Transcriptomic characteristics and impaired immune function of patients who retest positive for SARS-CoV-2 RNA

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,has become a global public health crisis.Some patients who have recovered from COVID-19 subsequently test positive again for SARS-CoV-2 RNA after discharge from hospital.How such retest-positive(RTP)patients become infected again is not known.In this study,30 RTP patients,20 convalescent patients,and 20 healthy controls were enrolled for the analysis of immunological characteristics of their peripheral blood mononuclear cells.We found that absolute numbers of CD4^(+)T cells,CD8^(+)T cells,and natural killer cells were not substantially decreased in RTP patients,but the expression of activation markers on these cells was significantly reduced.The percentage of granzyme B-producing T cells was also lower in RTP patients than in convalescent patients.Through transcriptome sequencing,we demonstrated that high expression of inhibitor of differentiation 1(ID1)and low expression of interferon-induced transmembrane protein 10(IFITM10)were associated with insufficient activation of immune cells and the occurrence of RTP.These findings provide insight into the impaired immune function associated with COVID-19 and the pathogenesis of RTP,which may contribute to a better understanding of the mechanisms underlying RTP.

Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface

During early pregnancy, an orchestrated evolutionary maternal adaption toward tolerance of the semiallogeneic fetus is required to ensure decidualization and early embryo development. Remodeling of the immune system involves natural killer cells （NKs）, macrophages, T cells and dendritic cells （DCs） altering the microenvironment in the deciduas. In particular, a unique population of NK cells with a CD56brightCD16 phenotype in the decidua has been proposed to play a key role in the maternal adaptation to pregnancy. However, there is a tendency for pregnancy immunology to reflect transplantation immunology regarding the assumption that the matemal immune system should be suppressed. This tendency is misleading. We discuss how the immune system is formed in early deciduas and the interactions between maternal NK cells and fetal growth. We propose that the maternal immune response must not be fully suppressed and is even necessary for the local response of uterine NK cells.

Restoration of HBV-specific CD8+T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-αtherapy

Patients with chronic hepatitis B(CHB)undergoing interferon(IFN)-α-based therapies often exhibit a poor HBeAg serological response.Thus,there is an unmet need for new therapies aimed at CHB.This study comprised two clinical trials,including 130 CHB patients,who were treatment-naïve;in the first,92 patients were systematically analyzed ex vivo for interleukin-2 receptor(IL-2R)expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy.In our second clinical trial,38 non-responder patients,in whom IFN-αtherapy had failed,were treated with or without low-dose IL-2 for 24 weeks.We then examined the hepatitis B virus(HBV)-specific CD8+T-cell response and the clinical outcome,in these patients.Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders,we observed a decrease in CD25 expression on their CD4+T cells,suggesting that IFN-αtherapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells(Tregs).Following sequential therapy with IL-2,we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1(PD-1)expression.In addition,sequential IL-2 administration rescued effective immune function,involving signal transducer and activator of transcription 1(STAT1)activation.Importantly,IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+T cells,which translated into improved clinical outcomes,including HBeAg seroconversion,among the non-responder CHB patients.Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.

Analysis of uterine CD49a^(+) NK cell subsets in menstrual blood reflects endometrial status and association with recurrent spontaneous abortion

Maternal uterine immune cells,especially natural killer(NK)cells,are important for successful pregnancy,and an abnormal number or function of uterine NK cells is closely correlated with an impaired endometrial environment and miscarriage.However,there are currently no noninvasive testing methods using reliable indicators that accurately predict uterine changes leading to miscarriage.Here,we confirmed that before implantation,menstrual blood(MB)from healthy donors had 70%CD49a^(+)tissue-resident NK(trNK)cells,the majority of which were CD49a^(+)Eomes+NK cells.Importantly,MB from patients with recurrent spontaneous abortion(RSA)had many fewer CD49a^(+)trNK cells than MB from controls.Analysis of uNK cell populations in MB may better predict an abnormal endometrial environment associated with miscarriage than peripheral blood(PB)analysis.Therefore,we suggest using MB-and CD49a-related markers as a promising noninvasive way to evaluate endometrial status.

Pyroptotic macrophages stimulate the SARS-CoV-2-associated cytokine storm

Coronavirus disease 2019(COVID-19)is an unprecedented pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).As of 22 February 2021,the worldwide pandemic has resulted in more than 110 million cases and 2.4 million deaths.1 Clinical investigation of COVID-19 patients has shown that a systemic cytokine storm can occur,especially in severe cases.2 Treatment of the SARS-CoV-2-associated cytokine storm with tocilizumab3 or anakinra4 has been shown to immediately improve the clinical outcome in most severe and critical COVID-19 patients.These data highlight the systemic cytokine storm as an important exacerbating event in severe COVID-19;however,our understanding of the molecular mechanisms involved in the initiation of the SARS-CoV-2-associated cytokine storm is limited.In the present study,we uncovered a reasonable explanation for cytokine storm initiation through the analysis of 13 autopsy samples from severe COVID-19 patients.

Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial

Tocilizumab has been reported to attenuate the“cytokine storm”in COVID-19 patients.We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment.We conducted a randomized,controlled,open-label multicenter trial among COVID-19 patients.The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone.The cure rate,changes of oxygen saturation and interference,and inflammation biomarkers were observed.Thirty-three patients were randomized to the tocilizumab group,and 32 patients to the control group.The cure rate in the tocilizumab group was higher than that in the control group,but the difference was not statistically significant(94.12%vs.87.10%,rate difference 95%CI−7.19%–21.23%,P=0.4133).The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12(P=0.0359).In moderate disease patients with bilateral pulmonary lesions,the hypoxia ameliorated earlier after tocilizumab treatment,and less patients(1/12,8.33%)needed an increase of inhaled oxygen concentration compared with the controls(4/6,66.67%;rate difference 95%CI−99.17%to−17.50%,P=0.0217).No severe adverse events occurred.More mild temporary adverse events were recorded in tocilizumab recipients(20/34,58.82%)than the controls(4/31,12.90%).Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative.For patients with bilateral pulmonary lesions and elevated IL-6 levels,tocilizumab could be recommended to improve outcome.