scholarly journals Ad26.COV2.S Prevents SARS-CoV-2 Induced Pathways of Inflammation and Thrombosis in Hamsters

2021 ◽  
Author(s):  
Malika Aid ◽  
Samuel Vidal ◽  
Cesar Piedra-Mora ◽  
Sarah Ducat ◽  
Chi Chan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Expression Profiles ◽  
Severe Disease ◽  
Gene Expression Profiles ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Type I ◽  
Adaptive Immune ◽  
Syrian Golden Hamsters ◽  
The Impact

Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease, and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 challenge in hamsters stimulates antiviral, myeloid, and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, single dose immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways such that the gene expression profiles of vaccinated hamsters are comparable to uninfected animals. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses. These data provide further insights into the mechanisms of Ad26.COV2.S based protection against severe COVID-19 in hamsters.

scholarly journals Translation of IRF-1 Restricts Hepatic Interleukin-7 Production to Types I and II Interferons: Implications for Hepatic Immunity

2021 ◽  
Vol 11 ◽  
Author(s):  
Sabrina Rueschenbaum ◽  
Chengcong Cai ◽  
Matthias Schmidt ◽  
Katharina Schwarzkopf ◽  
Ulf Dittmer ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Immune Responses ◽  
Glycogen Synthase ◽  
Innate Immune ◽  
Interferon Response ◽  
Target Cells ◽  
Type I ◽  
Adaptive Immune ◽  
Interleukin 7 ◽  
The Impact

Interleukin-7 (IL-7) is an important cytokine with pivotal pro-survival functions in the adaptive immune system. However, the role of IL-7 in innate immunity is not fully understood. In the present study, the impact of hepatic IL-7 on innate immune cells was assessed by functional experiments as well as in patients with different stages of liver cirrhosis or acute-on-chronic liver failure (ACLF). Human hepatocytes and liver sinusoidal endothelial cells secreted IL-7 in response to stimulation with interferons (IFNs) of type I and II, yet not type III. De novo translation of interferon-response factor-1 (IRF-1) restricted IL-7 production to stimulation with type I and II IFNs. LPS-primed human macrophages were identified as innate immune target cells responding to IL-7 signaling by inactivation of Glycogen synthase kinase-3 (GSK3). IL-7-mediated GSK3 inactivation augmented LPS-induced secretion of pro-inflammatory cytokines and blunted LPS tolerance of macrophages. The IFN-IRF-1-IL-7 axis was present in liver cirrhosis patients. However, liver cirrhosis patients with or without ACLF had significantly lower concentrations of IL-7 in serum compared to healthy controls, which might contribute to LPS-tolerance in these patients. In conclusion, we propose the presence of an inflammatory cascade where IFNs of type I/II induce hepatocellular IL-7 in an IRF-1-restriced way. Beyond its role in adaptive immune responses, IL-7 appears to augment the response of macrophages to LPS and to ameliorate LPS tolerance, which may improve innate immune responses against invading pathogens.

scholarly journals Dysregulated immunity in SARS-CoV-2 infected pregnant women

2020 ◽  
Author(s):  
Morgan L. Sherer ◽  
Jun Lei ◽  
Patrick Creisher ◽  
Minyoung Jang ◽  
Ramya Reddy ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cord Blood ◽  
Pregnant Women ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Receptor Expression ◽  
Johns Hopkins Hospital ◽  
Blood Samples ◽  
Placental Inflammation ◽  
The Impact

AbstractImportanceThe effects of SARS-CoV-2 infection on immune responses during pregnancy have not been systematically evaluated.ObjectiveTo assess the impact of SARS-CoV-2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to SARS-CoV-2 among pregnant and non-pregnant women.DesignImmune responses to SARS-CoV-2 were analyzed using samples from pregnant and non-pregnant women who had either tested positive or negative for SARS-CoV-2. We measured, proinflammatory and placental cytokine mRNAs, neonatal Fc receptor (FcRn) receptor expression, and tetanus antibody transfer in maternal and cord blood samples. Additionally, we measured anti-spike (S) IgG, anti-S-receptor binding domain (RBD) IgG, and neutralizing antibody (nAb) responses to SARS-CoV-2 in serum or plasma collected from non-pregnant women, pregnant women, and cord blood.SettingJohns Hopkins Hospital (JHH)ParticipantsPregnant women were recruited through JHH outpatient obstetric clinics and the JHH Labor & Delivery unit. Non-pregnant women were recruited after receiving outpatient SARS-CoV-2 testing within Johns Hopkins Health System, USA. Adult non-pregnant women with positive RT-PCR results for SARS-CoV-2, within the age range of 18-48 years, were included in the study.ExposuresSARS-CoV-2Main Outcomes and MeasuresParticipant demographic characteristics, antibody titers, cytokine mRNA expression, and FcRn receptor expression.ResultsSARS-COV-2 positive pregnant women expressed more IL1β, but not IL6, in blood samples collected within 14 days versus > 14 days after a confirmed SARS-CoV-2 test, with similar patterns observed in the fetal side of placentas, particularly among asymptomatic pregnant women. Pregnant women with confirmed SARS-CoV-2 infection also had reduced anti-S-RBD IgG titers and were less likely to have detectable nAb as compared with non-pregnant women. Although SARS-CoV-2 infection did not disrupt FcRn expression in the placenta, maternal transfer of nAb was inhibited by SARS-CoV-2 infection during pregnancy.Conclusions and RelevanceSARS-CoV-2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of COVID-19 therapeutics in pregnancy. The long-term implications of placental inflammation for neonatal health also requires greater consideration.

scholarly journals BNT162b2 boosted immune responses six months after heterologous or homologous ChAdOx1nCoV-19/BNT162b2 vaccination against COVID-19

2021 ◽  
Author(s):  
Georg Behrens ◽  
Joana Barros-Martins ◽  
Anne Cossmann ◽  
Gema Morillas Ramos ◽  
Metodi Stankov ◽  
...  
Keyword(s):  
Immune Responses ◽  
Protective Immunity ◽  
Large Scale ◽  
Booster Vaccination ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Immune Protection ◽  
Cell Immunity ◽  
The Impact ◽  
As Effects

Abstract Reports suggest that COVID-19 vaccine effectiveness is decreasing, either due to waning immune protection, emergence of new variants of concern, or both. Heterologous prime/boost vaccination with a vector-based approach (ChAdOx-1nCov-19, ChAd) followed by an mRNA vaccine (e.g. BNT162b2, BNT) appeared to be superior in inducing protective immunity, and large scale second booster vaccination is ongoing. However, data comparing declining immunity after homologous and heterologous vaccination as well as effects of a third vaccine application after heterologous ChAd/BNT vaccination are lacking. We longitudinally monitored immunity in ChAd/ChAd (n=41) and ChAd/BNT (n=88) vaccinated individuals and assessed the impact of a second booster with BNT in both groups. The second booster greatly augmented waning anti-spike IgG but only moderately increased spike-specific CD4+ and CD8+ T cells in both groups to cell frequencies already present after the boost. More importantly, the second booster efficiently restored neutralizing antibody responses against Alpha, Beta, Gamma, and Delta, but neutralizing activity against B.1.1.529 (Omicron) stayed severely impaired. Our data suggest that inferior SARS-CoV-2 specific immune responses after homologous ChAd/ChAd vaccination can be cured by a heterologous BNT vaccination. However, prior heterologous ChAd/BNT vaccination provides no additional benefit for spike-specific T cell immunity or neutralizing Omicron after the second boost.

scholarly journals Severe Adaptive Immune Suppression May Be Why Patients With Severe COVID-19 Cannot Be Discharged From the ICU Even After Negative Viral Tests

2021 ◽  
Vol 12 ◽  
Author(s):  
Yue Zhou ◽  
Xuelian Liao ◽  
Xiangrong Song ◽  
Min He ◽  
Fei Xiao ◽  
...  
Keyword(s):  
Immune Suppression ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Severe Disease ◽  
Gene Expression Profiles ◽  
Severe Infection ◽  
Underlying Mechanism ◽  
Adaptive Immune ◽  
Secondary Infections ◽  
Peripheral Immune Cells

During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. To explore the underlying mechanism, we collected blood samples from these patients and analyzed the gene expression profiles of peripheral immune cells. We found that all enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. In addition, no significant change was found in the expression of classic immunosuppression molecules including PD-1, PD-L1, and CTLA-4, suggesting that the adaptive immune suppression may not be due to the change of these genes. According to the published literatures and our data, this adaptive immunosuppression is likely to be caused by the “dysregulated host response” to severe infection, similar to the immunosuppression that exists in other severely infected patients with sepsis.

scholarly journals BNT162b2 boosted immune responses six months after heterologous or homologous ChAdOx1nCoV-19/BNT162b2 vaccination against COVID-19

2021 ◽  
Author(s):  
Georg MN Behrens ◽  
Joana Barros-Martins ◽  
Anne Cossmann ◽  
Gema Morillas Ramos ◽  
Metodi V Stankov ◽  
...  
Keyword(s):  
Immune Responses ◽  
Protective Immunity ◽  
Large Scale ◽  
Booster Vaccination ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Immune Protection ◽  
Cell Immunity ◽  
The Impact ◽  
As Effects

Reports suggest that COVID-19 vaccine effectiveness is decreasing, either due to waning immune protection, emergence of new variants of concern, or both. Heterologous prime/boost vaccination with a vector-based approach (ChAdOx-1nCov-19, ChAd) followed by an mRNA vaccine (e.g. BNT162b2, BNT) appeared to be superior in inducing protective immunity, and large scale second booster vaccination is ongoing. However, data comparing declining immunity after homologous and heterologous vaccination as well as effects of a third vaccine application after heterologous ChAd/BNT vaccination are lacking. We longitudinally monitored immunity in ChAd/ChAd (n=41) and ChAd/BNT (n=88) vaccinated individuals and assessed the impact of a second booster with BNT in both groups. The second booster greatly augmented waning anti-spike IgG but only moderately increased spike-specific CD4+ and CD8+ T cells in both groups to cell frequencies already present after the boost. More importantly, the second booster efficiently restored neutralizing antibody responses against Alpha, Beta, Gamma, and Delta, but neutralizing activity against B.1.1.529 (Omicron) stayed severely impaired. Our data suggest that inferior SARS-CoV-2 specific immune responses after homologous ChAd/ChAd vaccination can be cured by a heterologous BNT vaccination. However, prior heterologous ChAd/BNT vaccination provides no additional benefit for spike-specific T cell immunity or neutralizing Omicron after the second boost.

scholarly journals Thymosin alpha-1 Protected T Cells from Excessive Activation in Severe COVID-19

2020 ◽  
Author(s):  
Kuai Yu ◽  
Yongjian Wu ◽  
Jingjing He ◽  
Xuefei Liu ◽  
Bo Wei ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Severe Disease ◽  
Adaptive Immune Responses ◽  
Activated T Cells ◽  
Adaptive Immune ◽  
The Impact ◽  
Excessive Activation

Abstract Two typical features of uncontrolled inflammation, cytokine storm and lymphopenia, are associated with the severity of coronavirus disease 2019 (COVID-19), demonstrating that both innate and adaptive immune responses are involved in the development of this disease. Recent studies have explored the contribution of innate immune cells to the pathogenesis of the infection. However, the impact of adaptive immunity on this disease remains unknown. In order to clarify the role of adaptive immune response in COVID-19, we characterized the phenotypes of lymphocytes in PBMCs from patients at different disease stages using single-cell RNA sequencing (scRNA-seq) technology. Dynamics of the effector cell levels in lymphocytes revealed dysregulated adaptive immune responses in patients with severe disease. A new cluster of excessively activated CD8 T cells (Tea) was further identified, which displayed exhausted phenotypes and diminished function of antigen recognition. Interestingly, expression of PTMA, the proprotein of Tα1, was significantly increased in a group of highly proliferating CD8 T cells with memory stem cell features. We further showed that Tα1 significantly promoted the proliferation of activated T cells in vitro and relieved the lymphopenia in COVID-19 patients. Our data suggest that protection of T cells from excessive activation might be critical for the prevention of severe COVID-19.

scholarly journals Contribution of innate and adaptive immune cells to the elimination of Salmonella enterica serotype Enteritidis infection in young broiler chickens

2021 ◽  
Author(s):  
Nathalie Meijerink ◽  
Robin H.G.A. van den Biggelaar ◽  
Daphne A. van Haarlem ◽  
J. Arjan Stegeman ◽  
Victor P.M.G. Rutten ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Nk Cells ◽  
Salmonella Enterica ◽  
Broiler Chickens ◽  
Immune Modulation ◽  
Severe Disease ◽  
Antibody Responses ◽  
Adaptive Immune

AbstractSalmonella enterica serotype Enteritidis (SE) is a zoonotic pathogen which causes foodborne diseases in humans through contaminated poultry products, as well as severe disease symptoms in young chickens. More insight in innate and adaptive immune responses of chickens to SE infection is needed to understand elimination of SE. Seven-day-old broiler chickens were experimentally challenged with SE and numbers and responsiveness of innate immune cells including natural killer (NK) cells, macrophages and dendritic cells (DCs) were assessed during 21 days post-infection (dpi). In parallel, numbers and function of γδ T cells, CD8+ and CD4+ T cells as well as antibody titres were determined. SE was observed in the intestine and spleen of SE-infected chickens at 7 dpi. NK and T cells responded first to SE at 1 and 3 dpi as indicated by increased numbers of intestinal IL-2Rα+ and 20E5+ NK cells, in addition to enhanced activation of intestinal and splenic NK cells. At 7 dpi in the spleen, the presence of macrophages and the expression of activation markers on DCs was increased. At 21 dpi, an increase in intestinal γδ and CD8+ T cell numbers was observed. Furthermore, SE-specific proliferation of splenic CD4+ and CD8+ T cells was observed and SE-specific antibodies were detected in all blood samples of SE-infected chickens. In conclusion, SE results in enhanced numbers and activation of innate cells during early stages of infection and it is hypothesized that in concert with subsequent specific T cell and antibody responses, reduction of SE in infected chickens is achieved. A better understanding of innate and adaptive immune responses important in the elimination of SE will aid in developing immune-modulation strategies, which may increase resistance and prevent SE infection and colonization in young broiler chickens and hence increase food safety for humans.Author summarySalmonella enterica serotype Enteritidis (SE) causes foodborne zoonotic diseases in humans, as well as a severe disease in young chickens. As a consequence of which health and welfare of humans and chickens are affected, resulting in substantial economic losses. To enable development of immune-mediated prevention strategies in chickens, more insight in the immune responses to SE is needed to understand how the infection is eliminated. For this purpose, we investigated non-specific and specific immune responses upon experimental SE infection in young broiler chickens. In this study, we found SE in the intestine and spleen of SE-infected chickens at 7 days post-infection (dpi). We show that natural killer (NK) cells respond first by enhanced presence and activation, followed by increased presence of macrophages and activation of dendritic cells. These early responses are hypothesized to stimulate the observed subsequent specific T cell and antibody responses. Better understanding of immune responses important in the elimination of SE will aid in developing immune-modulation strategies, which may increase resistance and prevent SE infection and colonization in young chickens and hence reduce SE-related foodborne illness in humans.

scholarly journals Postnatal lymph node expansion of stromal progenitors towards reticular and CD34+ stromal cell subsets is determined by distinct transcriptional programs

2021 ◽  
Author(s):  
Joern Pezoldt ◽  
Carolin Wiechrs ◽  
Maria Litovchenko ◽  
Marjan Biočanin ◽  
Mangge Zou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Stromal Cell ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Developmental Trajectory ◽  
Mesenteric Lymph Nodes ◽  
Adaptive Immune Responses ◽  
Tissue Specific ◽  
Adaptive Immune

Abstract Gut-draining mesenteric lymph nodes (mLN) provide the framework and microenvironment to shape intestinal adaptive immune responses. We previously delineated transcriptional signatures in LN stromal cells (SC), pointing to tissue-specific variability in composition and immuno-modulatory function of SCs. Here, we dissect the tissue-specific epigenomic DNA accessibility and CpG methylation landscape of LN non-endothelial SCs and identify a microbiota-independent core epigenomic signature of LN SCs. By combined analysis of transcription factor (TF) binding sites together with the gene expression profiles of non-endothelial SCs, we delineated TFs poising skin-draining peripheral LN (pLN) SCs for pro-inflammatory responses. Furthermore, using scRNA-seq, we dissected the developmental trajectory of mLN SCs derived from postnatal to aged mice, identifying two distinct putative progenitors, namely CD34+SC and fibroblastic reticular stromal cell (FRC) progenitors, which both feed the rapid postnatal LN expansion. Finally, we identified Irf3 as a key differentiation TF inferred from the epigenomic signature of mLN SCs that is dynamically expressed along the differentiation trajectories of FRCs, and validated Irf3 as a regulator of Cxcl9+ FRC differentiation. Together, our data constitute a comprehensive transcriptional and epigenomic map of mLN development and dissect location-specific, microbiota-independent properties of mLN non-endothelial SCs. As such, our findings represent a valuable resource to identify core transcriptional regulators that impinge on the developing mLN early in life, thereby shaping long-lasting intestinal adaptive immune responses.

scholarly journals Postnatal lymph node expansion of stromal progenitors towards reticular and CD34+ stromal cell subsets is determined by distinct transcriptional programs

2021 ◽  
Author(s):  
Joern Pezoldt ◽  
Carolin Wiechers ◽  
Maria Litovchenko ◽  
Marjan Biocanin ◽  
Mangge Zou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Stromal Cell ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Developmental Trajectory ◽  
Mesenteric Lymph Nodes ◽  
Adaptive Immune Responses ◽  
Tissue Specific ◽  
Adaptive Immune

Gut-draining mesenteric lymph nodes (mLN) provide the framework and microenvironment to shape intestinal adaptive immune responses. We previously delineated transcriptional signatures in LN stromal cells (SC), pointing to tissue-specific variability in composition and immuno-modulatory function of SCs. Here, we dissect the tissue-specific epigenomic DNA accessibility and CpG methylation landscape of LN non-endothelial SCs and identify a microbiota-independent core epigenomic signature of LN SCs. By combined analysis of transcription factor (TF) binding sites together with the gene expression profiles of non-endothelial SCs, we delineated TFs poising skin-draining peripheral LN (pLN) SCs for pro-inflammatory responses. Furthermore, using scRNA-seq, we dissected the developmental trajectory of mLN SCs derived from postnatal to aged mice, identifying two distinct putative progenitors, namely CD34+ SC and fibroblastic reticular stromal cell (FRC) progenitors, which both feed the rapid postnatal LN expansion. Finally, we identified Irf3 as a key differentiation TF inferred from the epigenomic signature of mLN SCs that is dynamically expressed along the differentiation trajectories of FRCs, and validated Irf3 as a regulator of Cxcl9+ FRC differentiation. Together, our data constitute a comprehensive transcriptional and epigenomic map of mLN development and dissect location-specific, microbiota-independent properties of mLN non-endothelial SCs. As such, our findings represent a valuable resource to identify core transcriptional regulators that impinge on the developing mLN early in life, thereby shaping long-lasting intestinal adaptive immune responses.

Sign in / Sign up

Export Citation Format

Share Document