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In recent decades, chikungunya virus (CHIKV) has re-emerged, leading to outbreaks of chikungunya fever in Africa, Asia and Central and South America. The disease is characterized by a rapid onset febrile illness with (poly)arthralgia, myalgia, rashes, headaches and nausea. In 30 to 40% of the cases, CHIKV infection causes persistent (poly)arthralgia, lasting for months or even years after initial infection. Despite the drastic re-emergence and clinical impact there is no vaccine nor antiviral compound available to prevent or control CHIKV infection. Here, we evaluated the antiviral potential of tomatidine towards CHIKV infection. We demonstrate that tomatidine potently inhibits virus particle production of multiple CHIKV strains. Time-of -addition experiments in Huh7 cells revealed that tomatidine acts at a post-entry step of the virus replication cycle. Furthermore, a marked decrease in the number of CHIKV-infected cells was seen, suggesting that tomatidine predominantly acts early in infection yet after virus attachment and cell entry. Antiviral activity was still detected at 24 hours post-infection, indicating that tomatidine controls multiple rounds of CHIKV replication. Solasodine and sarsasapogenin, two structural derivatives of tomatidine, also showed strong albeit less potent antiviral activity towards CHIKV. In conclusion, this study identifies tomatidine as a novel compound to combat CHIKV infection in vitro.

The dogma is that the human immune system protects us against pathogens. Yet, several viruses, like dengue virus, antagonize the hosts’ antibodies to enhance their viral load and disease severity; a phenomenon called antibody-dependent enhancement of infection. This study offers novel insights in the molecular mechanism of antibody-mediated enhancement (ADE) of dengue virus infection in primary human macrophages. No differences were observed in the number of bound and internalized DENV particles following infection in the absence and presence of enhancing concentrations of antibodies. Yet, we did find an increase in membrane fusion activity during ADE of DENV infection. The higher fusion activity is coupled to a low antiviral response early in infection and subsequently a higher infection efficiency. Apparently, subtle enhancements early in the viral life cycle cascades into strong effects on infection, virus production and immune response. Importantly and in contrast to other studies, the antibody-opsonized virus particles do not trigger immune suppression and remain sensitive to interferon. Additionally, this study gives insight in how human macrophages interact and respond to viral infections and the tight regulation thereof under various conditions of infection.

Dengue virus infects immune cells, including monocytes, macrophages and dendritic cells (DC). We compared virus infectivity in macrophages and DC, and found that the virus origin determined the cell tropism of progeny virus. The highest efficiency of re-infection was seen for macrophage-derived dengue virus. Furthermore, in the presence of enhancing antibodies, macrophage-derived virus gave greater enhancement of infection compared with immature DC derived virus. Taken together, our results highlight the importance of macrophages in dengue infection.

Background Dengue virus (DENV) is the most common vector-borne viral infection worldwide with approximately 390 million cases and 25,000 reported deaths each year. MicroRNAs (miRNAs) are small non-coding RNA molecules responsible for the regulation of gene expression by repressing mRNA translation or inducing mRNA degradation. Although miRNAs possess antiviral activity against many mammalian-infecting viruses, their involvement in DENV replication is poorly understood. Methods Here, we explored the relationship between DENV and cellular microRNAs using bioinformatics tools. We overexpressed miRNA-133a in Vero cells to test its role in DENV replication and analyzed its expression using RT-qPCR. Furthermore, the expression of polypyrimidine tract binding protein (PTB), a protein involved in DENV replication, was analyzed by western blot. In addition, we profiled miRNA-133a expression in Vero cells challenged with DENV-2, using Taqman miRNA. Results Bioinformatic analysis revealed that the 3' untranslated region (3'UTR) of the DENV genome of all four DENV serotypes is targeted by several cellular miRNAs, including miRNA-133a. We found that overexpression of synthetic miRNA-133a suppressed DENV replication. Additionally, we observed that PTB transcription , a miRNA-133a target, is down-regulated during DENV infection. Based in our results we propose that 3'UTR of DENV down-regulates endogenous expression of miRNA-133a in Vero cells during the first hours of infection. Conclusions miRNA-133a regulates DENV replication possibly through the modulation of a host factor such as PTB. Further investigations are needed to verify whether miRNA-133a has an anti-DENV effect in vivo. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1364-y) contains supplementary material, which is available to authorized users.

The reappearance of West Nile virus (WNV) infection in last years has highlighted that arthropod-borne diseases are not circumscribed to tropical regions of the world. WNV is maintained in enzootic cycles involving, Culex spp. mosquitoes and avian hosts, with epizootic spread to mammals, including humans. Human infection results in mild symptomatic illness in 25% of cases or neurological disease in less than 1% of infected persons. Additional understandings on how WNV interacts with its hosts is recently growing; the virus exploits immune system, both at the peripheral tissues and the central nervous system, which could explain the differences in virulence, progression and severity of WNV infection. The continuing spread of WNV, combined with the lack of specific therapeutics or vaccines to combat or prevent infection, imparts a pressing need to identify the viral and host processes that control the outcome and immunity to WNV infection. Here, we provide an overview of a subset of information regarding the immune-pathological response generated during WNV infection.

Scope High incidence of inflammatory diseases afflicts the increasing aging-population infringing a great health burden. Dietary flavonoids, including the flavone apigenin, are emerging as important anti-inflammatory nutraceuticals due to their health benefits, lack of adverse effects and reduced costs. MicroRNAs (miRs) play a central role in inflammation by regulating gene expression, yet how dietary ingredients affect miRs is poorly understood. The aim of this study was to identify miRs involved in the anti-inflammatory activity of apigenin and apigenin-rich diets and determine their immune regulatory mechanisms in macrophages and in vivo. Methods and results A high-throughput quantitative reverse transcriptase PCR screen of 312 miRs in macrophages revealed that apigenin reduced LPS-induced miR-155 expression. Analyses of miR-155 precursor and primary transcript indicated that apigenin regulated miR-155 transcriptionally. Apigenin-reduced expression of miR-155 led to the increase of anti-inflammatory regulators forkhead box O3a and smooth-muscle-actin and MAD-related protein 2 in LPS-treated macrophages. In vivo, apigenin or a celery-based apigenin-rich diet reduced LPS-induced expression of miR-155 and decreased tumor necrosis factor α in lungs from LPS-treated mice. Conclusion These results demonstrate that apigenin and apigenin-rich diets exert effective anti-inflammatory activity in vivo by reducing LPS-induced expression of miR-155, thereby restoring immune balance.

Flaviviruses are the most prevalent arthropod-borne viruses worldwide, and nearly half of the 70 Flavivirus members identified are human pathogens. Despite the huge clinical impact of flaviviruses, there is no specific human antiviral therapy available to treat infection with any of the flaviviruses. Therefore, there is a continued search for novel therapies, and this review describes the current knowledge on the usage of RNA interference (RNAi) in combating flavivirus infections. RNAi is a process of sequence-specific gene silencing triggered by double-stranded RNA. Antiviral RNAi strategies against arthropod-borne flaviviruses have been reported and although several hurdles must be overcome to employ this technology in clinical applications, they potentially represent a new therapeutic tool.

El sindrome de respuesta sistemica consecuencia de una infeccion, denominado sepsis, constituye una causa significativa de muerte en el mundo. Historicamente se ha aceptado que la muerte por sepsis se debe a un estado de hiperactivacion inmunologica, que implica el desarrollo de una vasta respuesta pro-inflamatoria acompanada de alteraciones en el sistema de coagulacion. Ahora es claro que ademas de los sucesos inflamatorios, el curso clinico de la sepsis se caracteriza por el desarrollo de una respuesta anti-inflamatoria que busca contrarrestar la respuesta inicial, y es esta finalmente en gran parte responsable de la muerte de los pacientes. El proposito de esta revision es resumir los mecanismos actuales que explican la patogenesis de la sepsis, y especificamente el papel que desempenan las subpoblaciones celulares con propiedades inmuno-reguladoras durante el curso de la enfermedad. El mejor entendimiento de estos procesos contribuira a la busqueda de estrategias terapeuticas mas exitosas.

Scope: Flavones have reported anti-inflammatory activities, but the ability of flavone-rich foods to reduce inflammation is unclear. Here, we report the effect of flavone glycosylation in the regulation of inflammatory mediators in vitro and the absorption of dietary flavones in vivo. Methods and results: The anti-inflammatory activities of celery extracts, some rich in flavone aglycones and others rich in flavone glycosides, were tested on the inflammatory mediators tumor necrosis factor (TNF-) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) in lipopolysaccharide-stimulated macrophages. Pure flavone aglycones and aglycone-rich extracts effectively reduced TNF- production and inhibited the transcriptional activity of NF-B, while glycoside-rich extracts showed no significant effects. Deglycosylation of flavones increased cellular uptake and cytoplasmic localization as shown by high-performance liquid chromatography (HPLC) and microscopy using the flavonoid fluorescent dye diphenylboric acid 2-aminoethyl ester (DPBA). Celery diets with different glycoside or aglycone contents were formulated and absorption was evaluated in mice fed with 5 or 10% celery diets. Relative absorption in vivo was significantly higher in mice fed with aglycone-rich diets as determined by HPLC-MS/MS (where MS/MS is tandem mass spectrometry). Conclusion: These results demonstrate that deglycosylation increases absorption of dietary flavones in vivo and modulates inflammation by reducing TNF- and NF-B, suggesting the potential use of functional foods rich in flavones for the treatment and prevention of inflammatory diseases.

Introduction: The mechanisms involved in the immunopathogenesis of sepsis are not well established. The clinical and therapeutic relevance of several soluble mediators has been described and the contribution of cellular components with immunoregulatory roles has begun to be elucidated. Objective: To describe changes in the frequency and production of IFN- γ and IL-10 occurring in NK cells and γδ T lymphocytes in a cohort of patients with different manifestations of septic syndrome. Materials and methods: This was a prospective cohort study. Patients with sepsis (n=26), and severe sepsis (n=83) from adult emergency rooms and intensive care units, as well as healthy volunteers (n=8), were included. For all participants, the frequency and phenotype of NK cells and γδ T lymphocytes and the percentage of IFN- γ and IL-10 positive NK and γδ T cells were evaluated by flow cytometry. The NK cells were phenotyped based on the expression of CD56 and CD16 and the γδ T cells on the expression of d 1 and d 2 chains. Results: Patients with sepsis and severe sepsis exhibited an increase in the frequency of NK cells with changes in the proportion of the CD56 bright /CD16¯, CD56 bright /CD16 dim and CD56 dim CD16¯ subpopulations; these cells showed a proinflammatory cytokine profile. A decrease in the V d 2 subset of γδ T lymphocyte s was also observed. Conclusions: Our results indicate a role for NK and γδ T cells during sepsis, however, their exact contribution in the pathogenesis of sepsis syndrome requires further studies.