COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and ...immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.
The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to ...analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.
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•Quantitative lipidomic and metabolomic profiling of COVID-19 plasma•Plasma metabolite panel distinguished COVID-19 from healthy controls (AUC = 0.975)•Differential correlation analyses uncovered metabolic dysregulation in COVID-19•GM3-enriched exosomes are positively correlated with COVID-19 pathogenesis
Plasma metabolite panel effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma monosialodihexosyl gangliosides (GM3s) were negatively correlated with CD4+ T cell count in COVID-19 patients, and GM3-enriched exosomes were positively correlated with disease severity. These observations suggest that GM3-enriched exosomes may participate in pathological processes associated with COVID-19 progression.
The vascular response to pro-atherosclerotic factors is a multifactorial process involving endothelial cells (ECs), macrophages (MACs), and smooth muscle cells (SMCs), although the mechanism by which ...these cell types communicate with each other in response to environmental cues is yet to be understood. Here, we show that miR-155, which is significantly expressed and secreted in Krüppel-like factor 5 (KLF5)-overexpressing vascular smooth muscle cells (VSMCs), is a potent regulator of endothelium barrier function through regulating endothelial targeting tight junction protein expression. VSMCs-derived exosomes mediate the transfer of KLF5-induced miR-155 from SMCs to ECs, which, in turn, destroys tight junctions and the integrity of endothelial barriers, leading to an increased endothelial permeability and enhanced atherosclerotic progression. Moreover, overexpression of miR-155 in ECs inhibits endothelial cell proliferation/migration and re-endothelialization in vitro and in vivo and thus increases vascular endothelial permeability. Blockage of the exosome-mediated transfer of miR-155 between these two cells may serve as a therapeutic target for atherosclerosis.
In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not ...fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4
effector-GNLY (granulysin), CD8
effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.
SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and ...inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-β, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-β and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.
A comprehensive immune landscape for HBV infection is pivotal to achieve HBV cure.
We performed single-cell RNA sequencing of 2 43 000 cells from 46 paired liver and blood samples of 23 individuals, ...including six immune tolerant, 5 immune active (IA), 3 acute recovery (AR), 3 chronic resolved and 6 HBV-free healthy controls (HCs). Flow cytometry and histological assays were applied in a second HBV cohort for validation.
Both IA and AR were characterised by high levels of intrahepatic exhausted CD8+ T (Tex) cells. In IA, Tex cells were mainly derived from liver-resident GZMK+ effector memory T cells and self-expansion. By contrast, peripheral CX3CR1+ effector T cells and GZMK+ effector memory T cells were the main source of Tex cells in AR. In IA but not AR, significant cell-cell interactions were observed between Tex cells and regulatory CD4+ T cells, as well as between Tex and FCGR3A+ macrophages. Such interactions were potentially mediated through human leukocyte antigen class I molecules together with their receptors CANX and LILRBs, respectively, contributing to the dysfunction of antiviral immune responses. By contrast, CX3CR1+GNLY+ central memory CD8+ T cells were concurrently expanded in both liver and blood of AR, providing a potential surrogate marker for viral resolution. In clinic, intrahepatic Tex cells were positively correlated with serum alanine aminotransferase levels and histological grading scores.
Our study dissects the coordinated immune responses for different HBV infection phases and provides a rich resource for fully understanding immunopathogenesis and developing effective therapeutic strategies.
Eukaryotic cells are constantly exposed to various environmental stimuli. It remains largely unexplored how environmental cues bring about epigenetic fluctuations and affect heterochromatin ...stability. In the fission yeast
, heterochromatic silencing is quite stable at pericentromeres but unstable at the mating-type (
) locus under chronic heat stress, although both loci are within the major constitutive heterochromatin regions. Here, we found that the compromised gene silencing at the
locus at elevated temperature is linked to the phosphorylation status of Atf1, a member of the ATF/CREB superfamily. Constitutive activation of mitogen-activated protein kinase (MAPK) signaling disrupts epigenetic maintenance of heterochromatin at the
locus even under normal temperature. Mechanistically, phosphorylation of Atf1 impairs its interaction with heterochromatin protein Swi6
, resulting in lower site-specific Swi6
enrichment. Expression of non-phosphorylatable Atf1, tethering Swi6
to the
-flanking site or absence of the anti-silencing factor Epe1 can largely or partially rescue heat stress-induced defective heterochromatic maintenance at the
locus.
The tumor acidic microenvironment, a common biochemical event in solid tumors, offers evolutional advantage for tumors cells and even enhances their aggressive phenotype. However, little is known ...about the molecular mechanism underlying the acidic microenvironment-induced invasion and metastasis.
We examined the expression of the acid-sending ion channel (ASIC) family members after acidic exposure using RT-PCR and immunofluoresence. Gene manipulation was applied to reveal the potential of ASIC2 on invasion, proliferation, colony formation of colorectal cancer (CRC). We assessed the in vivo tumor growth by subcutaneous transplantation and metastasis by spleen xenografts. Chromatin immunoprecipitation-sequencing was used to uncover the binding sites of NFAT1. Finally, we examined the expression of ASIC2 in CRC tissues using immunohistochemistry.
Acidic exposure led to up-regulation of the acid-sensing ion channel, ASIC2, in colorectal cancer (CRC) cells. ASIC2 overexpression in CRC cell lines, SW480 and HCT116, significantly enhanced cell proliferation in vitro and in vivo, while ASIC2 knockdown had the reverse effect. Importantly, ASIC2 promoted CRC cell invasion under acidosis in vitro and liver metastasis in vivo. Mechanistically, ASIC2 activated the calcineurin/NFAT1 signaling pathway under acidosis. Inhibition of the calcineurin/NFAT pathway by cyclosporine A (CsA) profoundly attenuated ASIC2-induced invasion under acidosis. ChIP-seq assay revealed that the nuclear factor, NFAT1, binds to genes clustered in pathways involved in Rho GTPase signaling and calcium signaling. Furthermore, immunohistochemistry showed that ASIC2 expression is increased in CRC samples compared to that in adjacent tissues, and ASIC2 expression correlates with T-stage, distant metastasis, recurrence, and poor prognosis.
ASIC2 promotes metastasis of CRC cells by activating the calcineurin/NFAT1 pathway under acidosis and high expression of ASIC2 predicts poor outcomes of patients with CRC.
The coronavirus disease 2019 (COVID-19) pandemic poses a great threat to public health. Individuals who are immunocompromised because of the progression of the primary disease or receiving ...immunosuppressive medications are prone to severe COVID-19 complications and poor outcomes. Abundant data have shown that many COVID-19 vaccines are safe and effective in large-scale populations; however, these clinical trials have excluded immunocompromised populations. Available evidence indicates that immunocompromised populations have a blunted immune response to other vaccines, raising concerns regarding the efficacy of COVID-19 vaccination in these populations. Thus, there is an urgent need to delineate the efficacy of COVID-19 vaccines in these vulnerable populations. Here, we review the characteristics of specific humoral and cellular responses to COVID-19 vaccination in immunocompromised populations, including HIV-infected patients and those receiving immunosuppressive treatment, especially solid organ transplant recipients and those undergoing anti-CD20 treatment. We also addressed the challenges that immunocompromised populations will face in the future pandemic and the need for basic and clinical translational studies to highlight the best vaccination strategies for these populations.
Globally, there were an estimated 7.1 million new syphilis infections in 2020, with more than 30% of these new infections reported in African countries such as Sierra Leone. Despite this, there is no ...HIV-specific syphilis screening program in Sierra Leone. Thus, data are needed to inform public health practice. In this study, we aimed to determine the prevalence of syphilis seropositivity and factors associated with syphilis seropositivity among people living with HIV (PLHIV). A cross-sectional study was conducted at 10 health facilities in Sierra Leone, among adults with HIV, aged 18 years or older, from September 2022 to January 2023. Parameters of interest were collected including age, sex, marriage, antiretroviral therapy (ART) regimen, HIV viral load, duration of ART treatment, and hospital level of care. The syphilis antibody was detected by a rapid test based on immunochromatography assay. Data were analyzed using R-software version 4.2.3 (R Core Team, Vienna, Austria). Pearson's chl.sup.2 test, Fisher's exact test and Kruskal-Wallis H test were applied to assess the differences in syphilis seropositivity between groups as appropriate. Univariate logistic regression and multivariate logistic regression analysis was used to assess factors associated with syphilis seropositivity. The level of statistical significance was set at P < 0.05. Of the 3082 PLHIV individuals in our study, 2294 (74.4%) were female and 2867 (93.0%) were receiving ART. With a median age of 36 years, 211 (6.8%, 95% CI 6.0-7.7) were positive for syphilis. The prevalence of syphilis was highest in people aged 60 years and over (21.1%, 95%CI 14.7-29.2), followed by people aged 50-60 years (15.5%, 95%CI 11.9-19.9) and in the widowed population (11.9%, 95%CI 8.9-15.8). There were no differences in syphilis seropositivity between gender, ART status, ART regimen, duration of ART, HIV viral load and hospital level of care. Older age (50-60 years: adjusted OR 3.49, 95%CI 2.09-5.85 P < 0.001; 60-100 years: adjusted OR 4.28, 95%CI 2.21-8.17, P < 0.001) was an independent predictor of seropositive syphilis. We observed a high prevalence of syphilis among PLHIV. Older people and widowed population have higher syphilis seropositivity. Older age was an independent predictor of syphilis positivity. Therefore, we call for the integration of syphilis screening, treatment and prevention in HIV services.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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