Fig 1.
CCR2 mediated recruitment of aberrant myeloid compartment and high CCR2 and CCR5 ligands.
Left: Diagrammatic summary representation of CCR2- and CCR5-mediated recruitment of aberrant myeloid compartment via elevated airway CCR2 and CCR5 agonist ligand expression in airways of patients with severe COVID-19 infection. Right: Heatmap showing inflammatory mediators in airway samples from 14 COVID-19 patients (x axis) highlighting specifically elevated CCR2 and CCR5 cognate ligands MCP-1 [CCL2], MIP-1α [CCL3], and MIP-1β [CCL4] levels (average elevation relative to uninfected controls graded in purple as per key). Reprinted from Immunity, 54 (4), Szabo PA, et al. Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19. 797–814. Copyright (2021), with permission from Elsevier et al. CCL, chemokine-chemokine ligand; CCR, chemokine-chemokine receptor; COVID-19, Coronavirus Disease 2019; MCP, monocyte chemoattractant protein; MIP, monocyte inflammatory protein.
Fig 2.
Three stages of immunological pathway leading to mortality in COVID-19: Stage I (Initiation), with early induction of predominant chemokines upon SARS-CoV-2 infection and viral sepsis.
Treatment at this stage with CVC (highlighted in blue text and arrows) is postulated to maintain normalized myeloid compartmentalization at early stage of infection, or block aberrant myeloid infiltration upon CCL2, 3, and 5 signaling following SARS-CoV-2 infection and consequent cytokine amplification (Stage II), and subsequent tissue damage and eventual death (Stage III—consummation). Lu L, et al. Preventing Mortality in COVID-19 Patients: Which Cytokine to Target in a Raging Storm? Front Cell Dev Biol. 2020;8:677. https://doi.org/10.3389/fcell.2020.00677. CCL, chemokine-chemokine ligand; CCR, chemokine-chemokine receptor; COVID-19, Coronavirus Disease 2019; CVC, cenicriviroc; IL, interleukin; IP, interferon gamma-induced protein; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; TNF, tumor necrosis factor.