Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype

Abstract

After more than one year since the COVID-19 outbreak, patients with severe disease still constitute the bottleneck of the pandemic management. Aberrant inflammatory responses, ranging from cytokine storm to immune-suppression, were described in COVID-19 and no treatment was demonstrated to change the prognosis significantly. Therefore, there is an urgent need for understanding the underlying pathogenic mechanisms to guide therapeutic interventions. This study was designed to assess myeloid cell activation and phenotype leading to recovery in patients surviving severe COVID-19. We evaluated longitudinally patients with COVID-19 related respiratory insufficiency, stratified according to the need of intensive care unit admission (ICU, n = 11, and No-ICU, n = 9), and age and sex matched healthy controls (HCs, n = 11), by flow cytometry and a wide array of serum inflammatory/immune-regulatory mediators. All patients featured systemic immune-regulatory myeloid cell phenotype as assessed by both unsupervised and supervised analysis of circulating monocyte and dendritic cell subsets. Specifically, we observed a reduction of CD14lowCD16+ monocytes, and reduced expression of CD80, CD86, and Slan. Moreover, mDCs, pDCs, and basophils were significantly reduced, in comparison to healthy subjects. Contemporaneously, both monocytes and DCs showed increased expression of CD163, CD204, CD206, and PD-L1 immune-regulatory markers. The expansion of M2-like monocytes was significantly higher at admission in patients featuring detectable SARS-CoV-2 plasma viral load and it was positively correlated with the levels of specific antibodies. In No-ICU patients, we observed a peak of the alterations at admission and a progressive regression to a phenotype similar to HCs at discharge. Interestingly, in ICU patients, the expression of immuno-suppressive markers progressively increased until discharge. Notably, an increase of M2-like HLA-DRhighPD-L1+ cells in CD14++CD16− monocytes and in dendritic cell subsets was observed at ICU discharge. Furthermore, IFN-γ and IL-12p40 showed a decline over time in ICU patients, while high values of IL1RA and IL-10 were maintained. In conclusion, these results support that timely acquisition of a myeloid cell immune-regulatory phenotype might contribute to recovery in severe systemic SARS-CoV-2 infection and suggest that therapeutic agents favoring an innate immune system regulatory shift may represent the best strategy to be implemented at this stage.

Acute HIV-1 and SARS-CoV-2 Infections Share Slan+ Monocyte Depletion—Evidence from an Hyperacute HIV-1 Case Report

“…The patient featured fever and asthenia preceding 13 days the diagnosis, and elevated aminotransferases, compatible with a HIV-induced hepatitis and high inflammatory response. The comparison was performed with a cohort of 20 acute SARS-CoV-2 patients, included in a previous study [ 19 ]. As controls, we enrolled 11 healthy subjects and a treatment naïve chronic HIV-1 patient, asymptomatic despite an advanced disease stage as illustrated by the low CD4+ T-cell count ( Table 1 ).…”

“…M1-like classical monocyte expansion was observed in the acute HIV-1 patient, whereas in SARS-CoV-2 infection the immunomodulatory M2-like classical monocytes dominated in our study. The latter might be a negative feedback loop to an earlier excessive inflammatory response seen in SARS-CoV2 [ 19 ]. Importantly, this was not the case in HIV-1, where the M1-like expansion further increased in the case of untreated chronic HIV-1 infection.…”

“…This has been mainly associated with severe disease [ 43 , 44 ], although the expansion of this immunomodulatory population might be a response to the extensive tissue damage and inflammation that occur in severe SARS-CoV-2 disease. As such, we recently reported that COVID-19 recovery is associated with the maintenance of this M2-like phenotype expansion [ 19 ].…”

“…The clinical and epidemiological details are depicted in Table 1 . The COVID-19 patients were previously included in a recently published study [ 19 ]. Clinical data were collected by the clinicians integrating the research team.…”

“…Monocyte/macrophage activation syndrome was reported in severe COVID-19 cases, with interferon-γ (IFNγ), interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNFα), and IL-18 having central immunopathogenic roles in the hyper-inflammation [ 18 ]. Our lab demonstrated that the expansion of M2-like monocytes was significantly higher in patients with detectable SARS-CoV-2 plasma viral load and that systemic immune-regulatory myeloid cell phenotype was the main feature associated with the recovery of hospitalized patients [ 19 ].…”