Elevated plasma sTIM-3 levels in patients with severe COVID-19

Abstract

Background: The pathogenesis of coronavirus disease 2019 (COVID-19) is still incompletely understood, but it seems to involve immune activation and immune dysregulation. Objective: We examined the parameters of activation of different leukocyte subsets in COVID-19-infected patients in relation to disease severity. Methods: We analyzed plasma levels of myeloperoxidase (a marker of neutrophil activation), soluble (s) CD25 (sCD25) and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T-cell activation and exhaustion), and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19-infected patients at hospital admission and 2 additional times during the first 10 days in relation to their need for intensive care unit (ICU) treatment. Results: Our major findings were as follows: (1) severe clinical outcome (ICU treatment) was associated with high plasma levels of sTIM-3 and myeloperoxidase, suggesting activated and potentially exhausted T cells and activated neutrophils, respectively; (2) in contrast, sCD14 and sCD163 showed no association with need for ICU treatment; and (3) levels of sCD25, sTIM-3, and myeloperoxidase were inversely correlated with degree of respiratory failure, as assessed by the ratio of PaO 2 to fraction of inspired oxygen, and were positively correlated with the cardiac marker N-terminal pro-B-type natriuretic peptide. Conclusion: Our findings suggest that neutrophil activation and, in particular, activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T-celltargeted treatment options and downregulation of neutrophil activation could be of importance in this disorder. (J Allergy Clin Immunol 2021;147:92-8.)

Akt-Fas to Quell Aberrant T Cell Differentiation and Apoptosis in Covid-19

“…Ueland et al recapitulate the findings by Diao et al and report that sTIM-3, an exhaustion marker associated with chronic infections including HIV, Hepatitis B, Hepatitis C, and pulmonary tuberculosis, had a rise in expression in severe (ICU) patients, which correlated with the measured degree of pulmonary infiltration and the cardiac marker NTproBNP (16). Ueland et al hypothesize that T cells are traveling to these organs and are responsible for their harm, but temporarily upregulate sTIM-3 as "a mechanism to prevent persistent and overshooting T-cell activation, which could harm the host" (16). They still, however, claim their findings suggest that T-cell activation and exhaustion play a role in Covid-19 and posit T-cell targeted treatment options may be of interest (16).…”

“…Ueland et al hypothesize that T cells are traveling to these organs and are responsible for their harm, but temporarily upregulate sTIM-3 as “a mechanism to prevent persistent and overshooting T-cell activation, which could harm the host” ( 16 ). They still, however, claim their findings suggest that T-cell activation and exhaustion play a role in Covid-19 and posit T-cell targeted treatment options may be of interest ( 16 ). Varchetta et al report an increase in TIM-3 and CD69 expression in CD8+ T cells and note the extent of CD8+ T cell lymphopenia was significantly greater in patients that succumbed to Covid-19 ( 17 ).…”

“…Israelow et al observe hyperactivation of CD8+ cells and their infiltration into the lung in a murine model of Covid-19 (23). Indeed, an increase in the frequency of effector cells has been shown in one analysis of T cell physiological correlates of Covid-19 disease severity; CD8+ T cells in severe cases expressed increased levels of Granzyme and Perforin than in patients with mild disease (16). Whether this represents increased effector function or a marker for exhaustion in Covid-19 is unknown considering that in the Covid-19 disease state, since Kalfaoglu et al show even PD-1 was not inducing lymphocyte exhaustion (21).…”

Influenza infection, SARS, MERS and COVID-19: Cytokine storm – The common denominator and the lessons to be learned

“…Levels of 8 soluble checkpoint molecules including PD-1 and TIM-3 were negatively correlated with absolute counts of total, CD4, and CD8 T cells but not neutrophil counts, and TIM-3 was identified to have good predictive value for COVID-19 progression. Ueland et al confirmed the association between levels of soluble TIM-3 and COVID-19 severity [ 44 ]. These findings are interesting because recent data shows that TIM-3 play a dual role: it participates in the activation of infected macrophages and negatively regulates Th1 immune response [ 45 ].…”

“…Kong et al assessed levels of soluble forms of checkpoint molecules in patients with COVID-19 [ 43 ]. According to the current knowledge, soluble forms may reflect the degree of membrane expression of the corresponding checkpoint proteins [ 44 ]. Kong et al found that levels of 13 out of 14 tested molecules were significantly higher in patients with severe COVID-19 than in those with mild, moderate, or asymptomatic infection [ 43 ].…”