Mutual regulation of CD4+ T cells and intravascular fibrin in infections.

Innate myeloid cells especially neutrophils and their extracellular traps are known to promote intravascular coagulation and thrombosis formation in infections and various other conditions. Innate myeloid cell dependent fibrin formation can support systemic immunity while its dysregulation enhances the severity of infectious diseases. Less is known about the immune mechanisms preventing dysregulation of fibrin homeostasis in infection. During experimental systemic infections local fibrin deposits in the liver microcirculation cause rapid arrest of CD4+ T cells. Arrested T helper cells mostly represent Th17 cells that partially originate from the small intestine. Intravascular fibrin deposits activate mouse and human CD4+ T cells which can be mediated by direct fibrin - CD4+ T cell interactions. Activated CD4+ T cells suppress fibrin deposition and microvascular thrombosis by directly counteracting coagulation activation by neutrophils and classical monocytes. T cell activation, which is initially triggered by IL- 12p40- and MHC-II dependent mechanisms, enhances intravascular fibrinolysis via LFA-1. Moreover, CD4+ T cells disfavor the association of the fibrinolysis inhibitor TAFI with fibrin whereby fibrin deposition is increased by TAFI in the absence but not presence of T cells. In human infections thrombosis development is inversely related to microvascular levels of CD4+ T cells. Thus, fibrin promotes LFA-1 dependent T helper cell activation in infections which drives a negative feedback cycle that rapidly restricts intravascular fibrin and thrombosis development.

Neutrophils - Biology and Diversity.

Neutrophils, the most abundant white blood cells in the human circulation, play crucial roles in various diseases, including kidney disease. Traditionally viewed as short-lived pro-inflammatory phagocytes that release reactive oxygen species, cytokines and neutrophil extracellular traps, recent studies have revealed their complexity and heterogeneity, thereby challenging this perception. Neutrophils are now recognized as transcriptionally active cells capable of proliferation and reverse migration, displaying phenotypic and functional heterogeneity. They respond to a wide range of signals and deploy various cargo to influence the activity of other cells in the circulation and in tissues. They can regulate the behavior of multiple immune cell types, exhibit innate immune memory, and contribute to both acute and chronic inflammatory responses while also promoting inflammation resolution in a context-dependent manner. Here, we explore the origin and heterogeneity of neutrophils, their functional diversity, and the cues that regulate their effector functions. We also examine their emerging role in infectious and non-infectious diseases with a particular emphasis on kidney disease. Understanding the complex behavior of neutrophils during tissue injury and inflammation may provide novel insights, thereby paving the way for potential therapeutic strategies to manage acute and chronic conditions. By deciphering their multifaceted role, targeted interventions can be developed to address the intricacies of neutrophil-mediated immune responses and improve disease outcomes.

In-depth profiling of COVID-19 risk factors and preventive measures in healthcare workers.

PURPOSE: To determine risk factors for coronavirus disease 2019 (COVID-19) in healthcare workers (HCWs), characterize symptoms, and evaluate preventive measures against SARS-CoV-2 spread in hospitals. METHODS: In a cross-sectional study conducted between May 27 and August 12, 2020, after the first wave of the COVID-19 pandemic, we obtained serological, epidemiological, occupational as well as COVID-19-related data at a quaternary care, multicenter hospital in Munich, Germany. RESULTS: 7554 HCWs participated, 2.2% of whom tested positive for anti-SARS-CoV-2 antibodies. Multivariate analysis revealed increased COVID-19 risk for nurses (3.1% seropositivity, 95% CI 2.5-3.9%, p = 0.012), staff working on COVID-19 units (4.6% seropositivity, 95% CI 3.2-6.5%, p = 0.032), males (2.4% seropositivity, 95% CI 1.8-3.2%, p = 0.019), and HCWs reporting high-risk exposures to infected patients (5.5% seropositivity, 95% CI 4.0-7.5%, p = 0.0022) or outside of work (12.0% seropositivity, 95% CI 8.0-17.4%, p < 0.0001). Smoking was a protective factor (1.1% seropositivity, 95% CI 0.7-1.8% p = 0.00018) and the symptom taste disorder was strongly associated with COVID-19 (29.8% seropositivity, 95% CI 24.3-35.8%, p < 0.0001). An unbiased decision tree identified subgroups with different risk profiles. Working from home as a preventive measure did not protect against SARS-CoV-2 infection. A PCR-testing strategy focused on symptoms and high-risk exposures detected all larger COVID-19 outbreaks. CONCLUSION: Awareness of the identified COVID-19 risk factors and successful surveillance strategies are key to protecting HCWs against SARS-CoV-2, especially in settings with limited vaccination capacities or reduced vaccine efficacy.

Prospective Longitudinal Serosurvey of Healthcare Workers in the First Wave of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Pandemic in a Quaternary Care Hospital in Munich, Germany.

BACKGROUND: High infection rates among healthcare personnel in an uncontained pandemic can paralyze health systems due to staff shortages. Risk constellations and rates of seroconversion for healthcare workers (HCWs) during the first wave of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are still largely unclear. METHODS: Healthcare personnel (n = 300) on different organizational units in the LMU Munich University Hospital were included and followed in this prospective longitudinal study from 24 March until 7 July 2020. Participants were monitored in intervals of 2 to 6 weeks using different antibody assays for serological testing and questionnaires to evaluate risk contacts. In a subgroup of infected participants, we obtained nasopharyngeal swabs to perform whole-genome sequencing for outbreak characterization. RESULTS: HCWs involved in patient care on dedicated coronavirus disease 2019 (COVID-19) wards or on regular non-COVID-19 wards showed a higher rate of SARS-CoV-2 seroconversion than staff in the emergency department and non-frontline personnel. The landscape of risk contacts in these units was dynamic, with a decrease in unprotected risk contacts in the emergency department and an increase on non-COVID-19 wards. Both intensity and number of risk contacts were associated with higher rates of seroconversion. On regular wards, staff infections tended to occur in clusters, while infections on COVID-19 wards were less frequent and apparently independent of each other. CONCLUSIONS: Risk of SARS-CoV-2 infection for frontline HCWs was increased during the first pandemic wave in southern Germany. Stringent measures for infection control are essential to protect all patient-facing staff during the ongoing pandemic.

Endocannabinoids, endocannabinoid-like compounds and cortisone in head hair of health care workers as markers of stress and resilience during the early COVID-19 pandemic.

The pandemic caused by SARS-CoV-2 impacted health systems globally, creating increased workload and mental stress upon health care workers (HCW). During the first pandemic wave (March to May 2020) in southern Germany, we investigated the impact of stress and the resilience to stress in HCW by measuring changes in hair concentrations of endocannabinoids, endocannabinoid-like compounds and cortisone. HCW (n = 178) recruited from multiple occupation and worksites in the LMU-University-Hospital in Munich were interviewed at four interval visits to evaluate mental stress associated with the COVID-19 pandemic. A strand of hair of up to 6 cm in length was sampled once in May 2020, which enabled retrospective individual stress hormone quantifications during that aforementioned time period. Perceived anxiety and impact on mental health were demonstrated to be higher at the beginning of the COVID-19 pandemic and decreased significantly thereafter. Resilience was stable over time, but noted to be lower in women than in men. The concentrations of the endocannabinoid anandamide (AEA) and the structural congeners N-palmitoylethanolamide (PEA), N-oleoylethanolamide (OEA) and N-stearoylethanolamide (SEA) were noted to have decreased significantly over the course of the pandemic. In contrast, the endocannabinoid 2-arachidonoylglycerol (2-AG) levels increased significantly and were found to be higher in nurses, laboratory staff and hospital administration than in physicians. PEA was significantly higher in subjects with a higher resilience but lower in subjects with anxiety. SEA was also noted to be reduced in subjects with anxiety. Nurses had significantly higher cortisone levels than physicians, while female subjects had significant lower cortisone levels than males. Hair samples provided temporal and measurable objective psychophysiological-hormonal information. The hair endocannabinoids/endocannabinoid-like compounds and cortisone correlated to each other and to professions, age and sex quite differentially, relative to specific periods of the COVID-19 pandemic.

Peripheral priming induces plastic transcriptomic and proteomic responses in circulating neutrophils required for pathogen containment.

Neutrophils rapidly respond to inflammation and infection, but to which degree their functional trajectories after mobilization from the bone marrow are shaped within the circulation remains vague. Experimental limitations have so far hampered neutrophil research in human disease. Here, using innovative fixation and single-cell-based toolsets, we profile human and murine neutrophil transcriptomes and proteomes during steady state and bacterial infection. We find that peripheral priming of circulating neutrophils leads to dynamic shifts dominated by conserved up-regulation of antimicrobial genes across neutrophil substates, facilitating pathogen containment. We show the TLR4/NF-κB signaling-dependent up-regulation of canonical neutrophil activation markers like CD177/NB-1 during acute inflammation, resulting in functional shifts in vivo. Blocking de novo RNA synthesis in circulating neutrophils abrogates these plastic shifts and prevents the adaptation of antibacterial neutrophil programs by up-regulation of distinct effector molecules upon infection. These data underline transcriptional plasticity as a relevant mechanism of functional neutrophil reprogramming during acute infection to foster bacterial containment within the circulation.