Expression of TMPRSS2 is up-regulated by bacterial flagellin, LPS, and Pam3Cys in human airway cells.

Many viruses require proteolytic activation of their envelope proteins for infectivity, and relevant host proteases provide promising drug targets. The transmembrane serine protease 2 (TMPRSS2) has been identified as a major activating protease of influenza A virus (IAV) and various coronaviruses (CoV). Increased TMPRSS2 expression has been associated with a higher risk of severe influenza infection and enhanced susceptibility to SARS-CoV-2. Here, we found that Legionella pneumophila stimulates the increased expression of TMPRSS2-mRNA in Calu-3 human airway cells. We identified flagellin as the dominant structural component inducing TMPRSS2 expression. The flagellin-induced increase was not observed at this magnitude for other virus-activating host proteases. TMPRSS2-mRNA expression was also significantly increased by LPS, Pam3Cys, and Streptococcus pneumoniae, although less pronounced. Multicycle replication of H1N1pdm and H3N2 IAV but not SARS-CoV-2 and SARS-CoV was enhanced by flagellin treatment. Our data suggest that bacteria, particularly flagellated bacteria, up-regulate the expression of TMPRSS2 in human airway cells and, thereby, may support enhanced activation and replication of IAV upon co-infections. In addition, our data indicate a physiological role of TMPRSS2 in antimicrobial host response.

Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness.

The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.

Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19.

The systemic immune response to viral infection is shaped by master transcription factors, such as NF-κB, STAT1, or PU.1. Although long noncoding RNAs (lncRNAs) have been suggested as important regulators of transcription factor activity, their contributions to the systemic immunopathologies observed during SARS-CoV-2 infection have remained unknown. Here, we employed a targeted single-cell RNA sequencing approach to reveal lncRNAs differentially expressed in blood leukocytes during severe COVID-19. Our results uncover the lncRNA PIRAT (PU.1-induced regulator of alarmin transcription) as a major PU.1 feedback-regulator in monocytes, governing the production of the alarmins S100A8/A9, key drivers of COVID-19 pathogenesis. Knockout and transgene expression, combined with chromatin-occupancy profiling, characterized PIRAT as a nuclear decoy RNA, keeping PU.1 from binding to alarmin promoters and promoting its binding to pseudogenes in naïve monocytes. NF-κB-dependent PIRAT down-regulation during COVID-19 consequently releases a transcriptional brake, fueling alarmin production. Alarmin expression is additionally enhanced by the up-regulation of the lncRNA LUCAT1, which promotes NF-κB-dependent gene expression at the expense of targets of the JAK-STAT pathway. Our results suggest a major role of nuclear noncoding RNA networks in systemic antiviral responses to SARS-CoV-2 in humans.

[Pulmonary manifestations in long COVID]. / Pulmonale Manifestationen bei Long-COVID.

BACKGROUND: Pulmonary manifestations are very common sequelae after severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections, which are summarized under the term long COVID (coronavirus disease) syndrome. AIM/METHODS: This article summarizes the current literature on pulmonary manifestations with a focus on expert opinions and recommendations. RESULTS: After chronic fatigue, dyspnea is the most common symptom in patients with long COVID syndrome. Pathological findings are mainly found after a severe acute course of COVID-19 and include radiological changes with characteristics of interstitial lung diseases, restrictive ventilation patterns and limitations in diffusion capacity as the most common pathological finding. Although both symptoms and pathological pulmonary alterations improve over time, some patients may still suffer from abnormalities months after the acute infection. The relevance of the pathological findings, as well as the involvement of functional respiratory limitations, cardiopulmonary deconditioning, non-somatic causes and pre-existing lung diseases, is currently unclear. The advanced diagnostic assessment thus focusses on high-risk patients and includes, in addition to imaging and pulmonary function tests, a cardiopulmonary exercise test and, if the findings are unclear, an echocardiography to diagnose a pulmonary vascular component. The therapeutic options currently include treatment of the underlying causes of the symptoms (e.g. interstitial lung diseases, cough) according to the respective guidelines and rehabilitation measures. DISCUSSION: The current knowledge about pulmonary manifestations in long COVID patients is constantly being expanded, but due to limited availability of clinical trials, there are still no evidence-based guidelines for the diagnosis and therapy of pulmonary manifestations in long COVID syndrome.

Pulmonale Manifestationen bei Long-COVID Pulmonary manifestations in long COVID

Hintergrund Pulmonale Manifestationen sind sehr häufige Folgeerscheinungen nach einer Severe-acute-respiratory-syndrome-coronavirus-type-2(SARS-CoV-2)-Infektion, die unter dem Begriff Long-COVID-Syndrom (COVID „coronavirus disease“) zusammengefasst werden. Ziel und Methoden Zusammenfassung der aktuellen Literatur zu den pulmonalen Manifestationen mit einem Fokus auf Expertenempfehlungen. Ergebnisse Dyspnoe ist nach der chronischen Fatigue das häufigste Symptom bei Patienten mit Long-COVID-Syndrom. Auffällige Befunde finden sich vor allem nach schwerem akutem COVID-19-Verlauf und beinhalten radiologische Veränderungen im Sinne interstitieller Lungenerkrankungen, restriktive lungenfunktionelle Befunde und Einschränkungen der Diffusionskapazität als häufigsten pathologischen Befund. Obwohl sich sowohl Beschwerden als auch pathologische pulmonale Befunde im Verlauf bessern, können einige Patienten noch Monate nach der akuten Infektion unter Auffälligkeiten leiden. Dabei ist die Relevanz der pathologischen Befunde sowie eine Beteiligung funktioneller respiratorischer Einschränkungen, einer kardiopulmonalen Dekonditionierung, nichtsomatischer Ursachen und vorbestehender Erkrankungen aktuell unklar. Die diagnostische Abklärung fokussiert entsprechend auf Risikopatienten und schließt neben einer bildgebenden und lungenfunktionellen Abklärung eine Belastungsuntersuchung und bei unklaren Befunden eine Echokardiographie zur Diagnose einer pulmonalvaskulären Komponente ein. Die therapeutischen Möglichkeiten beinhalten aktuell die leitliniengerechte Therapie von Ursachen der Beschwerden (beispielsweise interstitielle Lungenerkrankungen, Husten) und Rehabilitationsmaßnahmen. Schlussfolgerung Das aktuelle Wissen zum Krankheitsbild wird ständig erweitert, allerdings existieren aufgrund mangelnder Studienlage noch keine evidenzbasierten Leitlinien zur Diagnostik und Therapie pulmonaler Manifestationen beim Long-COVID-Syndrom.

The clinical role of host and bacterial-derived extracellular vesicles in pneumonia.

Pneumonia is among the leading causes of morbidity and mortality worldwide. Due to constant evolution of respiratory bacteria and viruses, development of drug resistance and emerging pathogens, it constitutes a considerable health care threat. To enable development of novel strategies to control pneumonia, a better understanding of the complex mechanisms of interaction between host cells and infecting pathogens is vital. Here, we review the roles of host cell and bacterial-derived extracellular vesicles (EVs) in these interactions. We discuss clinical and experimental as well as pathogen-overarching and pathogen-specific evidence for common viral and bacterial elicitors of community- and hospital-acquired pneumonia. Finally, we highlight the potential of EVs for improved management of pneumonia patients and discuss the translational steps to be taken before they can be safely exploited as novel vaccines, biomarkers, or therapeutics in clinical practice.

[Role of genetic factors in pneumonia and COVID-19]. / Bedeutung der Genetik für die Pneumonie und COVID-19.

Pneumonia causes the highest mortality of all infectious diseases worldwide. The most common pathogens are bacteria but there are also epidemic or pandemic lung infections caused by influenza or coronaviruses, such as the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the occurrence of antibiotic resistance and immune pathologies, such as in sepsis, important challenges lie in considering the susceptibility of individual patients. Here, age, medication and comorbidities are considered; however, there is also clear evidence of genetic influences on the individual risk of developing pneumonia or developing a severe course of the disease. This article discusses the genetic influences on pneumonia and the clinical significance.