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A Review of the Multipronged Attack of Herpes Simplex Virus 1 on the Host Transcriptional Machinery
(2021)
During lytic infection, herpes simplex virus (HSV) 1 induces a rapid shutoff of host RNA synthesis while redirecting transcriptional machinery to viral genes. In addition to being a major human pathogen, there is burgeoning clinical interest in HSV as a vector in gene delivery and oncolytic therapies, necessitating research into transcriptional control. This review summarizes the array of impacts that HSV has on RNA Polymerase (Pol) II, which transcribes all mRNA in infected cells. We discuss alterations in Pol II holoenzymes, post-translational modifications, and how viral proteins regulate specific activities such as promoter-proximal pausing, splicing, histone repositioning, and termination with respect to host genes. Recent technological innovations that have reshaped our understanding of previous observations are summarized in detail, along with specific research directions and technical considerations for future studies.
Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro.
After more than one year of the COVID-19 pandemic, antiviral treatment options against SARS-CoV-2 are still severely limited. High hopes that had initially been placed on antiviral drugs like remdesivir have so far not been fulfilled. While individual case reports provide striking evidence for the clinical efficacy of remdesivir in the right clinical settings, major trials failed to demonstrate this. Here, we highlight and discuss the key findings of these studies and underlying reasons for their failure. We elaborate on how such shortcomings should be prevented in future clinical trials and pandemics. We suggest in conclusion that any novel antiviral agent that enters human trials should first be tested in a post-exposure setting to provide rapid and solid evidence for its clinical efficacy before initiating further time-consuming and costly clinical trials for more advanced disease. In the COVID-19 pandemic this might have established remdesivir early on as an efficient antiviral agent at a more suitable disease stage which would have saved many lives, in particular in large outbreaks within residential care homes.
Several new N-substituted 1,2-benzisothiazol-3(2H)-ones (BITs) were synthesised through a facile synthetic route for testing their anti-dengue protease inhibition. Contrary to the conventional multistep synthesis, we achieved structurally diverse BITs with excellent yields using a two-step, one-pot reaction strategy. All the synthesised compounds were prescreened for drug-like properties using the online Swiss Absorption, Distribution, Metabolism and Elimination (SwissADME) model, indicating their favourable pharmaceutical properties. Thus, the synthesised BITs were tested for inhibitory activity against the recombinant dengue virus serotype-2 (DENV-2) NS2BNS3 protease. Dose–response experiments and computational docking analyses revealed that several BITs bind to the protease in the vicinity of the catalytic triad with IC\(_{50}\) values in the micromolar range. The DENV2 infection assay showed that two BITs, 2-(2-chlorophenyl)benzo[d]isothiazol-3(2H)-one and 2-(2,6-dichlorophenyl)benzo[d]isothiazol-3(2H)-one, could suppress DENV replication and virus infectivity. These results indicate the potential of BITs for developing new anti-dengue therapeutics.
Candida albicans is ubiquitously present, and colonization in the nose and oral cavity is common. In healthy patients, it usually does not act as a pathogen, but in some cases can cause diseases. The influence of C. albicans as a trigger of T cell activation on the pathogenesis of chronic rhinosinusitis (CRS) is controversial, and its exact role is not clear to date. The aim of the present study was to detect and characterize C. albicans-specific CD4+ and CD8+ T cells in patients with CRS, with and without nasal polyps. Tissue and blood samples were collected from patients suffering from chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP), and from healthy controls. A peptide pool derived from C. albicans antigen was added to tissue and blood samples. After 6 days, lymphocytes were analyzed by multicolor flow cytometry. Activation was assessed by the intracellular marker Ki-67, and the cytokine secretion was measured. Tissue CD8+ T cells of CRSsNP patients showed a significantly higher proportion of Ki-67+ cells after activation with C. albicans antigen compared to peripheral blood CD8+ T cells. Cytokine secretion in response to C. albicans antigen was similar for all study groups. In this study, C. albicans-specific CD4+ and CD8+ T cells were detected in peripheral blood and mucosal tissue in all study groups. In patients suffering from CRSsNP, C. albicans-specific CD8+ T cells were relatively enriched in the nasal mucosa, suggesting that they might play a role in the pathogenesis of CRSsNP.
ITN—VIROINF: Understanding (harmful) virus-host interactions by linking virology and bioinformatics
(2021)
Many recent studies highlight the fundamental importance of viruses. Besides their important role as human and animal pathogens, their beneficial, commensal or harmful functions are poorly understood. By developing and applying tailored bioinformatical tools in important virological models, the Marie Skłodowska-Curie Initiative International Training Network VIROINF will provide a better understanding of viruses and the interaction with their hosts. This will open the door to validate methods of improving viral growth, morphogenesis and development, as well as to control strategies against unwanted microorganisms. The key feature of VIROINF is its interdisciplinary nature, which brings together virologists and bioinformaticians to achieve common goals.
Myeloid-derived suppressor cells (MDSCs) represent a major population controlling T cell immune responses. However, little is known about their molecular requirements for homing and T cell interaction to mediate suppression. Here, we investigated the functional role of the homing and collagen IV receptor VLA-1 (α1β1-integrin) on in vitro GM-CSF generated murine MDSCs from wild-type (WT) and CD49a/α1-integrin (Itga1\(^{−/−}\)) gene-deficient mice. Here, we found that effector (Teff) but not naive (Tn) CD4\(^+\) T cells express VLA-1 and monocytes further up-regulated their expression after culture in GM-CSF when they differentiated into the monocytic subset of resting MDSCs (R-MDSCs). Subsequent activation of R-MDSCs by LPS+IFN-γ (A-MDSCs) showed increased in vitro suppressor potential, which was independent of VLA-1. Surprisingly, VLA-1 deficiency did not influence A-MDSC motility or migration on collagen IV in vitro. However, interaction times of Itga1\(^{−/−}\) A-MDSCs with Teff were shorter than with WT A-MDSCs on collagen IV but not on fibronectin substrate in vitro. After injection, A-MDSCs homed to the splenic red pulp where they co-localized with Teff and showed immediate suppression already after 6 h as shown by inhibition of T cell proliferation and induction of apoptosis. Injection of A-MDSCs from Itga1\(^{−/−}\) mice showed equivalent homing into the spleen but a reduced suppressive effect. Interaction studies of A-MDSCs with Teff in the subcapsular red pulp with intravital two-photon microscopy revealed also here that MDSC motility and migration parameters were not altered by VLA-1 deficiency, but the interaction times with Teff were reduced. Together, our data point to a new role of VLA-1 adhesion to collagen IV as a prerequisite for extended contact times with Teff required for suppression.
Like human Th1 cells, mouse Th1 cells also secrete IFN‐γ upon stimulation with a superagonistic anti‐CD28 monoclonal antibody (CD28‐SA). Crosslinking of the CD28‐SA via FcR and CD40‐CD40L interactions greatly increased IFN‐γ release. Our data stress the utility of the mouse as a model organism for immune responses in humans.
Aims
It has been hypothesized that cardiac decompensation accompanying acute heart failure (AHF) episodes generates a pro-inflammatory environment boosting an adaptive immune response against myocardial antigens, thus contributing to progression of heart failure (HF) and poor prognosis. We assessed the prevalence of anti-myocardial autoantibodies (AMyA) as biomarkers reflecting adaptive immune responses in patients admitted to the hospital for AHF, followed the change in AMyA titres for 6 months after discharge, and evaluated their prognostic utility.
Methods and results
AMyA were determined in n = 47 patients, median age 71 (quartiles 60; 80) years, 23 (49%) female, and 24 (51%) with HF with preserved ejection fraction, from blood collected at baseline (time point of hospitalization) and at 6 month follow-up (visit F6). Patients were followed for 18 months (visit F18). The prevalence of AMyA increased from baseline (n = 21, 45%) to F6 (n = 36, 77%; P < 0.001). At F6, the prevalence of AMyA was higher in patients with HF with preserved ejection fraction (n = 21, 88%) compared with patients with reduced ejection fraction (n = 14, 61%; P = 0.036). During the subsequent 12 months after F6, that is up to F18, patients with newly developed AMyA at F6 had a higher risk for the combined endpoint of death or rehospitalization for HF (hazard ratio 4.79, 95% confidence interval 1.13–20.21; P = 0.033) compared with patients with persistent or without AMyA at F6.
Conclusions
Our results support the hypothesis that AHF may induce patterns of adaptive immune responses. More studies in larger populations and well-defined patient subgroups are needed to further clarify the role of the adaptive immune system in HF progression.
SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema and hemorrhage. In addition to the lung, cytokine storm-induced inflammatory cascade also affects other organs. SARS-CoV-2 infection-related vascular inflammation is characterized by endotheliopathy in the lung and other organs. Whether SARS-CoV-2 causes endotheliopathy by directly infecting endothelial cells is not known and is the focus of the present study. We observed 1) the co-localization of SARS-CoV-2 with the endothelial cell marker CD31 in the lungs of SARS-CoV-2-infected mice expressing hACE2 in the lung by intranasal delivery of adenovirus 5-hACE2 (Ad5-hACE2 mice) and non-human primates at both the protein and RNA levels, and 2) SARS-CoV-2 proteins in endothelial cells by immunogold labeling and electron microscopic analysis. We also detected the co-localization of SARS-CoV-2 with CD31 in autopsied lung tissue obtained from patients who died from severe COVID-19. Comparative analysis of RNA sequencing data of the lungs of infected Ad5-hACE2 and Ad5-empty (control) mice revealed upregulated KRAS signaling pathway, a well-known pathway for cellular activation and dysfunction. Further, we showed that SARS-CoV-2 directly infects mature mouse aortic endothelial cells (AoECs) that were activated by performing an aortic sprouting assay prior to exposure to SARS-CoV-2. This was demonstrated by co-localization of SARS-CoV-2 and CD34 by immunostaining and detection of viral particles in electron microscopic studies. Moreover, the activated AoECs became positive for ACE-2 but not quiescent AoECs. Together, our results indicate that in addition to pneumocytes, SARS-CoV-2 also directly infects mature vascular endothelial cells in vivo and ex vivo, which may contribute to cardiovascular complications in SARS-CoV-2 infection, including multipleorgan failure.