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During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development., Manipulation of Toll-like receptors (TLRs) affects HIV-1 infection and latency reversal. Here, the authors show that HIV-1 is endocytosed and recognized by TLR8 in human primary CD4+T cells and that TLR8 stimulation induces an inflammatory response that promotes HIV-1 replication and reversal of latency.

Background We aimed to evaluate the clinical usefulness of qSOFA as a risk stratification tool for patients admitted with infection compared to traditional SIRS criteria or our triage system; the Rapid Emergency Triage and Treatment System (RETTS). Methods The study was an observational cohort study performed at one Emergency Department (ED) in an urban university teaching hospital in Norway, with approximately 20,000 visits per year. All patients >16 years presenting with symptoms or clinical signs suggesting an infection (n = 1535) were prospectively included in the study from January 1 to December 31, 2012. At arrival in the ED, vital signs were recorded and all patients were triaged according to RETTS vital signs, presenting infection, and sepsis symptoms. These admission data were also used to calculate qSOFA and SIRS. Treatment outcome was later retrieved from the patients’ electronic records (EPR) and mortality data from the Norwegian population registry. Results Of the 1535 admitted patients, 108 (7.0%) fulfilled the Sepsis2 criteria for severe sepsis. The qSOFA score ≥2 identified only 33 (sensitivity 0.32, specificity 0.98) of the patients with severe sepsis, whilst the RETTS-alert ≥ orange identified 92 patients (sensitivity 0.85, specificity 0.55). Twenty-six patients died within 7 days of admission; four (15.4%) of them had a qSOFA ≥2, and 16 (61.5%) had RETTS ≥ orange alert. Of the 68 patients that died within 30 days, only eight (11.9%) scored ≥2 on the qSOFA, and 45 (66.1%) had a RETTS ≥ orange alert. Discussion In order to achieve timely treatment for sepsis, a sensitive screening tool is more important than a specific one. Our study is the fourth study were qSOFA finds few of the sepsis cases in prehospital or at arrival to the ED. We add information on the RETTS triage system, the two highest acuity levels together had a high sensitivity (85%) for identifying sepsis at arrival to the ED - and thus, RETTS should not be replaced by qSOFA as a screening and trigger tool for sepsis at arrival. Conclusion In this observational cohort study, qSOFA failed to identify two thirds of the patients admitted to an ED with severe sepsis. Further, qSOFA failed to be a risk stratification tool as the sensitivity to predict 7-day and 30-day mortality was low. The sensitivity was poorer than the other warning scores already in use at the study site, RETTS-triage and the SIRS criteria. Electronic supplementary material The online version of this article (doi:10.1186/s13049-017-0399-4) contains supplementary material, which is available to authorized users.

Background: Invasive pneumococcal disease (IPD) is responsible for significant mortality and morbidity worldwide. There are however few longitudinal studies on the changes in case fatality rate of IPD in recent years. We carried out a prospective observational study of patients with IPD in Nord Trøndelag county in Norway from 1993 to 2011 to study the clinical variables and disease outcome. The main outcome was all-cause mortality after 30 and 90 days. Methods: Patients with positive blood cultures were registered prospectively by the microbiology laboratory and clinical variables were registered retrospectively from patients’ hospital records. The severity of sepsis was assigned according to the 2001 International Sepsis Definition Conference criteria. The association between mortality and predictive factors was studied using a logistic regression model. Results: The total number of patients was 414 with mean age of 67 years and 53 % were male. Comorbidity was assessed by the Charlson Comorbidity Index (CCI). A CCI-score of 0 was registered in 144 patients (34.8 %), whereas 190 had a score of 1–2 (45.9 %) and 80 (19.3 %) had a score ≥3. 68.8 % of the patients received appropriate antibiotics within the first 6 h. The 30-day mortality risk increased by age and was 3-fold higher for patients aged ≥80 years (24.9, 95 % CI 16.4–33.4 %) compared to patients aged

Although the pathogenic role of T cells in atherogenesis is well established, the function of the various T-cell subsets is far from clear. Whereas activation of the T-helper type 1 (Th1) subset promotes inflammatory and proatherogenic responses and activation of Th2 cells mediates both proatherogenic and antiatherogenic effects, the newly discovered regulatory T-cell subset seems to attenuate atherogenesis. However, the dynamics of T-cell response within the plaque are still poorly understood, and both antigen-dependent and antigen-independent stimuli may be involved in the expansion of T cells in atherosclerotic plaques. Nevertheless, the different nature of the various T-cell subsets and their complex role in atherogenesis underscore the need for future research in this field of atheroimmunology. This research is not only of interest for the basic research field, but may also have relevance for clinical cardiology, potentially leading to new targets for therapy in atherosclerotic disorders.

Chronic heart failure (HF) is a disorder characterized in part by immune activation and inflammation. Thus, patients with HF have elevated levels of a number of inflammatory cytokines, both in the circulation and in the failing heart itself. Several mechanisms for this immune activation, which are not mutually exclusive, have been suggested, including neurohormonal activation, hemodynamic overload, and activation of the innate immune system secondary to cardiac stress. Importantly, experimental studies have shown that inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1b, and monocyte chemoattractant peptide-1 may contribute to the development and progression of HF by promoting myocardial hypertrophy, activating matrix metalloproteinases, provoking contractile dysfunction, and inducing apoptosis. However, inflammatory cytokines may also have adaptive and cardioprotective effects. This important aspect of cytokine biology must be kept in mind when designing new immunomodulatory treatment modalities in HF.

This review considers the recent clinical and relevant preclinical evidence that thalidomide may have therapeutic benefit in chronic heart failure (HF), and considers some of the mechanisms by which thalidomide may elicit potentially beneficial effects. Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic HF by influencing heart contractility, inducing matrix degradation and fibrosis, and promoting apoptosis, contributing to myocardial remodeling. On the basis of these issues, immunomodulating therapy has emerged as an option in the management of chronic HF. Failure of anti-tumor necrosis factor (TNF) therapy has lead to further interest in a more general immunomodulatory approach, directed against the imbalanced cytokine network rather than at one particular cytokine.Some recent studies suggest that thalidomide, a glutamic acid derivative with proposed antiangiogenic, anti-inflammatory, and immunomodulatory properties, should be added to the list of potential immunomodulating agents in chronic HF. Thus, in a recent double-blind, placebo-controlled study in patients with chronic HF, thalidomide was found to significantly improve left ventricular ejection fraction. Although thalidomide has been regarded as an anti-TNF drug, it was found to increase plasma levels of TNFalpha in a placebo-controlled study in patients with HF, suggesting that other mechanisms may contribute to its beneficial effects. Such mechanisms could involve inhibition of neutrophils, matrix stabilizing, and antifibrotic effects, as well as a thalidomide-mediated decrease in the heart rate. However, our knowledge of the mechanisms of action of this drug is still scarce and will have to be further examined in forthcoming studies. Such studies should include experiments in animal models of HF as well as further preclinical trials, attempting to identify the potential mechanisms by which thalidomide may be beneficial in human HF.

Patients with chronic heart failure (HF) are characterized by systemic inflammation, as evident by raised circulating levels of several inflammatory cytokines with increasing levels according to the degree of disease severity. In addition to the myocardium itself, several tissues and cells can contribute to this inflammation, including leukocytes, platelets, tissue macrophages and endothelial cells. Although the mechanisms for the systemic inflammation is unknown, both infectious (e.g., endotoxins) and non-infectious (e.g., oxidative stress and hemodynamic overload) events could be operating, also including activation of Toll-like receptors as well as interaction with the neurohormone system. A growing body of evidence suggests that this systemic inflammation in chronic HF may play a role in the development and progression of this disorder, not only by promoting myocardial dysfunction, but also by inducing pathogenic consequences in other organs and tissues, thereby contributing to additional aspects of the HF syndrome such as cachexia, endothelial dysfunction and anemia. Although this inappropriate immune activation and inflammation could represent a new target for therapy in patients with chronic HF, the anti-tumor necrosis factor trials have been disappointing, and future research in this area will have to more precisely identify the most important mechanisms and actors in the immunopathogenesis of chronic HF in order to develop better immunomodulating agents for this disorder.

Accumulating evidence indicates that inflammatory cytokines play a pathogenic role in congestive heart failure (CHF) by influencing heart contractility, inducing hypertrophy, and promoting apoptosis or fibrosis, contributing to the continuous myocardial remodeling process. While several stimuli may be operating such as heat-shock protein, microbial antigen, bacterial lipopolysaccharide, shear and oxidative stress, hypoxia and oxidized low-density lipoprotein (LDL), it seems that the inflammatory response to these stimuli may represent a common final pathogenic pathway in CHF regardless of the initial event. Traditional cardiovascular drugs seem to have little influence on the overall cytokine network, and immunomudulatory therapy has emerged as a possible new treatment modality in CHF. Several animal studies, and some clinical pilot studies, have suggested that down-regulation of inflammatory cytokines may improve cardiac performance. On the other hand, preliminary results from the placebo-controlled studies suggest no effect, or even adverse effect, of antitumor necrosis factor (TNF) therapy on mortality and hospitalization. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'. These studies just underscore the difficulties and the challenges in developing treatment modalities that can modulate the cytokine network in CHF patients resulting in anti-inflammatory and beneficial net effects. Further research in this area will have to more precisely identify the most important actors in the immunopathogenesis of CHF in order to develop more specific immunomodulating agents for this disorder. However, at present the beneficial role of anticytokine therapy in patients with CHF remains unproven.

Chemokines control the migration of leukocytes to inflamed tissue, and in particular monocyte chemoattractant protein (MCP)-1 has been implicated in the pathogenesis of several cardiovascular disorders such as chronic heart failure (CHF) and myocarditis. We hypothesised that MCP-1 may directly contribute to an inflammatory response in the cardiomyocytes, and in the present study we examined in adult rat cardiomyocytes: (i) the effect of tumour necrosis factor (TNF)alpha on MCP-1 production, (ii) the effect of MCP-1 on production of other inflammatory cytokines, and (iii) if the anti-inflammatory cytokine interleukin (IL)-10 could suppress any TNFalpha-induced MCP- 1 production.We used enzyme immunoassays, RNase protection assays and slot blot analysis to measure protein and mRNA levels of various cytokines in adult rat cardiomyocyte cultures.(i) We found a approximately 6.4-fold increase of the MCP-1 level accompanied by an increase in MCP-1 mRNA accumulation in cardiomyocyte cultures after TNFalpha stimulation. (ii) In contrast, TNFalpha had no effect on IL-10 and only a modest effect on IL-1beta and IL-6 levels in these cells. (iii) Importantly, MCP-1 stimulated inflammatory response in cardiomyocytes by enhancing IL- 1beta and IL-6 levels in these cells as found at both the protein and mRNA level. (iv) Co-stim-ulation with IL-10 resulted in a approximately 55% reduction in TNFalpha-stimulated MCP-1 levels in cardiomyocyte culture supernatants.The present study demonstrates for the first time that MCP- 1 can directly affect cardiomyocytes, and we introduce MCP-1 as a potential enhancer and IL- 10 as a potential suppresser of inflammatory responses within the myocardium.

Inflammatory cytokines may negatively influence contractility and contribute to the remodelling process in the failing myocardium. Traditional cardiovascular drugs appear to have little influence on the overall cytokine network in chronic heart failure (CHF). Increased interest in anticytokine therapy has therefore evolved. Several small studies have used tumour necrosis factor (TNF)-α as a target, resulting in improved functional capacity and myocardial performance. Intravenous immunoglobulin (IVIG) represents another therapeutic approach in which the impact on myocardial performance appears to be correlated with anti-inflammatory effects. These studies demonstrate potential for immunomodulation as a therapy in addition to conventional cardiovascular treatment in CHF, but the most effective drugs in this regard have yet to be identified.