Adult patients with severe respiratory syncytial virus infections in the emergency department.

Respiratory syncytial virus (RSV) is a seasonal virus known to cause significant morbidity in pediatric patients; however, morbidity in adult patients has not been well investigated. We aimed to characterize adult patients with RSV infection in the emergency department (ED) and their clinical course. During the winter term 2022/23, all adult ED patients were screened for RSV, severe acute respiratory syndrome coronavirus type 2, and influenza infection using point-of-care polymerase chain reaction tests. All symptomatic RSV+ patients were further characterized based on their clinical presentation and course. A group comparison between RSV+ inpatients and RSV+ outpatients was conducted. The potential risk factors for inpatient treatment were evaluated using univariate and multivariate analyses. Of the 135 symptomatic RSV+ patients, 51.9% (70/135) were inpatients. Their length of stay were 9.4 (±10.4) days. Inpatients had a significantly higher mean age, lower oxygen saturation, higher leukocyte count, and higher C-reactive protein levels than outpatients. Among the preconditions, pulmonary diseases, tumors, and immunosuppression were significantly more frequent in the inpatient group. Thirty percent (21/70) of the inpatients required ICU treatment, 11% (8/70) required mechanical ventilation, and 9% (6/70) died. Malaise (P = .021, odds ratio 8.390) and detection of pulmonary infiltrations (P < .001, odds ratio 12.563) were the only independent predictors of inpatient treatment in the multivariate analysis. Our data show that RSV is a medically relevant pathogen among adult ED patients, often requiring inpatient treatment. In particular, elderly patients with some medical preconditions seem to be more prone to a severe course of infection requiring inpatient treatment. Lower respiratory tract involvement, proven by pulmonary infiltrates, seems to be crucial for a more severe disease course.

Immunotherapy-induced cytotoxic T follicular helper cells reduce numbers of retrovirus-infected reservoir cells in B cell follicles.

Antiretroviral therapy (ART) transformed HIV from a life-threatening disease to a chronic condition. However, eliminating the virus remains an elusive therapy goal. For several decades, Friend virus (FV) infection serves as a murine model to study retrovirus immunity. Similar to HIV, FV persists at low levels in lymph nodes B cell follicles avoiding elimination by immune cells. Such immune-privileged reservoirs exclude cytotoxic T cells from entry. However, CXCR5+ T cells are permitted to traffic through germinal centers. This marker is predominantly expressed by CD4+ follicular helper T cells (Tfh). Therefore, we explored immunotherapy to induce cytotoxic Tfh, which are rarely found under physiological conditions. The TNF receptor family member CD137 was first identified as a promising target for cancer immunotherapy. We demonstrated that FV-infected mice treatment with αCD137 antibody resulted in an induction of the cytotoxic program in Tfh. The therapy significantly increased numbers of cytotoxic Tfh within B cell follicles and contributed to viral load reduction. Moreover, αCD137 antibody combined with ART delayed virus rebound upon treatment termination without disturbing the lymph node architecture or antibody responses. Thus, αCD137 antibody therapy might be a novel strategy to target the retroviral reservoir and an interesting approach for HIV cure research.

Individuals With Weaker Antibody Responses After Booster Immunization Are Prone to Omicron Breakthrough Infections.

Background: Despite the high level of protection against severe COVID-19 provided by the currently available vaccines some breakthrough infections occur. Until now, there is no information whether a potential risk of a breakthrough infection can be inferred from the level of antibodies after booster vaccination. Methods: Levels of binding antibodies and neutralization capacity after the first, one and six month after the second, and one month after the third (booster) vaccination against COVID-19 were measured in serum samples from 1391 healthcare workers at the University Hospital Essen. Demographics, vaccination scheme, pre-infection antibody titers and neutralization capacity were compared between individuals with and without breakthrough infections. Results: The risk of developing an Omicron breakthrough infection was independent of vaccination scheme, sex, body mass index, smoking status or pre-existing conditions. In participants with low pre-infection anti-spike antibodies (≤ 2641.0 BAU/ml) and weaker neutralization capacity (≤ 65.9%) against Omicron one month after the booster vaccination the risk for developing an Omicron infection was 10-fold increased (P = 0.001; 95% confidence interval, 2.36 - 47.55). Conclusion: Routine testing of anti-SARS-CoV-2 IgG antibodies and surrogate virus neutralization can quantify vaccine-induced humoral immune response and may help to identify subjects who are at risk for a breakthrough infection. The establishment of thresholds for SARS-CoV-2 IgG antibody levels identifying "non"-, "low" and "high"-responders may be used as an indication for re-vaccination.

Torque Teno Virus load in lung cancer patients correlates with age but not with tumor stage.

BACKGROUND: Torque teno virus (TTV) is a ubiquitous non-pathogenic virus, which is suppressed in immunological healthy individuals but replicates in immune compromised patients. Thus, TTV load is a suitable biomarker for monitoring the immunosuppression also in lung transplant recipients. Since little is known about the changes of TTV load in lung cancer patients, we analyzed TTV plasma DNA levels in lung cancer patients and its perioperative changes after lung cancer surgery. MATERIAL AND METHODS: Patients with lung cancer and non-malignant nodules as control group were included prospectively. TTV DNA levels were measured by quantiative PCR using DNA isolated from patients plasma and correlated with routine circulating biomarkers and clinicopathological variables. RESULTS: 47 patients (early stage lung cancer n = 30, stage IV lung cancer n = 10, non-malignant nodules n = 7) were included. TTV DNA levels were not detected in seven patients (15%). There was no significant difference between the stage IV cases and the preoperative TTV plasma DNA levels in patients with early stage lung cancer or non-malignant nodules (p = 0.627). While gender, tumor stage and tumor histology showed no correlation with TTV load patients below 65 years of age had a significantly lower TTV load then older patients (p = 0.022). Regarding routine blood based biomarkers, LDH activity was significantly higher in patients with stage IV lung cancer (p = 0.043), however, TTV load showed no correlation with LDH activity, albumin, hemoglobin, CRP or WBC. Comparing the preoperative, postoperative and discharge day TTV load, no unequivocal pattern in the kinetics were. CONCLUSION: Our study suggest that lung cancer has no stage dependent impact on TTV plasma DNA levels and confirms that elderly patients have a significantly higher TTV load. Furthermore, we found no uniform perioperative changes during early stage lung cancer resection on plasma TTV DNA levels.

The retroviral vector family: something for everyone.

After 30 years of retroviral vector research it became clear that the parental viruses can be both friend and foe. Especially human immunodeficiency virus sparked a global pandemic, but could be converted into a versatile tool for cell therapy. For all retroviral genera, the way from virus to vector was similar resulting in split-vector systems based on the separation of the genes needed for vector particle formation and transgene expression. The first gene therapy trials, although clinically effective, revealed the genotoxicity of retroviral vectors caused by insertional mutagenesis. This issue was solved using self-inactivating vectors carrying weaker cellular promoters. Further fine-tuning was able to generate inducible systems. The current toolbox also contains vectors for the generation of induced pluripotent stem cells or efficient RNA interference. More recently the application of CRISPR-Cas9-mediated gene editing led to the development of genome-wide small guide RNA libraries targeting all human genes and single lentiviral vectors for an easy delivery of Cas9.

The Mouse Cytomegalovirus Gene m42 Targets Surface Expression of the Protein Tyrosine Phosphatase CD45 in Infected Macrophages.

The receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is drastically diminished. Screening of a set of MCMV deletion mutants allowed us to identify the viral gene m42 of being responsible for CD45 down-modulation. Moreover, expression of m42 independent of viral infection upon retroviral transduction of the RAW264.7 macrophage cell line led to comparable regulation of CD45 expression. In immunocompetent mice infected with an m42 deletion mutant lower viral titers were observed in all tissues examined when compared to wildtype MCMV, indicating an important role of m42 for viral replication in vivo. The m42 gene product was identified as an 18 kDa protein expressed with early kinetics and is predicted to be a tail-anchored membrane protein. Tracking of surface-resident CD45 molecules revealed that m42 induces internalization and degradation of CD45. The observation that the amounts of the E3 ubiquitin ligases Itch and Nedd4 were diminished in cells expressing m42 and that disruption of a PY motif in the N-terminal part of m42 resulted in loss of function, suggest that m42 acts as an activator or adaptor for these Nedd4-like ubiquitin ligases, which mark CD45 for lysosomal degradation. In conclusion, the down-modulation of CD45 expression in MCMV-infected myeloid cells represents a novel pathway of virus-host interaction.