Mild and Asymptomatic COVID-19 Convalescents Present Long-Term Endotype of Immunosuppression Associated With Neutrophil Subsets Possessing Regulatory Functions.

Izabela Siemińska,Marcin Surmiak,Marek Sanak,Maciej Siedlar,Kazimierz Węglarczyk,Dorota Kurowska-Baran,Jarek Baran

doi:10.3389/fimmu.2021.748097

Izabela Siemińska, Marcin Surmiak + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2021.748097

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Abstract

The SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)] is associated with severe lymphopenia and impaired immune response, including expansion of myeloid cells with regulatory functions, e.g., so-called low-density neutrophils, containing granulocytic myeloid-derived suppressor cells (LDNs/PMN-MDSCs). These cells have been described in both infections and cancer and are known for their immunosuppressive activity. In the case of COVID-19, long-term complications have been frequently observed (long-COVID). In this context, we aimed to investigate the immune response of COVID-19 convalescents after a mild or asymptomatic course of disease. We enrolled 13 convalescents who underwent a mild or asymptomatic infection with SARS-CoV-2, confirmed by a positive result of the PCR test, and 13 healthy donors without SARS-CoV-2 infection in the past. Whole blood was used for T-cell subpopulation and LDNs/PMN-MDSCs analysis. LDNs/PMN-MDSCs and normal density neutrophils (NDNs) were sorted out by FACS and used for T-cell proliferation assay with autologous T cells activated with anti-CD3 mAb. Serum samples were used for the detection of anti-SARS-CoV-2 neutralizing IgG and GM-CSF concentration. Our results showed that in convalescents, even 3 months after infection, an elevated level of LDNs/PMN-MDSCs is still maintained in the blood, which correlates negatively with the level of CD8+ and double-negative T cells. Moreover, LDNs/PMN-MDSCs and NDNs showed a tendency for affecting the production of anti-SARS-CoV-2 S1 neutralizing antibodies. Surprisingly, our data showed that in addition to LDNs/PMN-MDSCs, NDNs from convalescents also inhibit proliferation of autologous T cells. Additionally, in the convalescent sera, we detected significantly higher concentrations of GM-CSF, indicating the role of emergency granulopoiesis. We conclude that in mild or asymptomatic COVID-19 convalescents, the neutrophil dysfunction, including propagation of PD-L1-positive LDNs/PMN-MDSCs and NDNs, is responsible for long-term endotype of immunosuppression.

Highlights

Since the beginning of 2020, the COVID-19 pandemic has affected more than 200 million people worldwide, causing over 4.5 million deaths so far
Searching for the reason of suppression induced by neutrophil subsets from COVID–19 convalescents, we looked at the PD–L1 expression as a key marker related with such an activity and found that both populations of low–density neutrophils (LDNs)/PMN–myeloid-derived suppressor cells (MDSCs) and normal density neutrophils (NDNs) showed high expression of immunosuppressive PD– L1 (Figure 3B)
Our data suggest that propagation of LDNs/PMN– MDSCs and presence of NDNs with regulatory functions are responsible for long–term endotype of immunosuppression in this group

Summary

Introduction

Since the beginning of 2020, the COVID-19 pandemic has affected more than 200 million people worldwide, causing over 4.5 million deaths so far. Lymphopenia has been reported concurrently with onset of the clinical symptoms [6] In this context, an alternative hypothesis claims the collapse of the host protective immunity (“immunologic collapse”), leading to failure in control of viral replication and dissemination [11,12,13,14]. An alternative hypothesis claims the collapse of the host protective immunity (“immunologic collapse”), leading to failure in control of viral replication and dissemination [11,12,13,14] In this scenario, an increased production of prostaglandin D2 by the respiratory epithelium [15] causes inhibition of the dendritic cell response via DP1 receptor signaling and/or upregulation of myeloid cells with regulatory functions, including myeloid-derived suppressor cells (MDSCs), which may be one of the mechanisms attenuating inflammatory response [16, 17]. The early expansion of MDSCs may inhibit SARS-CoV-2 antigenspecific T-cell response and predict fatal outcome [18], suggesting these cells as important players during COVID-19

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