Timely acquisition of myeloid-cell immune-regulatory phenotype and COVID-19 outcome

ABSTRACT

Background: Uncontrolled inflammatory responses, ranging from cytokine storm to immune-paralysis were described in COVID-19 worse prognosis. Patients with an aggressive course are the bottleneck of COVID-19 pandemic management, and there is urgent need of understanding the underlying mechanisms to guide clinical decisions. Myeloid cell activation is likely a key player in SARS-CoV-2 infection. Methods: Here, we longitudinally evaluated COVID-19 patients with respiratory insufficiency admitted to Hospital Santa Maria (Lisbon, Portugal), comparing those that did not require intensive care admission (NO-ICU) with those requiring high flux oxygen and/or mechanical ventilation (ICU). At each time point, an ex-vivo immune-phenotype by flow cytometry was analysed with both supervised and unsupervised approaches and clustering analysis of circulating cell subsets of monocytes (Mo) and dendritic cells (DCs), in parallel with specific antibody responses and a wide array of inflammatory mediators. Results: Contrarily to other systemic viral infections, we found that COVID-19 patients with respiratory insufficiency featured systemic immune-suppressive/ regulatory myeloid cell responses. Specifically, we observed a global reduction of CD14lowCD16+ Mo, and reduced expression of CD80, CD86, and SLAN. Contemporaneously, both Mo and DC showed increased expression of CD163, CD204, CD206 and PD-L1 immune-regulatory markers. Moreover, cDC2s, pDCs and basophils were significantly reduced. Inflammatory cytokines and chemokines associated with myeloid cell chemotaxis correlated with the phenotype changes. In NO-ICU patients (n=9) we observed a peak of these alterations at admission and a progressive regression to healthy phenotype at hospital discharge (as compared to age-matched controls, n=11). On the other hand, in ICU patients (n=11), the expression of immuno-suppressive markers progressively increased until discharge. Notably, they featured significant reduction of HLA-DRhighPD-L1- and expansion of CD80-CD86- classical Mo and an increase of HLA-DRhighPD-L1+ cells in Mo and in all DC subsets at recovery. Conclusion: Altogether, these data favour an alternative view of a beneficial role of suppressive/regulatory myeloid responses in coping with COVID-19 pathogenesis. To further support our hypothesis, we are currently collecting data on lung injury and SARS-CoV-2 viremia to correlate with the kinetics of myeloid responses.