Interferon type 1 responses in primary and secondary infections

The mammalian host responds to a microbial infection with a rapid innate immune reaction that is dominated by type I interferon (IFN-I) release. Most cells of vertebrates can respond to microbial attack with IFN-I production, but the cell type responsible for most of the systemic IFN-I release is thought to be plasmacytoid dendritic cells (pDCs). Besides its anti-microbial and especially anti-viral properties IFN-I also exerts a regulatory role on many facets of the sequential adaptive immune response. One of these is being the recently described partial, systemic activation of the vast majority of B and T lymphocytes in mice, irrespective of antigen reactivity. The biological significance of this partial activation of lymphocytes is at present speculative. Secondary infections occurring within a short time span of a primary infection fail to elicit a similar lymphocyte activation response due to a refractory period in systemic IFN-I production. This period of exhaustion in IFN-I responses is associated with an increased susceptibility of the host to secondary infections. The latter correlates with well-established clinical observations of heightened susceptibility of patients to secondary microbial infections after viral episodes

In vivo elimination of MHC-I-deficient lymphocytes by activated natural killer cells is independent of granzymes A and B

NK cells kill target cells mainly via exocytosis of granules containing perforin (perf) and granzymes (gzm). In vitro, gzm delivery into the target cell cytosol results in apoptosis, and induction of apoptosis is severely impaired in the absence of gzm A and B. However, their importance for in vivo cytotoxicity by cytotoxic T cells has been questioned. We used an in vivo NK cytotoxicity assay, in which splenocytes from wild-type and β(2)microglobulin-deficient (MHC-I(neg)) mice are co-injected into recipients whose NK cells were activated by virus infection or synthetic Toll-like receptor ligands. Elimination of adoptively transferred MHC-I(neg) splenocytes was unimpaired in the absence of gzmA and gzmB, but dependent on perforin. This target cell rejection was NK cell dependent, since NK cell depletion abrogated it. Furthermore, target cell elimination in vivo was equally rapid in both wild-type and gzmAxB-deficient recipients, with the majority of specific target cells lost from lymphoid tissue within less than one to two hours after transfer. Thus, similar to T cell cytotoxicity, the contribution of gzmA and B to in vivo target cell elimination remains unresolved.This work was supported by the Australian National Health and Medical Research Council and by a government block grant to the John Curtin School of Medical Research

Pivotal Role of Antibody and Subsidiary Contribution of CD8+ T Cells to Recovery from Infection in a Murine Model of Japanese Encephalitis

The immunological correlates for recovery from primary Japanese encephalitis virus (JEV) infection in humans and experimental animals remain poorly defined. To investigate the relative importance of the adaptive immune responses, we have established a mouse model for Japanese encephalitis in which a low-dose virus inoculum was administered into the footpads of adult C57BL/6 mice. In this model, ~60% of the mice developed a fatal encephalitis and a virus burden in the central nervous system (CNS). Using mice lacking B cells (μMT-/- mice) and immune B cell transfer to wild-type mice, we show a critically important role for humoral immunity in preventing virus spread to the CNS. T cell help played an essential part in the maintenance of an effective antibody response necessary to combat the infection, since mice lacking major histocompatibility complex class II showed truncated IgM and blunted IgG responses and uniformly high lethality. JEV infection resulted in extensive CD8+ T cell activation, judged by upregulation of surface markers CD69 and CD25 and cytokine production after stimulation with a JEV NS4B protein-derived H-2Db-binding peptide and trafficking of virus-immune CD8+ T cells into the CNS. However, no significant effect of CD8+ T cells on the survival phenotype was found, which was corroborated in knockout mice lacking key effector molecules (Fas receptor, perforin, or granzymes) of cytolytic pathways triggered by T lymphocytes. Accordingly, CD8+ T cells are mostly dispensable for recovery from infection with JEV. This finding highlights the conflicting role that CD8+T cells play in the pathogenesis of JEV and closely related encephalitic flaviviruses such as West Nile virus

Intranasal Flu Vaccine Protective against Seasonal and H5N1 Avian Influenza Infections

Background Influenza A (flu) virus causes significant morbidity and mortality worldwide, and current vaccines require annual updating to protect against the rapidly arising antigenic variations due to antigenic shift and drift. In fact, current subunit or split flu vaccines rely exclusively on antibody responses for protection and do not induce cytotoxic T (Tc) cell responses, which are broadly cross-reactive between virus strains. We have previously reported that γ-ray inactivated flu virus can induce cross-reactive Tc cell responses. Methodology/Principal Finding Here, we report that intranasal administration of purified γ-ray inactivated human influenza A virus preparations (γ-Flu) effectively induces heterotypic and cross-protective immunity. A single intranasal administration of γ-A/PR8[H1N1] protects mice against lethal H5N1 and other heterotypic infections. Conclusions/Significance Intranasal γ-Flu represents a unique approach for a cross-protective vaccine against both seasonal as well as possible future pandemic influenza A virus infections.Mohammed Alsharifi, Yoichi Furuya, Timothy R. Bowden, Mario Lobigs, Aulikki Koskinen, Matthias Regner, Lee Trinidad, David B. Boyle and Arno Müllbache

Gamma-Irradiated Influenza Virus Uniquely Induces IFN-I Mediated Lymphocyte Activation Independent of the TLR7/MyD88 Pathway

Background: We have shown previously in mice, that infection with live viruses, including influenza/A and Semliki Forest virus (SFV), induces systemic partial activation of lymphocytes, characterized by cell surface expression of CD69 and CD86, but not CD25. This partial lymphocytes activation is mediated by type-I interferons (IFN-I). Importantly, we have shown that c-irradiated SFV does not induce IFN-I and the associated lymphocyte activation. Principal Findings: Here we report that, in contrast to SFV, c-irradiated influenza A virus elicits partial lymphocyte activation in vivo. Furthermore, we show that when using influenza viruses inactivated by a variety of methods (UV, ionising radiation and formalin treatment), as well as commercially available influenza vaccines, only c-irradiated influenza virus is able to trigger IFN-I-dependent partial lymphocyte activation in the absence of the TLR7/MyD88 signalling pathways. Conclusions: Our data suggest an important mechanism for the recognition of c-irradiated influenza vaccine by cytosolic receptors, which correspond with the ability of c-irradiated influenza virus to induce cross-reactive and cross-protective cytotoxic T cell responses.Yoichi Furuya, Jennifer Chan, En-Chi Wan, Aulikki Koskinen, Kerrilyn R. Diener, John D. Hayball, Matthias Regner, Arno Müllbacher, Mohammed Alsharif

On the Amplitude of Convective Velocities in the Deep Solar Interior

We obtain lower limits on the amplitude of convective velocities in the deep solar convection zone based only on the observed properties of the differential rotation and meridional circulation together with simple and robust dynamical balances obtained from the fundamental MHD equations. The linchpin of the approach is the concept of gyroscopic pumping whereby the meridional circulation across isosurfaces of specific angular momentum is linked to the angular momentum transport by the convective Reynolds stress. We find that the amplitude of the convective velocity must be at least 30 m s$^{-1}$ in the upper CZ ($r \sim 0.95 R$) and at least 8 m s$^{-1}$ in the lower CZ ($r \sim 0.75 R$) in order to be consistent with the observed mean flows. Using the base of the near-surface shear layer as a probe of the rotational influence, we are further able to show that the characteristic length scale of deep convective motions must be no smaller than 5.5--30 Mm. These results are compatible with convection models but suggest that the efficiency of the turbulent transport assumed in advection-dominated flux-transport dynamo models is generally not consistent with the mean flows they employ.Comment: 16 pages, 4 figures, accepted to the Astrophysical Journa

Deichrückverlegungen in Sachsen-Anhalt und wissenschaftliche Begleituntersuchungen am Beispiel des Roßlauer Oberluchs

Deichbau und andere flussbautechnische Maßnahmen haben dazu geführt, dass die Mittlere Elbe ihre ursprünglichen Überschwemmungsgebiete verloren hat. Um die Auswirkungen der alljährlich auftretenden Hochwasserereignisse einzudämmen, wurden große Bereiche der Talniederung durch Deiche vom Überflutungsgeschehen abgetrennt. Diese Eingriffe in den Naturhaushalt ermöglichten gleichfalls eine intensive ackerbauliche Nutzung oder eine hochwassersichere Bebauung der Auen. Die natürliche Auendynamik ist heute weitestgehend auf einen schmalen Bereich entlang der Elbe beschränkt. Hinter den Deichen sind die für die Elbeauen typischen Lebensräume von der lebenswichtigen Auendynamik abgeschnitten. Angepasste Auenarten und -lebensgemeinschaften treten zugunsten von Allerweltsarten zurück. Eine Wiederanbindung von Altauenbereichen an das Überflutungsgeschehen ist deshalb eine der vordringlichsten Maßnahmen zur Revitalisierung gefährdeter Auenlebensräume und stellt eine Chance dar, einen nachhaltigen und modernen Hochwasserschutz mit Naturschutzzielen zu verbinden. An der Elbe entspricht das aktuelle Hochwasserschutzsystem nicht den heutigen Anforderungen an den Hochwasserschutz. Um jedoch jederzeit auf mögliche große Hochwasserereignisse reagieren zu können, entstanden Anfang der 1990er Jahre in den Anliegerländern der Elbe zahlreiche Pläne für Deichrückverlegungen

Real-world evidence on siponimod treatment in patients with secondary progressive multiple sclerosis

BACKGROUND: Therapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing–remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape. METHODS: We conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions. RESULTS: Under siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy. CONCLUSION: Treatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s42466-022-00219-3

Micronutritional supplementation with a holoBLG-based FSMP (food for special medical purposes)-lozenge alleviates allergic symptoms in BALB/c mice: Imitating the protective farm effect

Background: Previously, the protective farm effect was imitated using the whey protein beta-lactoglobulin (BLG) that is spiked with iron-flavonoid complexes. Here, we formulated for clinical translation a lozenge as food for special medical purposes (FSMP) using catechin-iron complexes as ligands for BLG. The lozenge was tested in vitro and in a therapeutical BALB/c mice model. Methods: Binding of iron-catechin into BLG was confirmed by spectroscopy and docking calculations. Serum IgE binding of children allergic or tolerating milk was assessed to loaded (holo-) versus empty (apo-) BLG and for human mast cell degranulation. BLG and Bet v 1 double-sensitized mice were orally treated with the holoBLG or placebo lozenge, and immunologically analysed after systemic allergen challenge. Human PBMCs of pollen allergic subjects were flow cytometrically assessed after stimulation with apoBLG or holoBLG using catechin-iron complexes as ligands. Results: One major IgE and T cell epitope were masked by catechin-iron complexes, which impaired IgE binding of milk-allergic children and degranulation of mast cells. In mice, only supplementation with the holoBLG lozenge reduced clinical reactivity to BLG and Bet v 1, promoted Tregs, and suppressed antigen presentation. In allergic subjects, stimulation of PBMCs with holoBLG led to a significant increase of intracellular iron in circulating CD14+ cells with significantly lower expression of HLADR and CD86 compared to their stimulation with apoBLG. Conclusion: The FSMP lozenge targeted antigen presenting cells and dampened immune activation in human immune cells and allergic mice in an antigen-non-specific manner, thereby conferring immune resilience against allergic symptoms