Project description:Mayaro virus (MAYV), an alphavirus similar to chikungunya virus (CHIKV), causes an acute debilitating disease which results in the development of long-term arthralgia in more than 50% of infected individuals. Currently, the immune response and its role in the development of MAYV-induced persistent arthralgia remain unknown. In this study, we evaluated the immune response of individuals with confirmed MAYV infection in a one-year longitudinal study carried out in Loreto, Peru. We report that MAYV infection elicits robust immune responses that result in the development of a strong neutralizing antibody response and the secretion of pro-inflammatory immune mediators. The composition of these inflammatory mediators, in some cases, differed to those previously observed for CHIKV. Key mediators such as IL-13, IL-7 and VEGF were strongly induced following MAYV infection and were significantly increased in subjects that eventually developed persistent arthralgia. Although a strong neutralizing antibody response was observed in all subjects, it was not sufficient to prevent the long-term outcomes of MAYV infection. This study provides initial immunologic insight that may eventually contribute to prognostic tools and therapeutic treatments against this emerging pathogen.
Project description:EBV and Helicobacter pylori (H. pylori) cause highly prevalent persistent infections as early as in childhood. Both pathogens are associated with gastric carcinogenesis. H. pylori interferes with iron metabolism, enhancing the synthesis of acute-phase proteins hepcidin, C-reactive protein (CRP), and α-1 glycoprotein (AGP), but we do not know whether EBV does the same. In this study, we correlated the EBV antibody levels and the serum levels of hepcidin, CRP, and AGP in 145 children from boarding schools in Mexico City. We found that children IgG positive to EBV antigens (VCA, EBNA1, and EA) presented hepcidin, AGP, and CRP levels higher than uninfected children. Hepcidin and AGP remained high in children solely infected with EBV, while CRP was only significantly high in coinfected children. We observed positive correlations between hepcidin and EBV IgG antibodies (p < 0.5). Using the TCGA gastric cancer database, we also observed an association between EBV and hepcidin upregulation. The TCGA database also allowed us to analyze the two important pathways controlling hepcidin expression, BMP-SMAD and IL-1β/IL-6. We observed only the IL-1β/IL-6-dependent inflammatory pathway being significantly associated with EBV infection. We showed here for the first time an association between EBV and enhanced levels of hepcidin. Further studies should consider EBV when evaluating iron metabolism and anemia, and whether in the long run this is an important mechanism of undernourishment and EBV gastric carcinogenesis.
Project description:During 2010-2013, we recruited 16 persons with confirmed Mayaro virus infection in the Peruvian Amazon to prospectively follow clinical symptoms and serologic response over a 12-month period. Mayaro virus infection caused long-term arthralgia in more than half, similar to reports of other arthritogenic alphaviruses.
Project description:BackgroundHIV-positive patients on anti-retroviral therapy (ART) are at higher risk of developing many non-AIDS related chronic diseases, including chronic obstructive pulmonary disease (COPD), compared to HIV-negative individuals. While the mechanisms are not clear, a persistent pro-inflammatory state appears to be a key contributing factor. The aims of this study were to investigate whether HIV-positive patients without COPD present evidence of potentially predisposing abnormal pulmonary cytokine/chemokine environment and to explore the relationship between pulmonary and systemic cytokine levels.MethodsThis study included 39 HIV-seropositive and 34 HIV-seronegative subjects without COPD. All were subjected to outpatient bronchoscopy with bronchoalveolar lavage fluid (BALF) aspiration and blood sample collection. The levels of 21 cytokines and chemokines were measured in plasma and BALF using a bead-based multi-analyte assay.ResultsIn plasma, HIV-infected patients showed significantly increased circulating levels of pro-inflammatory (TNFα) and Th1-associated cytokines (IL-12p70) as well as several chemokines (CXCL11 and CX3CL1). However, no statistically significant differences were found in the numbers of cells, the concentrations of protein and urea as well as cytokine levels in the BALFs of HIV-positive patients when compared to controls. Correlation analysis indicated a potential modulatory effect of the BMI in HIV-seropositive individuals.ConclusionsWhile our results are consistent with the existence of a systemic pro-inflammatory state in HIV-infected patients, they did not detect significant differences in cytokine levels and other inflammatory markers in the lungs of HIV-positive individuals when compared to HIV-negative controls.
Project description:Influenza A virus (IAV) infection is a major worldwide public health problem. However, the factors involved in mediating the inflammatory response to this infection and their relationships remain poorly understood. Here, we show that IAV infection stimulates the expression of the soluble IL-6 receptor (sIL-6R), a multifunctional protein involved in IL-6 signaling. Interestingly, sIL-6R expression upregulated the levels of its own ligand, IL-6 and those of the pro-inflammatory cytokine IL-32. shRNA-mediated knockdown of sIL-6R suppressed IL-6 and IL-32, indicating that this regulation is dependent on sIL-6R during IAV infection. Furthermore, our results demonstrate that IL-32 participates in a negative feedback loop that inhibits sIL-6R while upregulating IL-6 expression during IAV infection. Therefore, we show that sIL-6R is a critical cellular factor involved in the acute inflammatory response to viral infection.
Project description:Ross River virus, a mosquitoborne alphavirus, causes epidemic polyarthritis in Australia and the Pacific region. We analyzed serum cytokine, chemokine, and growth factor levels in travelers returning to Germany from Australia. Serum samples showed elevated concentrations in the acute phase of the illness and, more pronounced, in the long-lasting convalescent phase.
Project description:Dengue virus (DENV) is transmitted by the mosquito vector, and causes a wide range of symptoms that lead to dengue fever (DF) or life-threatening dengue hemorrhagic fever (DHF). The host and viral correlates that contribute to DF and DHF are complex and poorly understood, but appear to be linked to inflammation and impaired coagulation. Full-length osteopontin (FL-OPN), a glycoprotein, and its activated thrombin-cleaved product, trOPN, integrate multiple immunological signals through the induction of pro-inflammatory cytokines.To understand the role of OPN in DENV-infection, we assessed circulating levels of FL-OPN, trOPN, and several coagulation markers (D-dimer, thrombin-antithrombin complex [TAT], thrombomodulin [TM], and ferritin in blood obtained from 65 DENV infected patients in the critical and recovery phases of DF and DHF during a dengue virus epidemic in the Philippines in 2010.Levels of FL-OPN, trOPN, D-dimer, TAT, and TM were significantly elevated in the critical phase in both the DF and DHF groups, as compared with healthy controls. During the recovery phase, FL-OPN levels declined while trOPN levels increased dramatically in both the DF and DHF groups. FL-OPN levels were directly correlated with D-dimer and ferritin levels, while the generation of trOPN was associated with TAT levels, platelet counts, and viral RNA load.Our study demonstrated the marked elevation of plasma levels of FL-OPN and thrombin-cleaved OPN product, trOPN, in DENV-infection for the first time. Further studies on the biological functions of these matricellular proteins in DENV-infection would clarify its pathogenesis.
Project description:Both T-cell activation during early HIV-1 infection and soluble markers of immune activation during chronic infection are predictive of HIV disease progression. Although the acute phase of HIV infection is associated with increased pro-inflammatory cytokine production, the relationship between cytokine concentrations and HIV pathogenesis is unknown.To identify cytokine biomarkers measurable in plasma during acute HIV-1 infection that predict HIV disease progression.Study including 40 South African women who became infected with HIV-1 and were followed longitudinally from the time of infection.The concentrations of 30 cytokines in plasma from women with acute HIV-1 infection were measured and associations between cytokine levels and both viral load set point 12 months postinfection and time taken for CD4 cell counts to fall below 350 cells/microl were determined using multivariate and Cox proportional hazards regression.We found that the concentrations of five plasma cytokines, IL-12p40, IL-12p70, IFN-gamma, IL-7 and IL-15 in women with acute infection predicted 66% of the variation in viral load set point 12 months postinfection. IL-12p40, IL-12p70 and IFN-gamma were significantly associated with lower viral load, whereas IL-7 and IL-15 were associated with higher viral load. Plasma concentrations of IL-12p40 and granulocyte-macrophage colony-stimulating factor during acute infection were associated with maintenance of CD4 cell counts above 350 cells/microl, whereas IL-1alpha, eotaxin and IL-7 were associated with more rapid CD4 loss.A small panel of plasma cytokines during acute HIV-1 infection was predictive of long-term HIV disease prognosis in this group of South African women.
Project description:Increases in aminotransferases levels are frequently encountered in HIV-positive patients and often remain unexplained. The role in this setting and natural history of hepatitis E in HIV-infected patients are unknown. The aim of the study was to assess HEV infection in HIV-infected patients attending a Parisian hospital, with a current or previous cryptogenic hepatitis.191 plasma samples collected from 108 HIV-infected patients with elevated aminotransferases levels were retrospectively tested for the presence of hepatitis E virus (HEV) infection markers: anti-HEV IgM antibodies, anti-HEV IgG antibodies, anti-HEV IgG avidity index and plasma HEV RNA.One acute infection, documented by positive tests for anti-HEV IgM antibody, low anti-HEV IgG avidity index and plasma HEV RNA (genotype 3e), and three past infections were diagnosed, without any observed case of persistent infection. The acute hepatitis was benign and resolved spontaneously within two weeks. This infection was probably contracted locally. Acute HEV hepatitis can occur in HIV-infected patients but rarely explains cryptogenic hepatitis, at least in an urban HIV population, regardless geographic origin and CD4 counts.
Project description:Interferon-induced transmembrane (IFITM) proteins restrict membrane fusion and virion internalization of several enveloped viruses. The role of IFITM proteins during alphaviral infection of human cells and viral counteraction strategies are insufficiently understood. Here, we characterized the impact of human IFITMs on the entry and spread of chikungunya virus and Mayaro virus and provide first evidence for a CHIKV-mediated antagonism of IFITMs. IFITM1, 2, and 3 restricted infection at the level of alphavirus glycoprotein-mediated entry, both in the context of direct infection and cell-to-cell transmission. Relocalization of normally endosomal IFITM3 to the plasma membrane resulted in loss of antiviral activity. rs12252-C, a naturally occurring variant of IFITM3 that may associate with severe influenza in humans, restricted CHIKV, MAYV, and influenza A virus infection as efficiently as wild-type IFITM3 Antivirally active IFITM variants displayed reduced cell surface levels in CHIKV-infected cells involving a posttranscriptional process mediated by one or several nonstructural protein(s) of CHIKV. Finally, IFITM3-imposed reduction of specific infectivity of nascent particles provides a rationale for the necessity of a virus-encoded counteraction strategy against this restriction factor.