host immune response to SARS-CoV-2. The figure below illustrates what is understood about functional and dysfunctional immune response to viral infection. Cell death releases attracts monocytes, macrophages and T cells, promoting further inflammation and establishing a pro-inflammatory feedback loop. In a defective immune response (left side) this may lead to further accumulation of immune cells in the lungs, causing overproduction of pro-inflammatory cytokines (IFN-y, IL6, IL2, IP10), which eventually damages the lung infrastructure. The resulting cytokine storm circulates to other organs, leading to multi-organ damage. In addition, non-neutralizing antibodies produced by B cells may enhance SARS-CoV-2 infection through antibody-dependent enhancement (ADE), further exacerbating organ damage. Alternatively, in a healthy immune response (right side), the initial inflammation attracts virus-specific T cells to the site of infection, where they can eliminate the infected cells before the virus spreads. Neutralizing antibodies in these individuals can block viral infection, and alveolar macrophages recognize neutralized viruses and apoptotic cells and clear them by phagocytosis. Altogether, these processes lead to clearance of the virus and minimal lung damage, resulting in recovery. Fight that Aggression with ImmunosuppressionCan we target this inflammatory response to improve outcomes for severe COVID-19? Signal transduction events downstream of the IL-6 receptor promote a hyperinflammatory state. Tocilizumab blocks that signaling by binding to the IL-6 receptor and preventing IL-6 from activating it, thereby inhibiting the downstream signal transduction. Figure from: Fu, et al. J Trans Med. Quick Lit - One-Page Literature ReviewWhat We're ReadingHere are the articles that our team is reading this week, which are particularly relevant to this issue. To see more in-depth summaries please head over to our Literature Database!
Test Yourself!Can you answer this question from last issue’s article of the week? In the Tang et al retrospective analysis reviewed last week, anticoagulant therapy was associated with lower mortality for which group of patients?
See the answer here! LinksQuestions, thoughts, insights? Share them here! Clinical Knowledge Portal Prior Dispatches: Issue 1: GI symptoms in COVID Issue 2: Predictors of Severe COVID Disease Issue 3: Hypercoagulability in COVID-19 |