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Streptomyces are renowned producers of antibiotics and other medically useful molecules. They undergo a developmental life cycle involving progression from vegetative growth to the erection of reproductive aerial hyphae, which differentiate into chains of spores. The second messengers c-di-GMP and c-di-AMP control this complex morphological transition. Studies on signalling mechanisms in this bacterial model led to the discovery of a tetrameric c-di-GMP, a sigma factor as an unexpected type of c-di-GMP effectors and a new class of c-di-AMP phosphodiesterases.

Twenty years ago, an enzyme homologous to the previously known angiotensin-converting enzyme (ACE) was identified, and subsequently named ACE2. In the renin-angiotensin system (RAS), ACE2 has counter-regulatory functions against the classical effector peptide angiotensin II, for example in blood pressure regulation and cardiovascular remodeling. However, ACE2 provides an initially unexpected interesting link between virology and cardiovascular medicine. That is, ACE2 represents the binding receptor for the cellular uptake of SARS-CoV and SARS-CoV-2 viruses. Thus, ACE2 is relevant for COVID-19. In this context, it was suspected that therapy with RAS blockers might promote transmission and complications of COVID-19 by upregulation of ACE2 expression. The aim of this short review is, to describe the link between the RAS, particularly ACE2, and COVID-19. Based on our analysis and evaluation of the available findings, we justify our conclusion: important drugs such as ACE inhibitors and angiotensin receptor blockers should continue to be prescribed according to guidelines to stable patients in the context of the COVID-19 pandemic.

Ustilago maydis, the causative agent of corn smut disease, depends on a variety of secreted effector proteins, to establish a biotrophic interaction with its host plant maize. The deletion of the gene um01987, which encodes the effector protein Pep1, leads to a complete loss of pathogenicity. Moreover the plant reacts to penetration attempts of the Δpep1-mutant strain with the induction of different defense reactions. This results in e.g. the formation of necrotic lesion as well as in the production of reactive oxygen species at the penetration sites. Pep1 is conserved among different species of smut fungi and contains a N-terminal signal peptide, a conserved core region as well as a low conserved glycine- and serine-rich C-terminus. In the present study, the effector protein Pep1 was heterologously expressed and purified. Via biochemical and molecular biological methods, two plant interaction partners of Pep1 were identified. By Activity based protein profiling it could be demonstrated, that Pep1 specifically inhibits the activity of papaine like cysteine proteases. Particularly, the activity of papaine like cysteine proteases, induced by the salicylic acid signaling pathway, was inhibited by Pep1 very efficiently. Obviously, these proteases are critical for the induction of maize plant defense. Additionally, Pep1 binds and inhibits plant class-III-heme-peroxidases. In cooperation with Christoph Hemetsberger, the in vitro inhibition of the horseradish peroxidase (HRP) could be shown. Moreover the physical interaction of Pep1 with the HRP was demonstrated. During the Δpep1-infection, a single peroxidase, the maize peroxidase-12, is transcriptionally upregulated. Virus induced gene silencing of the peroxidase-12 lead to a partial complementation of the Δpep1-mutant phenotype on POX12si plants. Thus, silencing of peroxidase-12 leads to the suppression of plant defense reactions, such as the formation of papillae, which enables the Δpep1-mutant strain to successfully penetrate the plant tissue. Taken together these results show, that Pep1 inhibits enzymes of the basal plant defense and therefore suppressing the innate immunity of maize against U. maydis., Ustilago maydis, der Erreger des Maisbeulenbrandes, benötigt zur Etablierung einer biotrophen Interaktion mit seiner Wirtspflanze Mais eine Vielzahl sekretierter Effektoren. Die Deletion des für den Effektor Pep1 kodierenden Gens um01987 führt zum vollständigen Pathogenitätsverlust. Die Pflanze reagiert auf Penetrationsversuche der Δpep1-Mutante mit der Induktion verschiedener Abwehrreaktionen, was sich z.B. durch die Bildung nekrotischer Läsionen sowie reaktiver Sauerstoffspezies an den Penetrationsstellen zeigt. Pep1 ist zwischen verschiedenen Brandpilzarten konserviert und besteht aus einem N-terminalen Signalpeptid, einem konservierten Kernbereich sowie einem weniger konservierten Glycin- und Serin-reichen C-Terminus. In der vorliegenden Arbeit wurde das heterolog in E. coli exprimierte Pep1 aufgereinigt. Durch biochemische und molekularbiologische Methoden konnten zwei pflanzliche Bindungspartner von Pep1 identifiziert. So konnte mittels Aktivitäts-basiertem Protein-Profiling gezeigt werden, dass Pep1 spezifisch apoplastische Papain-ähnliche Cysteinproteasen inhibiert. Diese Proteasen spielen offenbar eine wichtige Rolle in der Abwehrinduktion in der Maispflanze. Des Weiteren bindet und inaktiviert Pep1 pflanzliche Klasse-III-Häm-Peroxidasen. In Kooperation mit Christoph Hemetsberger konnte die Hemmung der Horseradish-Peroxidase (HRP) durch Pep1 in vitro gezeigt. Außerdem konnte die physische Interaktion von Pep1 mit der HRP bewiesen werden. Während der Δpep1-Infektion wird eine Mais Peroxidase, die sekretierte Peroxidase-12, transkriptionell induziert. Durch Virus-induziertes-Gen-silencing der Peroxidase-12 konnte eine partielle Restauration des Δpep1-Phänotyps auf POX12si-Pflanzen bewirkt werden. So führte das silencing der Peroxidase-12 zu einer Unterdrückung pflanzlicher Abwehrreaktionen, wie z.B. der Papillenbildung, was eine erfolgreiche Penetration der Δpep1-Mutante ermöglichte. Zusammenfassend zeigen diese Ergebnisse, dass Pep1 Enzyme der basalen Pflanzenabwehr inhibiert und somit die angeborene Resistenz der Wirtspflanze gegen U. maydis unterdrückt.

Dendritic cells (DC) are professional antigen-presenting cells in the immune system which are able to induce primary T-cell responses. Because of their central role in the initiation of immune responses, DC are an important tool for tumor-antigen-specific immunotherapy of cancer. DC vaccination using tumor-antigen-loaded DC has led to tumor regression in individual advanced-stage cancer patients. However, there is a discrepancy between strong and antigen-specific T cell responses in vaccinated cancer patients detectable ex vivo and only weak clinical responses. In most cases the immune system of advanced stage IV cancer patients allows only a temporary anti-tumor response and increasing evidence exists that active suppressive mechanisms of the immune system as well as of the tumor itself ultimately prevent "autoaggressive" immune reactions against the tumor. Active counter-regulation of effector T cells by tumor-antigen-specific regulatory T-cell (Treg) populations play a central role in limiting the efficacy of the vaccines. Nevertheless, recent studies have shown that DC,additionally activated byToll-Like-receptor ligands (TLRL) can neutralize these suppressive effects of Treg and facilitate the induction of long-lasting effector T cell responses even in the presence of activated Treg. These studies open a new way for "conditioning" of DC by TLRL and might significantly enhance the efficiency of DC-based melanoma vaccines in the future.