Adaptive Induction of Nonshivering Thermogenesis in Muscle Rather Than Brown Fat Could Counteract Obesity.

Warm-blooded animals such as birds and mammals are able to protect stable body temperature due to various thermogenic mechanisms. These processes can be facultative (occurring only under specific conditions, such as acute cold) and adaptive (adjusting their capacity according to long-term needs). They can represent a substantial part of overall energy expenditure and, therefore, affect energy balance. Classical mechanisms of facultative thermogenesis include shivering of skeletal muscles and (in mammals) non-shivering thermogenesis (NST) in brown adipose tissue (BAT), which depends on uncoupling protein 1 (UCP1). Existence of several alternative thermogenic mechanisms has been suggested. However, their relative contribution to overall heat production and the extent to which they are adaptive and facultative still needs to be better defined. Here we focus on comparison of NST in BAT with thermogenesis in skeletal muscles, including shivering and NST. We present indications that muscle NST may be adaptive but not facultative, unlike UCP1-dependent NST. Due to its slow regulation and low energy efficiency, reflecting in part the anatomical location, induction of muscle NST may counteract development of obesity more effectively than UCP1-dependent thermogenesis in BAT.

Expanding ecological assessment by integrating microorganisms into routine freshwater biomonitoring.

Bioindication has become an indispensable part of water quality monitoring in most countries of the world, with the presence and abundance of bioindicator taxa, mostly multicellular eukaryotes, used for biotic indices. In contrast, microbes (bacteria, archaea and protists) are seldom used as bioindicators in routine assessments, although they have been recognized for their importance in environmental processes. Recently, the use of molecular methods has revealed unexpected diversity within known functional groups and novel metabolic pathways that are particularly important in energy and nutrient cycling. In various habitats, microbial communities respond to eutrophication, metals, and natural or anthropogenic organic pollutants through changes in diversity and function. In this review, we evaluated the common trends in these changes, documenting that they have value as bioindicators and can be used not only for monitoring but also for improving our understanding of the major processes in lotic and lentic environments. Current knowledge provides a solid foundation for exploiting microbial taxa, community structures and diversity, as well as functional genes, in novel monitoring programs. These microbial community measures can also be combined into biotic indices, improving the resolution of individual bioindicators. Here, we assess particular molecular approaches complemented by advanced bioinformatic analysis, as these are the most promising with respect to detailed bioindication value. We conclude that microbial community dynamics are a missing link important for our understanding of rapid changes in the structure and function of aquatic ecosystems, and should be addressed in the future environmental monitoring of freshwater ecosystems.

Neurotoxicity and Immunotherapy.

BACKGROUND: Great progress has recently been made in immunotherapy of solid carcinomas. The advent of immunotherapy with checkpoint inhibitors has brought not only a completely different mechanism of action but also different types of adverse reactions. These adverse reactions are similar to those of autoimmune diseases and are referred to as immune-related adverse events. Most adverse reactions are due to lower grade toxic effects. Neurotoxicity is a less frequent. On the other hand, with the spread of immunotherapy, it can be assumed that adverse events with a lower incidence may occur in a relatively higher frequency due to borader usage of immunotherapeutics and thus, physicians outside of cancer centres may be presented with these events. The main therapeutic intervention is immunosuppressive therapy with corticoids. However, in some cases, or in case of delayed intervention, they may be fatal. PURPOSE: Therefore, it is of great importance to increase the physicians and patients knowledge of the possible complications of this promising treatment modality. It is essential to apply proper management and help patients engage positively to prevent these situations occurring. This study was supported by the following research programme of Ministry of Health of the Czech Republic - RVO (FNHK, 00179906). The author declares he has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Maternal diet, rather than obesity itself, has a main influence on milk triacylglycerol profile in dietary obese rats.

Triacylglycerols (TG) in milk derive from different sources, and their composition may be influenced by both maternal diet and obesity. We used two rat models to ascertain potential changes in TG composition in milk associated to maternal intake of an obesogenic diet during lactation and to distinguish them from the effects attributable to maternal adiposity. Milk samples were obtained from dams fed a cafeteria diet during lactation (CAF) and from dams made obese by cafeteria diet feeding, with dietary normalization before gestation (PCaf). Levels of specific TG species in milk collected at different time points of lactation were determined by shotgun lipidomics. CAF and PCaf dams presented a greater adiposity than their respective controls. The principal component analysis of TG peaks showed a clear separation between milk from CAF dams and milk from control and Pcaf dams, already evident at 5 days of lactation. Milk from CAF dams was enriched with TG species with greater number of carbons and double bonds and reduced in TG with lower number of carbons. TG composition of milk from Pcaf dams was similar to controls, although specific differences were observed at day 5 of lactation. Thus, the intake of a cafeteria diet during lactation, rather than maternal adiposity, alters milk composition. This effect is avoided with dietary normalization before gestation, although the remaining fat reserves may also influence TG composition at initial stages of lactation. Therefore, normalization of maternal diet prior to pregnancy should be considered as a strategy for achieving optimal milk composition.

Succession of Microbial Decomposers Is Determined by Litter Type, but Site Conditions Drive Decomposition Rates.

Soil microorganisms are diverse, although they share functions during the decomposition of organic matter. Thus, preferences for soil conditions and litter quality were explored to understand their niche partitioning. A 1-year-long litterbag transplant experiment evaluated how soil physicochemical traits of contrasting sites combined with chemically distinct litters of sedge (S), milkvetch (M) from a grassland, and beech (B) from forest site decomposition. Litter was assessed by mass loss; C, N, and P contents; and low-molecular-weight compounds. Decomposition was described by the succession of fungi, Actinobacteria, Alphaproteobacteria, and Firmicutes; bacterial diversity; and extracellular enzyme activities. The M litter decomposed faster at the nutrient-poor forest site, where the extracellular enzymes were more active, but microbial decomposers were not more abundant. Actinobacteria abundance was affected by site, while Firmicutes and fungi by litter type and Alphaproteobacteria by both factors. Actinobacteria were characterized as late-stage substrate generalists, while fungi were recognized as substrate specialists and site generalists, particularly in the grassland. Overall, soil conditions determined the decomposition rates in the grassland and forest, but successional patterns of the main decomposers (fungi and Actinobacteria) were determined by litter type. These results suggest that shifts in vegetation mostly affect microbial decomposer community composition.IMPORTANCE Anthropogenic disturbance may cause shifts in vegetation and alter the litter input. We studied the decomposition of different litter types under soil conditions of a nutrient-rich grassland and nutrient-poor forest to identify factors responsible for changes in the community structure and succession of microbial decomposers. This will help to predict the consequences of induced changes on the abundance and activity of microbial decomposers and recognize if the decomposition process and resulting quality and quantity of soil organic matter will be affected at various sites.

Litter traits and rainfall reduction alter microbial litter decomposers: the evidence from three Mediterranean forests.

The objective of the study was to evaluate changes in microbial communities with the predicted arrival of new species to Mediterranean forests under projected intensification of water stress conditions. For that, litter from three Mediterranean forests dominated respectively by Quercus pubescens Willd., Quercus ilex L. and Pinus halepensis Mill. were collected, and placed to their 'home' forest but also to the two other forests under natural and amplified drought conditions (i.e. rainfall reduction of 30%). Quantitative PCR showed that overall, actinobacteria and total bacteria were more abundant in Q. pubescens and Q. ilex than in P. halepensis litter. However, the abundance of both groups was dependent on the forest sites: placement of allochthonous litter to Q. pubescens and P. halepensis forests (i.e. P. halepensis and Q. pubescens, respectively) increased bacterial and fungal abundances, while no effect was observed in Q. ilex forest. P. halepensis litter in Q. pubescens and Q. ilex forests significantly reduced actinobacteria (A/F) and total bacteria (B/F) to fungi ratios. The reduction of rainfall did not influence actinobacteria and bacteria but caused an increase of fungi. As a result, a reduction of A/F ratio is expected with the plant community change towards the dominance of spreading P. halepensis under amplified drought conditions.

Effects of dietary fat source on lutein, zeaxanthin and total carotenoids content of the egg yolk in laying hens during the early laying period.

1. The study was conducted to investigate the effects of different dietary levels of an unsaturated or saturated fat source and the effects of different dietary energy levels in laying hen diets on the carotenoid content of the egg yolk. 2. Seventy-two ISA Brown laying hens aged 22 weeks old were allocated, for a 10 week period, to three treatments: control diet (HE group) with a 3.4% supplemented fat containing 2.1% soybean and 1.3% palm oil as fat sources and a ratio of unsaturated to saturated fatty acid (u/s) of 3.33; a lowered energy diet with 2.4% supplemented fat containing 1.4% soybean and 1.0% palm oil and u/s of 3.41 (LE+high u/s); a lowered energy diet with 2.4% supplemented fat containing 0.5% soybean and 1.9% palm oil and a u/s of 2.39 (LE+low u/s). A marigold plant extract supplement was used as a source of lutein. 3. Performance parameters (feed consumption, feed conversion, body weight), egg production rate and egg quality parameters were similar between treatments. Dietary fat digestibility at the middle of the study period was not different. Egg yolk total fat content was similar in all treatments at the middle and at the end of the study period. 4. Lutein, zeaxanthin, cis-lutein and total carotenoids content were significantly lower in eggs produced from the LE+low u/s group compared to those from the HE and the LE+high u/s groups (P < 0.01 for all parameters). 5. It was concluded that feeding laying hens with a diet containing 1% less supplemented fat and a lower u/s ratio compared to a control diet and to a diet with 1% less supplemented fat with a higher u/s ratio resulted in a significant reduction of carotenoid expression in the egg yolk at the end of experimental period. Performance and egg quality parameters were not affected by treatments.

Hepatic Injury Induced by a Single Dose of Nivolumab - a Case Report and Literature Review.

BACKGROUND: The use of nivolumab in the treatment of metastatic melanoma has become well established during past years. Despite its undeniable efficacy, immune-related side effects may occur, including acute liver injury. Liver toxicity caused by nivolumab is usually observed as liver enzyme elevation with mild or no symptoms; further, there is limited information regarding any histopathological findings. CASE: We report a case of a 38-year-old woman with metastatic melanoma who developed unusual nivolumab-induced hepatic injury after a single dose of nivolumab. A liver biopsy was performed to assess the aetiology of hepatic lesions as no other analysis concerning biochemistry, virology, autoantibodies, nor imaging studies revealed any pathology. The histopathological analysis showed an oedema in the portal fields and mixed inflammation consisting of eosinophilic and neutrophilic granulocytes. The major finding was a prominent, predominantly intracellular, cholestasis. CONCLUSION: To our knowledge, no such histopathological pattern of liver injury has been described in relation to nivolumab therapy elsewhere. This type of liver injury shows higher resistance to corticosteroids, which may warrant upfront high-dose corticotherapy combined with other immunosuppressive agents, including mycophenolate mofetil. This case highlights a necessary awareness regarding immunotherapy-related adverse events, which could be severe and potentially life-threatening.

[Pilot Study on MicroRNAs as Biomarkers of Response to Sunitinib Treatment in Patients with Metastatic Renall Cell Carcinoma]. / MikroRNA jako biomarkery odpovedi na lécbu sunitinibem u pacientu s metastatickým karcinomem ledvin - pilotní studie.

BACKGROUND: Renal cell carcinoma (RCC) accounts for 2-3% of all malignant tumours. Metastatic RCC (mRCC) is commonly treated with tyrosine kinase inhibitors (TKI). Effective TKIs administration can be achieved only by accurate prediction of therapeutical response. Therefore, the aim of this study was to analyse papers concerning predictive potential of microRNA (miRNA). MATERIAL AND METHODS: We chose seven candidate miRNAs and analysed their expression on 44 patients divided into cohort with poor and good response to sunitinib treatment. Patients were divided into two groups according to progression-free survival. RNA from tissue samples was isolated and expression of selected miRNAs was measured using quantitative PCR with miRNA-specific TaqMan probes. RESULTS: We successfully validated two miRNAs to be differentially expressed in responding and non-responding patients to sunitinib treatment. Other analysed miRNAs have not shown predictive potential. CONCLUSION: From miRNAs studied so far, two miRNAs had predictive value according to present study.Key words: microRNA - renal cell carcinoma - sunitib The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Supported by Ministry of Health of the Czech Republic, grant No. 15-34678A. All rights reserved.Submitted: 19. 3. 2018Accepted: 20. 3. 2018.

Mutant Wars2 gene in spontaneously hypertensive rats impairs brown adipose tissue function and predisposes to visceral obesity.

Brown adipose tissue (BAT) plays an important role in lipid and glucose metabolism in rodents and possibly also in humans. Identification of genes responsible for BAT function would shed light on underlying pathophysiological mechanisms of metabolic disturbances. Recent linkage analysis in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), identified two closely linked quantitative trait loci (QTL) associated with glucose oxidation and glucose incorporation into BAT lipids in the vicinity of Wars2 (tryptophanyl tRNA synthetase 2 (mitochondrial)) gene on chromosome 2. The SHR harbors L53F WARS2 protein variant that was associated with reduced angiogenesis and Wars2 thus represents a prominent positional candidate gene. In the current study, we validated this candidate as a quantitative trait gene (QTG) using transgenic rescue experiment. SHR-Wars2 transgenic rats with wild type Wars2 gene when compared to SHR, showed more efficient mitochondrial proteosynthesis and increased mitochondrial respiration, which was associated with increased glucose oxidation and incorporation into BAT lipids, and with reduced weight of visceral fat. Correlation analyses in RI strains showed that increased activity of BAT was associated with amelioration of insulin resistance in muscle and white adipose tissue. In summary, these results demonstrate important role of Wars2 gene in regulating BAT function and consequently lipid and glucose metabolism.

Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype.

This corrects the article DOI: 10.1038/ijo.2016.228.

[Non-specific immunotherapy inhibits angiogenesis - results of the monitoring of serum levels of vascular endothelial growth factor and matrix metalloproteinase 8 in patients with malignant melanoma receiving adjuvant high-dose interferon therapy]. / Nespecifická imunoterapie inhibuje angiogenezi - výsledky monitorování sérových hladin vaskulárního endotelového rustového faktoru a matrixmetaloproteinázy 8 v prubehu adjuvantní lécby vysokodávkovaným interferonem u pacientu s maligním melanomem.

OBJECTIVE: Interestingly, evidence is currently emerging that the activation of angiogenesis leads to immunomodulatory/immunosuppressive effects both at the local and systemic levels. These are very complex and interconnected processes. In this study, our aim was to establish interferon alpha-2b as an anti-angiogenic agent and show the complexity of angiogenesis and immunomodulation through the serum levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 8 (MMP-8) in high-risk resected malignant melanoma before and after adjuvant therapy with high-dose interferon alpha-2b (HDI). Clinical outcomes of patients were also evaluated. MATERIAL AND METHODS: We prospectively measured the serum levels of VEGF and MMP-8 by ELISA in 29 patients with high-risk resected malignant melanoma receiving adjuvant HDI. Blood samples were collected before and within one week after the treatment. RESULTS: To see the results clearly, we divided our patients into two groups. The first group of patients whose VEGF serum level decreased after HDI (66%) showed long-term complete remission. The mean VEGF serum level in these patients decreased from 779.4 pg/ml to 446.2 pg/ml. This downward trend in VEGF was statistically significant. The second group of patients who did not show a decrease in VEGF serum level after HDI (34%) had no clinical benefit from the treatment. The mean VEGF serum levels in group 2 patients were 408 pg/ml before the treatment and 500 pg/ml after HDI. Results for MMP-8 were ambivalent. CONCLUSIONS: Non-specific immunotherapy with interferons reduces angiogenesis. Our results are in line with the current view of the interconnection and complexity of angiogenesis and immunomodulation/immunosuppression. Non-specific immunotherapy with interferons disrupts the immunosup-pressive effect of the angiogenesis on the development of immune response against tumours and supports anti-tumour response in both direct and indirect way. The interference of HDI with the activation of angiogenesis and tumour progression could explain good clinical outcomes of patients with a decrease in serum VEGF. The outcomes of MMP-8 are inconclusive, its role remain unclear, and MMP-8 does not seem to function as a tumour suppressor.

Sequential analysis of soil factors related to common scab of potatoes.

The severity of common scab (CS) of potatoes has been correlated with multiple environmental factors. This study aimed at separating the effect of factors related to local conditions from those correlated to the disease development at all studied sites using a mathematical adjustment of the variables' means for site and field. The experiment was conducted at two sites differing in soil conditions, where a field with low disease severity occurs next to one with high severity. Three cultivars susceptible to CS were grown in four replicates on each field. Bacteria, actinobacteria and the txtB gene, involved in the biosynthesis of the main CS pathogenicity factor, thaxtomin, were quantified by real-time PCR. Bulk soil, tuberosphere soil and potato periderm were characterized by carbon, nitrogen, phosphorus, sulfur, calcium, magnesium and iron contents. The adjustment of the data for field effects eliminated the confounding local conditions and showed that at all fields the CS severity was negatively correlated with soil S content while the number of txtB gene copies was positively correlated with soil C and N contents. Thus, those factors might have a more general relationship to the pathogen occurrence and disease severity, which needs to be verified in other environmental conditions.

Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype.

BACKGROUND/OBJECTIVE: Futile substrate cycling based on lipolytic release of fatty acids (FA) from intracellular triacylglycerols (TAG) and their re-esterification (TAG/FA cycling), as well as de novo FA synthesis (de novo lipogenesis (DNL)), represent the core energy-consuming biochemical activities of white adipose tissue (WAT). We aimed to characterize their roles in cold-induced thermogenesis and energy homeostasis. METHODS: Male obesity-resistant A/J and obesity-prone C57BL/6J mice maintained at 30 °C were exposed to 6 °C for 2 or 7 days. In epididymal WAT (eWAT), TAG synthesis and DNL were determined using in vivo 2H incorporation from 2H2O into tissue TAG and nuclear magnetic resonance spectroscopy. Quantitative real-time-PCR and/or immunohistochemistry and western blotting were used to determine the expression of selected genes and proteins in WAT and liver. RESULTS: The mass of WAT depots declined during cold exposure (CE). Plasma levels of TAG and non-esterified FA were decreased by day 2 but tended to normalize by day 7 of CE. TAG synthesis (reflecting TAG/FA cycle activity) gradually increased during CE. DNL decreased by day 2 of CE but increased several fold over the control values by day 7. Expression of genes involved in lipolysis, glyceroneogenesis, FA re-esterification, FA oxidation and mitochondrial biogenesis in eWAT was induced during CE. All these changes were more pronounced in obesity-resistant A/J than in B6 mice and occurred in the absence of uncoupling protein 1 in eWAT. Expression of markers of glyceroneogenesis in eWAT correlated negatively with hepatic FA synthesis by day 7 in both strains. Leptin and fibroblast growth factor 21 plasma levels were differentially affected by CE in the two mouse strains. CONCLUSIONS: Our results indicate integrated involvement of (i) TAG/FA cycling and DNL in WAT, and (ii) hepatic very-low-density lipoprotein-TAG synthesis in the control of blood lipid levels and provision of FA fuels for thermogenesis in cold. They suggest that lipogenesis in WAT contributes to a lean phenotype.

[The Role of BRAF/MEK Inhibition in Metastatic Malignant Melanoma - a Case Study]. / Role BRAF/ MEK inhibice u metastazujícího maligního melanomu -  kazuistika.

BACKGROUND: Metastatic malignant melanoma belongs to a group of cancers with high mortality. In recent years, advances in our knowledge of the pathogenesis of melanoma and the discovery of new drugs has resulted in significant progress in the treatment of metastatic malignant melanoma patients. The development of resistance to these drugs, however, remains a challenge. One way how to avoid resistance, or at least delay it, is to administer combination therapy. OBSERVATION AND CONCLUSION: This case study demonstrates that combination therapy with a BRAF and a MEK inhibitor can be used to successfully treat metastatic malignant melanoma patients and suggests they should be employed in therapeutic algorithms for patients with metastatic malignant melanoma and BRAF gene mutations.

Adverse effects of AMP-activated protein kinase alpha2-subunit deletion and high-fat diet on heart function and ischemic tolerance in aged female mice.

AMP-activated protein kinase (AMPK) plays a role in metabolic regulation under stress conditions, and inadequate AMPK signaling may be also involved in aging process. The aim was to find out whether AMPK alpha2-subunit deletion affects heart function and ischemic tolerance of adult and aged mice. AMPK alpha2(-/-) (KO) and wild type (WT) female mice were compared at the age of 6 and 18 months. KO mice exhibited subtle myocardial AMPK alpha2-subunit protein level, but no difference in AMPK alpha1-subunit was detected between the strains. Both alpha1- and alpha2-subunits of AMPK and their phosphorylation decreased with advanced age. Left ventricular fractional shortening was lower in KO than in WT mice of both age groups and this difference was maintained after high-fat feeding. Infarct size induced by global ischemia/reperfusion of isolated hearts was similar in both strains at 6 months of age. Aged WT but not KO mice exhibited improved ischemic tolerance compared with the younger group. High-fat feeding for 6 months during aging abolished the infarct size-reduction in WT without affecting KO animals; nevertheless, the extent of injury remained larger in KO mice. The results demonstrate that adverse effects of AMPK alpha2-subunit deletion and high-fat feeding on heart function and myocardial ischemic tolerance in aged female mice are not additive.

[Possible Pitfalls of Ipilimumab Therapy in Malignant Melanoma -  a Case Report]. / Mozná úskalí lécby ipilimumabem u maligního melanomu -  kazuistika.

BACKGROUND: Metastatic melanoma is a malignancy with one of the highest mortality rates. However, with the introduction of new drugs during the last decade, the prognosis of patients began to improve. Ipilimumab is one of the first so  called modern drugs in melanoma treatment. The therapy is often complicated by adverse effects which are referred as immunerelated adverse events due to its mechanism of action. CASE: We present a case of 68-year- old women with metastatic melanoma who underwent treatment with ipilimumab. The patient encountered several adverse events during the treatment. Some of them are quite common (e.g. skin affections), others (e.g. endocrinopathies) are less frequent. CONCLUSION: This case study highlights the need for close observation not only during the actual treatment with ipilimumab, but also several weeks or months after the last dose. This case study also demonstrates further need of education of doctors who do not usually come in to contact with such patients.

Bacteria detected in the honeybee parasitic mite Varroa destructor collected from beehive winter debris.

AIMS: The winter beehive debris containing bodies of honeybee parasitic mite Varroa destructor is used for veterinary diagnostics. The Varroa sucking honeybee haemolymph serves as a reservoir of pathogens including bacteria. Worker bees can pick up pathogens from the debris during cleaning activities and spread the infection to healthy bees within the colony. The aim of this study was to detect entomopathogenic bacteria in the Varroa collected from the winter beehive debris. METHODS AND RESULTS: Culture-independent approach was used to analyse the mite-associated bacterial community. Total DNA was extracted from the samples of 10 Varroa female individuals sampled from 27 different sites in Czechia. The 16S rRNA gene was amplified using universal bacterial primers, cloned and sequenced, resulting in a set of 596 sequences representing 29 operational taxonomic units (OTU97). To confirm the presence of bacteria in Varroa, histological sections of the mites were observed. Undetermined bacteria were observed in the mite gut and fat tissue. CONCLUSION: Morganella sp. was the most frequently detected taxon, followed by Enterococcus sp., Pseudomonas sp., Rahnella sp., Erwinia sp., and Arsenophonus sp. The honeybee putative pathogen Spiroplasma sp. was detected at one site and Bartonella-like bacteria were found at four sites. PCR-based analysis using genus-specific primers enabled detection of the following taxa: Enterococcus, Bartonella-like bacteria, Arsenophonus and Spiroplasma. SIGNIFICANCE AND IMPACT OF THE STUDY: We found potentially pathogenic (Spiroplasma) and parasitic bacteria (Arsenophonus) in mites from winter beehive debris. The mites can be reservoirs of the pathogenic bacteria in the apicultures.

Tick salivary cystatin sialostatin L2 suppresses IFN responses in mouse dendritic cells.

Type I interferon (IFN), mainly produced by dendritic cells (DCs), is critical in the host defence against tick-transmitted pathogens. Here, we report that salivary cysteine protease inhibitor from the hard tick Ixodes scapularis, sialostatin L2, affects IFN-ß mediated immune reactions in mouse dendritic cells. Following IFN receptor ligation, the Janus activated kinases/signal transducer and activator of transcription (JAK/STAT) pathway is activated. We show that sialostatin L2 attenuates phosphorylation of STATs in spleen dendritic cells upon addition of recombinant IFN-ß. LPS-stimulated dendritic cells release IFN-ß which in turn leads to the induction of IFN-stimulated genes (ISG) through JAK/STAT pathway activation. The induction of two ISG, interferon regulatory factor 7 (IRF-7) and IP-10, was suppressed by sialostatin L2 in LPS-stimulated dendritic cells. Finally, the interference of sialostatin L2 with IFN action led to the enhanced replication of tick-borne encephalitis virus in DC. In summary, we present here that tick salivary cystatin negatively affects IFN-ß responses which may consequently increase the pathogen load after transmission via tick saliva.