Impact of the Interferon regulatory factor 5 on the antiviral host defense of the central nervous system

Interferon (IFN)-regulierende Faktoren (IRFs) sind eine Gruppe von Transkriptionsfaktoren, die an der Regulation vieler Mechanismen der Wirtsabwehr, wie der Induktion von IFN beteiligt sind. IRF5 induziert die Expression proinflammatorischer Zytokine. Mehrere Studien weißen außerdem darauf hin, dass IRF5 eine wichtige Rolle bei der antiviralen Wirtsabwehr spielt. In dieser Arbeit sollte die Rolle von IRF5 an der antiviralen Immunität näher untersucht werden. IRF5-/- Mäuse zeigen im Vergleich zu Wildtyp Mäusen (wt) eine erhöhte Suszeptibilität gegenüber intranasaler Infektion mit dem Vesikuläre-Stomatitis-Virus (VSV). Der Vergleich der viralen Replikation in peripheren Organen (Lunge, Leber und Milz) und im Gehirn zeigte, dass in wt Mäusen das Virus nach 4 Tagen vollständig eliminiert werden kann. In IRF5-/- Mäusen kommt es hingegen zur ungehinderten Ausbreitung und Vermehrung von VSV im Gehirn. Im Vergleich zu wt Mäusen zeigten IRF5-/- Mäuse geringere Konzentration an IFNa im Serum. Dennoch waren sie eingeschränkt in der Lage sowohl in der Lunge, wie auch im Gehirn antivirale Gene zu exprimieren. Dies wies darauf hin, dass auch Mechanismen der adaptiven Immunität von IRF5 beeinflusst sein könnten. Naive IRF5-/- Tiere besaßen weniger B- und T-Zellen. Ein wichtiger Mechanismus bei der Bekämpfung einer VSV-Infektion ist die Produktion VSV-neutralisierender Antikörper. Es konnte gezeigt werden, dass IRF5-/- Tiere einen Defekt in der humoralen Immunabwehr haben. Trotz der Kompensation dieses Defekts durch den adaptiven Transfer von B-Zellen war die Infektion mit VSV letal. Die Ergebnisse dieser Arbeit zeigen, dass IRF5 einen bedeutenden Einfluss auf die antivirale Wirtsabwehr besitzt. IRF5 ist ein wichtiger Faktor zur Induktion von IFN, der Entwicklung von B- und T-Zellen und ist an der Produktion neutralisierender Antikörper beteiligt. Die IRF5-abhängige Resistenz gegenüber VSV wird jedoch B-Zell-unabhängig, wahrscheinlich über Neuronen-intrinsische Effekte vermittelt.Interferon (IFN) Regulatory Factors (IRFs) are a group of transcription factors that are involved in the regulation of different mechanisms of the host response, like the induction of IFN. IRF5 has been shown to be involved in the induction of proinflammatory cytokines. Several studies suggest a role of IRF5 in the antiviral response. Hence, the overall aim of this study was to explore the IRF5-dependent innate and adaptive antiviral response. IRF5-/- mice are highly susceptible to intranasal infections with Vesicular Stomatitis Virus (VSV), whereas wild type mice (wt) survive. A comparison of viral replication in the peripheral organs (lung, liver and spleen) and the brain in IRF5-/- mice and wt mice demonstrated the clearance of the virus within 4 days in wt mice. In contrast, the virus replicates and spreads unlimited in IRF5-/- brains. In comparison to the wt mice, IRF5-/-mice showed decreased amounts of IFNa in the serum. Nevertheless these mice were able to express antiviral genes both in the lung and brain. This gave rise to the assumption that IRF5 could be involved in the adaptive immunity. Naive IRF5-/- mice had lesser B and T lymphocytes compared to their wt counterparts. An important mechanism to control VSV infections is the production of VSV-neutralizing antibodies. The data showed that IRF5-/- mice had a defective humoral immune response. Despite of the efforts to compensate for this defect by the adaptive transfer of B cells to IRF5-/- mice, the mice still succumbed to VSV infection. These results indicate that IRF5 has a strong impact on the antiviral host defense through different mechanisms. IRF5 is a crucial factor for type I IFN induction, adaptive immune responses such as B and T cell development and neutralizing antibody production. However, the IRF5-dependent resistance against VSV is mediated by B-cell independent mechanisms and most probably by neuron-intrinsic effects

A TLR7 antagonist restricts interferon-dependent and -independent immunopathology in a mouse model of severe influenza

Cytokine-mediated immune-cell recruitment and inflammation contribute to protection in respiratory virus infection. However, uncontrolled inflammation and the “cytokine storm” are hallmarks of immunopathology in severe infection. Cytokine storm is a broad term for a phenomenon with diverse characteristics and drivers, depending on host genetics, age, and other factors. Taking advantage of the differential use of virus-sensing systems by different cell types, we test the hypothesis that specifically blocking TLR7-dependent, immune cell–produced cytokines reduces influenza-related immunopathology. In a mouse model of severe influenza characterized by a type I interferon (IFN-I)–driven cytokine storm, TLR7 antagonist treatment leaves epithelial antiviral responses unaltered but acts through pDCs and monocytes to reduce IFN-I and other cytokines in the lung, thus ameliorating inflammation and severity. Moreover, even in the absence of IFN-I signaling, TLR7 antagonism reduces inflammation and mortality driven by monocyte-produced chemoattractants and neutrophil recruitment into the infected lung. Hence, TLR7 antagonism reduces diverse types of cytokine storm in severe influenza

Oxide ceramic electrolytes for all-solid-state lithium batteries – cost-cutting cell design and environmental impact

All-solid-state batteries are a hot research topic due to the prospect of high energy density and higher intrinsic safety, compared to conventional lithium-ion batteries. Of the wide variety of solid-state electrolytes currently researched, oxide ceramic lithium-ion conductors are considered the most difficult to implement in industrial cells. Although their high lithium-ion conductivity combined with a high chemical and thermal stability make them a very attractive class of materials, cost-cutting synthesis and scalable processing into full batteries remain to be demonstrated. Additionally, they are Fluorine-free and can be processed in air but require one or more high temperature treatment steps during processing counteracting their ecological benefits. Thus, a viable cell design and corresponding assessment of its ecological impact is still missing. To close this gap, we define a target cell combining the advantages of the two most promising oxidic electrolytes, lithium lanthanum zirconium oxide (LLZO) and lithium aluminium titanium phosphate (LATP). Even though it has not been demonstrated so far, the individual components are feasible to produce with state-of-the-art industrial manufacturing processes. This model cell then allows us to assess the environmental impact of the ceramic electrolyte synthesis and cell component manufacturing not just on an abstract level (per kg of material) but also with respect to their contributions to the final cell. The in-depth life cycle assessment (LCA) analysis revealed surprising similarities between oxide-based all-solid-state batteries and conventional Li-ion batteries. The overall LCA inventory on the material level is still dominated by the cathode active material, while the fabrication through ceramic manufacturing processes is a major contributor to the energy uptake. A clear path that identifies relevant research and development directions in terms of economic benefits and environmental sustainability could thus be developed to promote the competitiveness of oxide based all-solid-state batteries in the market

TGFβ induces a SAMHD1-independent post-entry restriction to HIV-1 infection of human epithelial Langerhans cells

Sterile alpha motif (SAM) and histidine-aspartic (HD) domains protein 1 (SAMHD1) was previously identified as a critical post-entry restriction factor to HIV-1 infection in myeloid dendritic cells. Here we show that SAMHD1 is also expressed in epidermis-isolated Langerhans cells (LC), but degradation of SAMHD1 does not rescue HIV-1 or vesicular stomatitis virus G-pseudotyped lentivectors infection in LC. Strikingly, using Langerhans cells model systems (mutz-3-derived LC, monocyte-derived LC [MDLC], and freshly isolated epidermal LC), we characterize previously unreported post-entry restriction activity to HIV-1 in these cells, which acts at HIV-1 reverse transcription, but remains independent of restriction factors SAMHD1 and myxovirus resistance 2 (MX2). We demonstrate that transforming growth factor-β signaling confers this potent HIV-1 restriction in MDLC during their differentiation and blocking of mothers against decapentaplegic homolog 2 (SMAD2) signaling in MDLC restores cells’ infectivity. Interestingly, maturation of MDLC with a toll-like receptor 2 agonist or transforming growth factor-α significantly increases cells’ susceptibility to HIV-1 infection, which may explain why HIV-1 acquisition is increased during coinfection with sexually transmitted infections. In conclusion, we report a SAMHD1-independent post-entry restriction in MDLC and LC isolated from epidermis, which inhibits HIV-1 replication. A better understanding of HIV-1 restriction and propagation from LC to CD4+ T cells may help in the development of new microbicides or vaccines to curb HIV-1 infection at its earliest stages during mucosal transmission

SARS-CoV-2 S2–targeted vaccination elicits broadly neutralizing antibodies

Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we found that prior HCoV-OC43 S-targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo. Last, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that it may prevent repertoire focusing caused by repeated homologous vaccination. These data establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses

Dendritic cells promote the spread of human T-cell leukemia virus type 1 via bidirectional interactions with CD4+ T cells

Human T-cell leukemia virus type-1 (HTLV-1) propagates within and between individuals via cell-to-cell transmission, and primary infection typically occurs across juxtaposed mucosal surfaces during breastfeeding and sexual intercourse. It is therefore likely that dendritic cells (DCs) are among the first potential targets for HTLV-1. However, it remains unclear how DCs contribute to virus transmission and dissemination in the early stages of infection. We show that an HTLV-1-infected cell line (MT-2) and naturally-infected CD4+ T-cells transfer p19+ viral particles to the surface of allogeneic DCs via cell-to-cell contacts. Similarly organized cell-to-cell contacts facilitate DC-mediated transfer of HTLV-1 to autologous CD4+ T-cells. These findings shed light on the cellular structures involved in anterograde and retrograde transmission, and suggest a key role for DCs in the natural history and pathogenesis of HTLV-1 infection

Down-RANKing the threat of HSV-1: RANKL upregulates MHC-class-I-restricted anti-viral immunity in herpes simplex virus infection

Herpes simplex virus (HSV-1) is a major cause of viral skin infection in humans. Klenner and colleagues now show that the epidermal receptor activator of NFκB ligand (RANKL) is critical for the induction of anti-viral CD8+ effector T cells (CTL) during cutaneous HSV-1 infection. Activation via RANKL prevents Langerhans cell apoptosis, thus leading to enhanced antigen transport to regional lymph nodes, increasing the CTL-priming capacity of lymph node dendritic cells

Hepatitis C virus replication in mouse cells is restricted by IFN-dependent and -independent mechanisms.

Current treatment strategies for hepatitis C virus (HCV) infection include pegylated interferon (IFN)-alfa and ribavirin. Approximately 50% of patients control HCV infection after treatment, but the broad range of patients' outcomes and responses to treatment, among all genotypes, indicates a role for host factors. Although the IFN system is important in limiting HCV replication, the virus has evolved mechanisms to circumvent the IFN response. However, direct, IFN-independent antiviral processes also might help control HCV replication. We examined the role of IFN-independent responses against HCV replication