Systematic assessment of COVID-19 host genetics using whole genome sequencing data.

Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases.

Diagnostic Accuracy of Lung and Abdominal Ultrasound for Tuberculosis in a German Multicenter Cohort of Patients With Presumed Tuberculosis Disease.

Background: There is limited evidence on point-of-care ultrasound for tuberculosis (TB), but studies suggest high sensitivity, especially for lung ultrasound (LUS). However, insufficient data are available on specificity of the examination and its generalizability to a broader patient population.

Aims: Our study aimed to establish accuracy for lung, chest, and abdominal ultrasound, individually and in combination, for TB diagnosis.

Protocol for developing Pseudomonas aeruginosa type III secretion system-neutralizing monoclonal antibodies from human B cells.

Monoclonal antibodies (mAbs) targeting bacterial virulence factors may represent promising therapeutics in the fight against severe bacterial infections. Here, we present an approach for developing human-derived antibodies targeting the type III secretion system (T3SS) of Pseudomonas aeruginosa (PA) by neutralizing the function of the T3SS-tip protein PcrV. The protocol involves identifying individuals with protective antibodies, isolating PcrV-specific B cells from these individuals, and producing and testing anti-PcrV mAbs derived from single B cells.

The role of inflammasomes as central inflammatory hubs in infection.

() infection represents a global health problem and is characterized by formation of granuloma with a necrotic center and a systemic inflammatory response. Inflammasomes have a crucial role in the host immune response towards . These intracellular multi-protein complexes are assembled in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs).

Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones.

Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antitubercular drug candidates with two compounds in clinical phases. BTZs inhibit decaprenylphosphoryl-β-d-ribose oxidase 1 (DprE1), a key enzyme in cell wall biosynthesis of mycobacteria. Their mechanism of action involves an in-situ-reduction of the nitro moiety to a reactive nitroso intermediate capable of covalent binding to Cys387 in the catalytic cavity.

Design, synthesis and antimycobacterial activity of imidazo[1,5-]quinolines and their zinc-complexes.

Tuberculosis has remained one of the world's deadliest infectious diseases. The complexity and numerous adverse effects of current treatment options as well as the emergence of multi-drug resistant (Mtb) demand research and innovation efforts to yield new anti-mycobacterial agents. In this study, we synthesized a series of imidazo[1,5-]quinolines, including 4 new analogs, and evaluated their activity against Mtb.

Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality.

The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19.

Incidence and risk factors for HIV-tuberculosis coinfection in the Cologne-Bonn region: a retrospective cohort study.

Purpose: The risk of developing active tuberculosis (TB) is considerably increased in people living with HIV/AIDS (PLWH). However, incidence of HIV/TB coinfection is difficult to assess as surveillance data are lacking in many countries. Here, we aimed to perform a quantitative analysis of HIV/TB coinfections within the Cologne/Bonn HIV cohort and to determine risk factors for active TB.

RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling.

The toll-like receptor 4 (TLR4) is a central regulator of innate immunity that primarily recognizes bacterial lipopolysaccharide cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4 triggers degradation of TLR4's trafficking factor TMED7.

Fully Human Herpesvirus-Specific Neutralizing IgG Antibodies Generated by EBV Immortalization of Splenocytes-Derived from Immunized Humanized Mice.

Antiviral neutralizing antibodies (nAbs) are commonly derived from B cells developed in immunized or infected animals and humans. Fully human antibodies are preferred for clinical use as they are potentially less immunogenic. However, the function of B cells varies depending on their homing pattern and an additional hurdle for antibody discovery in humans is the source of human tissues with an immunological microenvironment.

Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa.

Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B cell and antibody response to the virulence-associated type III secretion system (T3SS) in a cohort of patients chronically infected with PA. Single-cell analytics revealed a diverse B cell receptor repertoire directed against the T3SS needle-tip protein PcrV, enabling the production of monoclonal antibodies (mAbs) abrogating T3SS-mediated cytotoxicity.

The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm.

The novel coronavirus pandemic, first reported in December 2019, was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection leads to a strong immune response and activation of antigen-presenting cells, which can elicit acute respiratory distress syndrome (ARDS) characterized by the rapid onset of widespread inflammation, the so-called cytokine storm. In response to viral infections, monocytes are recruited into the lung and subsequently differentiate into dendritic cells (DCs).

Characterization of Two Novel Inhibitors of the Mycobacterium tuberculosis Cytochrome Complex.

Drug-resistant tuberculosis is a global health care threat calling for novel effective treatment options. Here, we report on two novel cytochrome inhibitors (MJ-22 and B6) targeting the Mycobacterium tuberculosis respiratory chain with excellent intracellular activities in human macrophages. Both hit compounds revealed very low mutation frequencies and distinct cross-resistance patterns with other advanced cytochrome inhibitors.

Immunological fingerprint in coronavirus disease-19 convalescents with and without post-COVID syndrome.

Background: Symptoms lasting longer than 12  weeks after severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection are called post-coronavirus disease (COVID) syndrome (PCS). The identification of new biomarkers that predict the occurrence or course of PCS in terms of a post-viral syndrome is vital. T-cell dysfunction, cytokine imbalance, and impaired autoimmunity have been reported in PCS.

Implementing best practices on data generation and reporting of assays within the ERA4TB consortium.

Tuberculosis (TB) is the historical leading cause of death by a single infectious agent. The European Regimen Accelerator for Tuberculosis (ERA4TB) is a public-private partnership of 30+ institutions with the objective to progress new anti-TB regimens into the clinic. Thus, robust and replicable results across independent laboratories are essential for reliable interpretation of treatment efficacy.

A Reinvestigation of the Role of the Sorbic Acid Tail on the Antibacterial and Anti-Tuberculosis Properties of Moiramide B.

Due to worldwide increasing resistances, there is a considerable need for antibacterial compounds with modes of action not yet realized in commercial antibiotics. One such promising structure is the acetyl-CoA carboxylase (ACC) inhibitor moiramide B which shows strong antibacterial activity against gram-positive bacteria such as Bacillus subtilis and weaker activities against gram-negative bacteria. However, the narrow structure-activity relationship of the pseudopeptide unit of moiramide B represents a formidable challenge for any optimization strategy.

Immune response to mRNA-based COVID-19 booster vaccination in people living with HIV.

Objectives: Our objective was to assess immune responses and their influencing factors in people living with HIV after messenger RNA (mRNA)-based COVID-19 booster vaccination (third dose).

Methods: This was a retrospective cohort study of people living with HIV who received booster vaccination with BNT-162b2 or mRNA-1273 between October 2021 and January 2022. We assessed anti-spike receptor-binding domain (RBD) immunoglobulin G (IgG), virus neutralizing activity (VNA) titres reported as 100% inhibitory dilution (ID ), and T-cell response (using interferon-gamma-release-assay [IGRA]) at baseline and quarterly follow-up visits.

Activity of the old antimicrobial nitroxoline against Mycobacterium abscessus complex isolates.

Objectives: The old antimicrobial nitroxoline is approved to treat urinary tract infection (UTI) and is currently rediscovered for treatment of drug resistant pathogens. Mycobacteria of the Mycobacterium abscessus complex (MYABS) are rapid-growing nontuberculous mycobacteria that are associated with difficult to treat infections of the lungs in patients with pulmonary disorders such as cystic fibrosis. In this study we assessed the in vitro activity of nitroxoline against molecularly characterized drug-resistant MYABS isolates from clinical samples to address potential repurposing of nitroxoline in difficult-to-treat MYABS infection.

Monocyte-crosstalk drives interferon-mediated signaling following SARS-CoV-2 exposure.

Cells of the innate immune system represent the first line of defense against SARS-CoV-2 and play an essential role in activating adaptive immunity, which mediates long-term protection. In addition, the same cells are key drivers of tissue damage by causing the hyperinflammatory state and cytokine storm that makes COVID-19 a deadly disease. Thus, careful dissection of the host-pathogen interaction on a cellular level is essential to understanding SARS-CoV-2 pathogenesis and developing new treatment modalities against COVID-19.

Detailed stratified GWAS analysis for severe COVID-19 in four European populations.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.

Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination.

Durable cell-mediated immune responses require efficient innate immune signaling and the release of pro-inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS-CoV-2 mRNA vaccination primes human monocyte-derived macrophages for activation of the NLRP3 inflammasome.

Implementing the Lolli-Method and pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools: a pilot project.

Purpose: School closures have been used as part of lockdown strategies to contain the spread of SARS-CoV-2, adversely affecting children's health and education. To ensure the accessibility of educational institutions without exposing society to the risk of increased transmissions, it is essential to establish SARS-CoV-2 testing strategies that are child-friendly, scalable and implementable in a daily school routine. Self-sampling using non-invasive saliva swabs combined with pooled RT-qPCR testing (Lolli-Method) has been proven to be a sensitive method for the detection of SARS-CoV-2.