Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery

This study was supported by the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 research call COV20/00181)—co-financed by the European Development Regional Fund “A way to achieve Europe” and by Consejería de Sanidad de la Comunidad de Madrid (CÍVICO study 2020/0082). R.L.G. and O.C.M. hold a research contract “Rio Hortega” (CM19/00120 and CM19/00092, respectively) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation. MCL holds a predoctoral fellowship (FPU19/06393) from the Spanish Ministry of Science and Innovation.An early analysis of circulating monocytes may be critical for predicting COVID-19 course and its sequelae. In 131 untreated, acute COVID-19 patients at emergency room arrival, monocytes showed decreased surface molecule expression, including low HLA-DR, in association with an inflammatory cytokine status and limited anti-SARS-CoV-2-specific T cell response. Most of these alterations had normalized in post-COVID-19 patients 6 months after discharge. Acute COVID-19 monocytes transcriptome showed upregulation of anti-inflammatory tissue repair genes such as BCL6, AREG and IL-10 and increased accessibility of chromatin. Some of these transcriptomic and epigenetic features still remained in post-COVID-19 monocytes. Importantly, a poorer expression of surface molecules and low IRF1 gene transcription in circulating monocytes at admission defined a COVID-19 patient group with impaired SARS-CoV-2-specific T cell response and increased risk of requiring intensive care or dying. An early analysis of monocytes may be useful for COVID-19 patient stratification and for designing innate immunity-focused therapies.Depto. de MedicinaFac. de MedicinaTRUEUnión EuropeaMinisterio de Ciencia e Innovación (España)Comunidad de MadridInstituto de Salud Carlos IIIpu

Longitudinal dynamics of SARS-CoV-2-specific cellular and humoral immunity after natural infection or BNT162b2 vaccination

The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations

Papel de las células supresoras de estirpe mieloide en la evolución de pacientes con trasplante renal

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that expand due to chronic inflammation and participate in the suppression of both innate and adaptive immune responses. Three subsets of MDSC have been described according to phenotypic criteria: polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC) and early-stage MDSC (eMDSC). MDSC display numerous mechanisms to carry out their immunosuppressive functions such as the production of arginase 1, indoleamine 2,3-dioxygenase, nitric oxide synthase and reactive oxygen species or the expansion of regulatory T cells. This myeloid compartment has been widely studied related to cancer since MDSC have been seen to favour tumor progression, metastasis and have been associated to poor prognosis. In recent years, MDSC were shown to be relevant for tolerance induction after transplantation. However, the analysis of MDSC effects in human kidney transplantation is limited to a few studies including small numbers of patients. In this context, the group Inmunodeficiencias e Inmunologia del Trasplante (GIDIT) from Hospital 12 de Octubre began to study MDSC in patients who underwent a kidney transplant. Their initial results showed that CD33+ CD11b+ CD14+ CD15- HLA-DR-/low cells expanded after transplantation; moreover, a higher number of these cells increased risk for developing cancer in kidney transplant recipients (KTR). Based on these results we aimed to assess MDSC immunosuppression in vitro when cocultured with lymphocytes and to quantify suppressive soluble factors associated with MDSC function. CD33+ CD11b+ CD14+ CD15- HLA-DR-/low were expanded in KTR compared to healthy controls. When co-cultured with lymphocytes, KTR-isolated MDSC were able to suppress both CD4 and CD8 T cells proliferation and production of cytokines. Furthermore, higher M-MDSC counts correlated with higher circulatory arginase 1 activity and interleukin 10 (IL-10), and lower total antioxidant capacity. Taken together, these results suggest that high levels of MDSC and their associated immunosuppressive environment could be promoting de novo malignancy development after kidney transplantation

Papel de las células supresoras de estirpe mieloide en la evolución de pacientes con trasplante renal

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that expand due to chronic inflammation and participate in the suppression of both innate and adaptive immune responses. Three subsets of MDSC have been described according to phenotypic criteria: polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC) and early-stage MDSC (eMDSC). MDSC display numerous mechanisms to carry out their immunosuppressive functions such as the production of arginase 1, indoleamine 2,3-dioxygenase, nitric oxide synthase and reactive oxygen species or the expansion of regulatory T cells. This myeloid compartment has been widely studied related to cancer since MDSC have been seen to favour tumor progression, metastasis and have been associated to poor prognosis. In recent years, MDSC were shown to be relevant for tolerance induction after transplantation. However, the analysis of MDSC effects in human kidney transplantation is limited to a few studies including small numbers of patients. In this context, the group Inmunodeficiencias e Inmunologia del Trasplante (GIDIT) from Hospital 12 de Octubre began to study MDSC in patients who underwent a kidney transplant. Their initial results showed that CD33+ CD11b+ CD14+ CD15- HLA-DR-/low cells expanded after transplantation; moreover, a higher number of these cells increased risk for developing cancer in kidney transplant recipients (KTR). Based on these results we aimed to assess MDSC immunosuppression in vitro when cocultured with lymphocytes and to quantify suppressive soluble factors associated with MDSC function. CD33+ CD11b+ CD14+ CD15- HLA-DR-/low were expanded in KTR compared to healthy controls. When co-cultured with lymphocytes, KTR-isolated MDSC were able to suppress both CD4 and CD8 T cells proliferation and production of cytokines. Furthermore, higher M-MDSC counts correlated with higher circulatory arginase 1 activity and interleukin 10 (IL-10), and lower total antioxidant capacity. Taken together, these results suggest that high levels of MDSC and their associated immunosuppressive environment could be promoting de novo malignancy development after kidney transplantation

A Short Corticosteroid Course Reduces Symptoms and Immunological Alterations Underlying Long-COVID

Despite the growing number of patients with persistent symptoms after acute SARS-CoV-2 infection, the pathophysiology underlying long-COVID is not yet well characterized, and there is no established therapy. We performed a deep immune profiling in nine patients with persistent symptoms (PSP), before and after a 4-day prednisone course, and five post-COVID-19 patients without persistent symptoms (NSP). PSP showed a perturbed distribution of circulating mononuclear cell populations. Symptoms in PSP were accompanied by a pro-inflammatory phenotype characterized by increased conventional dendritic cells and augmented expression of antigen presentation, co-stimulation, migration, and activation markers in monocytes. The adaptive immunity compartment in PSP showed a Th1-predominance, decreased naïve and regulatory T cells, and augmentation of the PD-1 exhaustion marker. These immune alterations reverted after the corticosteroid treatment and were maintained during the 4-month follow-up, and their normalization correlated with clinical amelioration. The current work highlights an immunopathogenic basis together with a possible role for steroids in the treatment for long-COVID

Hemodialysis-Associated Immune Dysregulation in SARS-CoV-2-Infected End-Stage Renal Disease Patients

Patients on hemodialysis show dysregulated immunity, basal hyperinflammation and a marked vulnerability to COVID-19. We evaluated the immune profile in COVID-19 hemodialysis patients and the changes associated with clinical deterioration after the hemodialysis session. Recruited patients included eight hemodialysis subjects with active, PCR-confirmed SARS-CoV-2 infection, five uninfected hemodialysis patients and five healthy controls. In SARS-CoV-2-infected hemodialysis patients TNF-α, IL-6 and IL-8 were particularly increased. Lymphopenia was mostly due to reduction in CD4+ T, B and central memory CD8+ T cells. There was a predominance of classical and intermediate monocytes with reduced HLA-DR expression and enhanced production of pro-inflammatory molecules. Immune parameters were analysed pre- and post-hemodialysis in three patients with COVID-19 symptoms worsening after the hemodialysis session. There was a higher than 2.5-fold increase in GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-17A and IL-21 in serum, and augmentation of monocytes-derived TNF-α, IL-1β and IL-8 and CXCL10 (p < 0.05). In conclusion, COVID-19 in hemodialysis patients associates with alteration of lymphocyte subsets, increasing of pro-inflammatory cytokines and monocyte activation. The observed worsening during the hemodialysis session in some patients was accompanied by augmentation of particular inflammatory cytokines, which might suggest biomarkers and therapeutic targets to prevent or mitigate the hemodialysis-related deterioration during SARS-CoV-2 infection

Hemodialysis-Associated Immune Dysregulation in SARS-CoV-2-Infected End-Stage Renal Disease Patients

Fondos FEDER ; Ayuda Formación del Profesorado FPU19/06393 ; Contrato de Investigaciçon “Rio Hortega” (CM19/00120)Patients on hemodialysis show dysregulated immunity, basal hyperinflammation and a marked vulnerability to COVID-19. We evaluated the immune profile in COVID-19 hemodialysis patients and the changes associated with clinical deterioration after the hemodialysis session. Recruited patients included eight hemodialysis subjects with active, PCR-confirmed SARS-CoV-2 infection, five uninfected hemodialysis patients and five healthy controls. In SARS-CoV-2-infected hemodialysis patients TNF-α, IL-6 and IL-8 were particularly increased. Lymphopenia was mostly due to reduction in CD4+ T, B and central memory CD8+ T cells. There was a predominance of classical and intermediate monocytes with reduced HLA-DR expression and enhanced production of pro-inflammatory molecules. Immune parameters were analysed pre- and post-hemodialysis in three patients with COVID-19 symptoms worsening after the hemodialysis session. There was a higher than 2.5-fold increase in GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-17A and IL-21 in serum, and augmentation of monocytes-derived TNF-α, IL-1β and IL-8 and CXCL10 (p &lt; 0.05). In conclusion, COVID-19 in hemodialysis patients associates with alteration of lymphocyte subsets, increasing of pro-inflammatory cytokines and monocyte activation. The observed worsening during the hemodialysis session in some patients was accompanied by augmentation of particular inflammatory cytokines, which might suggest biomarkers and therapeutic targets to prevent or mitigate the hemodialysis-related deterioration during SARS-CoV-2 infection.European CommissionInstituto de Salud Carlos IIIMinisterio de Ciencia e Innovación (España)Comunidad de MadridDepto. de MedicinaDepto. de Inmunología, Oftalmología y ORLTRUEpubDescuento UC