Abstract
The relationship between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host immunity is poorly understood. We performed an extensive analysis of immune responses in 32 patients with severe COVID-19, some of whom succumbed. A control population of healthy subjects was included. Patients with COVID-19 had an altered distribution of peripheral blood lymphocytes, with an increased proportion of mature natural killer (NK) cells and low T-cell numbers. NK cells and CD8+ T cells overexpressed T-cell immunoglobulin and mucin domain-3 (TIM-3) and CD69. NK cell exhaustion was attested by increased frequencies of programmed cell death protein 1 (PD-1) positive cells and reduced frequencies of natural killer group 2 member D (NKG2D)-, DNAX accessory molecule-1 (DNAM-1)- and sialic acid-binding Ig-like lectin 7 (Siglec-7)-expressing NK cells, associated with a reduced ability to secrete interferon (IFN)γ. Patients with poor outcome showed a contraction of immature CD56bright and an expansion of mature CD57+ FcεRIγneg adaptive NK cells compared to survivors. Increased serum levels of IL-6 were also more frequently identified in deceased patients compared to survivors. Of note, monocytes secreted abundant quantities of IL-6, IL-8, and IL-1β which persisted at lower levels several weeks after recovery with concomitant normalization of CD69, PD-1 and TIM-3 expression and restoration of CD8+ T cell numbers. A hyperactivated/exhausted immune response dominate in severe SARS-CoV-2 infection, probably driven by an uncontrolled secretion of inflammatory cytokines by monocytes. These findings unveil a unique immunological profile in COVID-19 patients that will help to design effective stage-specific treatments for this potentially deadly disease.
Highlights
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is responsible for a pandemic, which has far caused over 33 million cases of Coronavirus Disease-19 (COVID-19) with a current case/fatality rate of 3%.1 The infection is usually associated with mild symptoms, ranging from low-grade fever to anosmia/dysgeusia, conjunctivitis and diarrhea, but may be responsible for severe interstitial pneumonia, myocarditis, acute kidney injury, acute respiratory distress syndrome (ARDS), multiorgan failure and death.[2]The systemic involvement of SARS-CoV-2 is thought to derive from the ubiquitous expression of angiotensin converting enzyme 2 receptors in humans, that the virus uses to enter the cells, and which are highly expressed in the epithelial cells of the lungs.[3]
There were statistically significant increments in natural killer (NK) cells expressing the CD69 C-type lectin (Fig. 2a), a marker of NK cell activation, and of NK cells expressing the checkpoint molecules T-cell immunoglobulin and mucin domain-3 (TIM-3) (Fig. 2b) and PD-1 (Fig. 2c), whereas the frequencies of natural killer group 2 member D (NKG2D), Siglec-7, DNAX accessory molecule-1 (DNAM-1), and CXCR6expressing NK cells were significantly reduced in COVID-19 patients (Fig. 2d–g)
There was an increase of NK cells expressing the transcription factor Aiolos, a member of the Ikaros family that plays an important role in hematopoietic development[15] (Fig. 2h), while no changes were noted in the frequencies of NKG2C, NKG2A, NKp46, NKp30, CD16, TRAIL-expressing NK cells
Summary
The systemic involvement of SARS-CoV-2 is thought to derive from the ubiquitous expression of angiotensin converting enzyme 2 receptors in humans, that the virus uses to enter the cells, and which are highly expressed in the epithelial cells of the lungs.[3] Laboratory tests indicate that patients with severe progression of COVID-19 show signs of secondary haemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome characterized by a potentially fatal cytokine storm with multiorgan failure, which may be triggered by viral infections.[4] Akin to HLH, COVID-19 is characterized by lymphopenia, and increased serum ferritin, D-dimer, C-reactive protein (CRP), and lactic-dehydrogenase (LDH), the levels of which are considered predictors of poor outcome.[5] several serum cytokine concentrations are increased during COVID-19, supporting the hypothesis that virally driven hyperinflammation plays a key pathogenetic role.[2]
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