Glutamine promotes human CD8+ T cells and counteracts imiquimod-induced T cell hyporesponsiveness.

T cells protect tissues from cancer. Although investigations in mice showed that amino acids (AA) critically regulate T cell immunity, this remains poorly understood in humans. Here, we describe the AA composition of interstitial fluids in keratinocyte-derived skin cancers (KDSCs) and study the effect of AA on T cells using models of primary human cells and tissues. Gln contributed to ∼15% of interstitial AAs and promoted interferon gamma (IFN-γ), but not granzyme B (GzB) expression, in CD8+ T cells. Furthermore, the Toll-like receptor 7 agonist imiquimod (IMQ), a common treatment for KDSCs, down-regulated the metabolic gatekeepers c-MYC and mTORC1, as well as the AA transporter ASCT2 and intracellular Gln, Asn, Ala, and Asp in T cells. Reduced proliferation and IFN-γ expression, yet increased GzB, paralleled IMQ effects on AA. Finally, Gln was sufficient to promote IFN-γ-production in IMQ-treated T cells. Our findings indicate that Gln metabolism can be harnessed for treating KDSCs.

[Human monkeypox (Mpox)]. / Humane Affenpocken (Mpox).

Until recently, human monkeypox (Mpox) were rarely observed outside of Africa, where the Mpox virus (MPXV) is endemic in some regions. In early May 2022, a global Mpox outbreak occurred. Crucial to this outbreak was human-to-human transmission during sexual activity. In particular, young men who have sex with men (MSM) became ill. In July 2022, this Mpox epidemic was declared a public health emergency of international concern by the World Health Organization. As of 26 September 2023, 90,618 confirmed cases of Mpox have been reported worldwide, with Germany accounting for around 3700 cases. The strongest increase in incidence occurred from May to mid-August 2022; since then, the number of cases has declined significantly as a result of intensive prevention efforts (education, vaccination). Currently, there are only sporadic, smaller outbreaks-in Germany (Berlin) most recently in August 2023. Despite the current calm epidemiological situation worldwide, isolated cases must therefore still be expected in Germany. The clinical picture of the "new" clade IIb-associated Mpox variant, which is mostly transmitted sexually from person to person, differs markedly from that of the "classical" Mpox (clades I and IIa), which, apart from rapidly breaking human infection chains, essentially occur as a zoonosis.

[Bacterial infections of the skin in the context of climate change and migration]. / Bakterielle Infektionen der Haut im Kontext von Klimawandel und Migration.

BACKGROUND: In the context of climate change and migration, both common and previously less common pathogens are gaining importance as cutaneous bacterial infections. OBJECTIVE: To inform medical professionals about challenges to dermatology posed by climate change and migration. MATERIALS AND METHODS: Review of the current literature on emerging antimicrobial resistance and emerging pathogens in general and on the epidemiological situation in Germany in particular. RESULTS: Climate change has a direct impact on microbiological ecosystems in Germany's warming coastal waters leading to an increase of marine V. vulnificus counts and human infections. Secondary to global warming, transmitting vectors of, for example, Lyme disease, rickettsioses and tularemia are also increasing. In addition, infectious diseases like cutaneous diphtheria and mycobacteriosis have been diagnosed in migrants, mostly likely acquired before migration or on the migration route and first diagnosed in Germany. In this context, antimicrobial resistance (e.g. methicillin-resistant Staphylococcus aureus [MRSA] and multidrug-resistant gram-negative bacteria) is gaining importance. CONCLUSION: Due to progressive changes in global climate and ongoing migration, the aforementioned pathogens of infectious skin diseases and changes in antimicrobial resistance patterns have to be expected. Physicians should be aware of these developments in order to offer appropriate diagnostics and treatment. Epidemiological and biogeographic monitoring will be indispensable for managing emerging changes.

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). DCs are critical players in the development of the acute lung inflammation that causes ARDS. Here we focus on the interaction of a specific SARS-CoV-2 open reading frame protein, ORF8, with DCs. We show that ORF8 binds to DCs, causes a pre-maturation of differentiating DCs, and induces the secretion of multiple proinflammatory cytokines by these cells. In addition, we identified DC-SIGN as a possible interaction partner of ORF8 on DCs. Blockade of ORF8 leads to reduced production of IL-1ß, IL-6, IL-12p70, TNF-α, MCP-1 (also named CCL2), and IL-10 by DCs. Therefore, a neutralizing antibody blocking the ORF8-mediated cytokine and chemokine response could be an improved therapeutical strategy against severe SARS-CoV-2.

Dermatovenerological infections.

In dermatology, infections caused by bacteria, viruses, fungi, and parasites play an important role. A large proportion of pathogen-related infections of the skin and mucous membranes are transmitted sexually. All areas of infectious diseases and dermatovenerology are subject to highly exciting, dynamic change. This is driven by changes in the epidemiology of long-established diseases, changes in the resistance of pathogens to anti-infectives, recurrence of known pathogens, and the emergence of completely new pathogens. In this article, we address "resistance to anti-infectives", "sexually transmitted infections", and "emerging viral infections", three core areas of dermatovenerology that will shape the field in the years to come.

Outpatient care concept and potential inpatient cost savings associated with the administration of dalbavancin - A real-world data and retrospective cost analysis.

BACKGROUND: The treatment of acute bacterial skin and skin structure infections (ABSSSI) usually involves intravenous (i.v.) antibiotics requiring hospitalisation and increasing hospital costs. Since 2014, dalbavancin is approved for ABSSSIs treatment. However, evidence of its health economic impact on the German healthcare system is still limited. METHODS: Diagnosis-related groups (DRG) based cost analysis was used to evaluate real-world data (RWD) from a German tertiary care center. All patients treated with i.v. antibiotics in the Department of Dermatology and Venereology at the University Hospital of Cologne were included to detect potential cost savings from a payer perspective. Thus, for the inpatient care German diagnosis-related groups (G-DRG) tariffs, length of stay (LOS), main- and secondary DRG-diagnoses and for the outpatient setting 'Einheitlicher Bewertungsmaßstab' (EBM) codes were evaluated. RESULTS: This retrospective study identified 480 inpatient cases treated for ABSSSI between January 2016 until December 2020. Complete cost data were available for 433 cases and the detection of long-hospital-stay patients based on surcharges for exceeding the upper limit LOS led to 125 cases (29%) including 67 females (54%) and 58 males (46%) with an overall mean age of 63.6 years; all treated for International Classification of Diseases (ICD -10th revision) code A46 'erysipelas'. A sub-analysis focussed on DRG J64B with a total of 92 cases exceeding the upper limit LOS by a median of 3 days resulted in a median surcharge of €636 (mean value €749; SD €589; IQR €459-€785) per case. In comparison, we calculated outpatient treatment costs of approximately €55 per case. Thus, further treatment of these patients in an outpatient setting before exceeding the upper limit LOS might result in a cost-saving potential of approximately €581 per case. CONCLUSION: Dalbavancin appears a cost-efficient option to reduce inpatient treatment costs by transitioning to an outpatient setting of patients with ABSSSI potentially exceeding the upper limit LOS.

Macrophage Biology in Human Granulomatous Skin Inflammation.

Cutaneous granulomatoses represent a heterogeneous group of diseases, which are defined by macrophage infiltration in the skin. Skin granuloma can be formed in the context of infectious and non-infectious conditions. Recent technological advances have deepened our understanding of the pathophysiology of granulomatous skin inflammation, and they provide novel insights into human tissue macrophage biology at the site of ongoing disease. Here, we discuss findings on macrophage immune function and metabolism derived from three prototypic cutaneous granulomatoses: granuloma annulare, sarcoidosis, and leprosy.

An LKB1-mitochondria axis controls TH17 effector function.

CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.

[Virus-induced exanthems in returning travellers]. / Virusbedingte Exantheme nach Fernreisen.

Dermatological diseases are among the most common travel-associated diseases. In particular, viral infections not only with tropical and subtropical pathogens, but also with viruses common in Germany, which are often accompanied by skin rashes and general symptoms, are of great importance. In addition to an accurate travel history and possible risk exposures, epidemiological information on country-specific risks in combination with molecular and serological analyses is helpful in making the correct diagnosis. This article provides an overview of important virus-induced exanthems in returned travellers.