Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease

Abstract

Infection by the novel SARS-CoV-2 coronavirus produces a range of outcomes, with the majority of cases producing mild or asymptomatic effects, and a smaller subset progressing to critical or fatal COVID-19 disease featuring severe acute respiratory distress. Although the mechanisms driving severe disease progression remain unknown, it is possible that the abrupt clinical deterioration observed in patients with critical disease corresponds to a discrete underlying expansion of viral tropism, from infection of cells comprising respiratory linings and alveolar epithelia to direct infection and activation of inflammatory monocytes and macrophages. Dysregulated immune responses could then contribute to disease severity. This article discusses the potential role of monocyte/macrophage (Mo/Mϕ) infection by SARS-CoV-2 in mediating the immune response in severe COVID-19. Additional mechanisms of immune-enhanced disease, comprising maladaptive immune responses that may aggravate rather than alleviate severity, are also discussed. Severe acute clinical worsening in COVID-19 patients may be influenced by the emergence of antibodies that participate in hyperinflammatory monocyte response, release of neutrophil extracellular traps (NETs), thrombosis, platelet apoptosis, viral entry into Fc gamma receptor (FcγR)-expressing immune cells, and induction of autoantibodies with cross-reactivity against host proteins. While the potential roles of Mo/Mϕ infection and immune-enhanced pathology in COVID-19 are consistent with a broad range of clinical and laboratory findings, their prominence remains tentative pending further validation. In the interim, these proposed mechanisms present immediate avenues of inquiry that may help to evaluate the safety of candidate vaccines and antibody-based therapeutics, and to support consideration of pathway-informed, well-tolerated therapeutic candidates targeting the dysregulated immune response.

A high CMV-specific T cell response associates with SARS-CoV-2-specific IL-17 T cell production

“…Th17-dominated immunity is not the most effective type of response against viruses, which is associated with type 1 immunity and IFNγ production [ 34 ]. This agrees with recent studies that show IL-17 as a dysfunctional type of response against SARS-CoV-2, responsible for so-called “immune misfiring” [ 35 ], and associated with a worse prognosis of the disease, including mortality [ 36 , 37 ]. Nevertheless, we could not confirm a relationship between the Th17 phenotype displayed by hiT CMV individuals and disease severity.…”

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Other hub-high traffic genes in this module, such as BTAF1 ( 216 ), EZH2 ( 346 ), NPM1 ( 347 ), TPT1 ( 151 , 269 , 348 ), LDHA ( 217 , 268 ), PTPRC ( 189 ), SOS1 ( 349 , 350 ), DDX5 ( 351 , 352 ), BCL10 ( 162 , 353 ), EEF1B2 ( 354 ), CALM1 ( 344 ), EIF4A2 , EIF4B ( 336 , 355 , 356 ), EEF1A1 ( 269 , 354 ), HNRNPA1 ( 228 , 347 ), and IFNG ( 8 , 357 , 358 ), have important roles in development/inhibition of COVID-19. Overexpression of SARS-CoV-2 ORF6 caused HNRNPA1 nuclear accumulation, subverting the host mRNA export system and reducing nucleus size ( 359 ).…”

Mechanisms of Immunothrombosis by SARS-CoV-2

“…CSS is also associated with delayed secretion of type I and III interferons [ 88 ], and low levels thereof [ 89 ], probably due to membrane protein in SARS-CoV-2 via RIG-I/MDA-5-MAVS signaling [ 90 ]. Furthermore, CSS has hypercytokinemia [ 91 ], macrophage polarization from M2 to M1 [ 92 ], with activation of the Plcγ2 pathway and a reduction in Tmem178 levels in macrophages [ 93 ], T-cell cytotoxicity defects [ 16 ], complement activation [ 94 ], and increased NETs [ 95 , 96 ]. As a result of all these changes, patients suffer from hyperinflammation [ 97 ], cytokine release [ 98 ], cytokine storms [ 99 , 100 ], multiorgan disease [ 101 ], and thrombosis [ 15 ].…”