Yellow fever virus infection in human hepatocyte cells triggers an imbalance in redox homeostasis with increased reactive oxygen species production, oxidative stress, and decreased antioxidant enzymes.

Yellow fever (YF) presents a wide spectrum of severity, with clinical manifestations in humans ranging from febrile and self-limited to fatal cases. Although YF is an old disease for which an effective and safe vaccine exists, little is known about the viral- and host-specific mechanisms that contribute to liver pathology. Several studies have demonstrated that oxidative stress triggered by viral infections contributes to pathogenesis. We evaluated whether yellow fever virus (YFV), when infecting human hepatocytes cells, could trigger an imbalance in redox homeostasis, culminating in oxidative stress. YFV infection resulted in a significant increase in reactive oxygen species (ROS) levels from 2 to 4 days post infection (dpi). When measuring oxidative parameters at 4 dpi, YFV infection caused oxidative damage to lipids, proteins, and DNA, evidenced by an increase in lipid peroxidation/8-isoprostane, carbonyl protein, and 8-hydroxy-2'-deoxyguanosine, respectively. Furthermore, there was a significant reduction in the activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), in addition to a reduction in the ratio of reduced to oxidized glutathione (GSH/GSSG), indicating a pro-oxidant environment. However, no changes were observed in the enzymatic activity of the enzyme catalase (CAT) or in the gene expression of SOD isoforms (1/2/3), CAT, or GPx. Therefore, our results show that YFV infection generates an imbalance in redox homeostasis, with the overproduction of ROS and depletion of antioxidant enzymes, which induces oxidative damage to cellular constituents. Moreover, as it has been demonstrated that oxidative stress is a conspicuous event in YFV infection, therapeutic strategies based on antioxidant biopharmaceuticals may be new targets for the treatment of YF.

Serotype-associated immune response and network immunoclusters in children and adults during acute Dengue virus infection.

The present study was designed as an exploratory investigation to characterize the overall profile of chemokines, growth factors, and pro-inflammatory/regulatory cytokines during acute DENV infection according to DENV-1, DENV-2, DENV-4 serotypes and age: children: <1-10-year-old (yo); adolescents:11-20 yo; adults 21-40 yo; and older adults: 41-75 yo. The levels of soluble immunemediators were measured in serum by high-throughput microbeads array in 636 subjects including 317 DENV-infected and 319 age-matching non-infected control (NI). Overall, most soluble mediators were increased in DENV-infected patients as compared to NI group regardless of age and DENV serotype, with high magnitude order of increase for CCL2, CXCL10, IL-1ß, IFN-γ, IL1-Ra (fold change >3x), except PDGF in which no fold change was observed. Moreover, despite the age ranges, DENV-1 and DENV-4 presented increased levels of VEGF, IL-6, and TNF-α in serum but decreased levels of PDGF, while DENV-2 exhibited increased levels of CXCL8, CCL4, and IL-12. Noteworthy was that DENV-2 showed increased levels of IL-12, IL-15, IL-17, IL-4, IL-9, and IL-13, and maintained an unaltered levels of PDGF at younger ages (<1-10 yo and 11-20 yo), whereas in older ages (21-40 yo and 41-75 yo), the results showed increased levels of CCL2, IL-6, and TNF-α, but lower levels of PDGF. In general, DENV infection at younger age groups exhibited more complex network immunoclusters as compared to older age groups. Multivariate analysis revealed a clustering of DENV cases according to age for a set of soluble mediators especially in subjects infected with DENV-2 serotype. Altogether, our findings demonstrate that the profile of circulating soluble mediators differs substantially in acute DENV according to age and DENV serotypes suggesting the participation of serotype-associated immune response, which may represent a potential target for development of therapeutics and could be used to assist medical directive for precise clinical management of severe cases.

Effects of Toxoplasma gondii infection on cognition, symptoms, and response to digital cognitive training in schizophrenia.

Studies indicate that neuroscience-informed digital cognitive training can remediate cognitive impairments in schizophrenia, but the factors contributing to these deficits and response to treatment remain unclear. Toxoplasma gondii is a neuroinvasive parasite linked to cognitive decline that also presents a higher prevalence in schizophrenia. Here, we compared the cognition and symptom severity of IgG seropositive (TOXO+; n = 25) and seronegative (TOXO-; n = 35) patients who participated in a randomized controlled trial of digital cognitive training. At baseline, TOXO+ subjects presented lower global cognition than TOXO- (F = 3.78, p = 0.05). Specifically, TOXO+ subjects showed worse verbal memory and learning (F = 4.48, p = 0.03), social cognition (F = 5.71, p = 0.02), and higher antibody concentrations were associated with increased negative (r = 0.42, p = 0.04) and total (r = 0.40, p = 0.04) schizophrenia symptoms. After training, the TOXO+ group showed higher adherence to the intervention (X2 = 9.31, p = 0.03), but there were no differences in changes in cognition and symptoms between groups. These findings highlight the association between seropositivity to T. gondii and deteriorated cognition and symptoms in schizophrenia. Further research is needed to assess the specific efficacy of digital cognitive training on this population.

Serum albumin nanoparticles vaccine provides protection against a lethal Pseudomonas aeruginosa challenge.

Pseudomonas aeruginosa is an opportunistic pathogen that causes severe infections in immunocompromised individuals and in patients with cystic fibrosis. A range of vaccines to prevent infections caused by P. aeruginosa has already been tested, yet no vaccine against this pathogen is currently available. The goal of this study was to evaluate the potential of bovine serum albumin nanoparticles (BSA-NPs) associated with total P. aeruginosa ATCC 27853 antigens in inducing protection against the infection with virulent P. aeruginosa PA14 strain in murine model of nasal infection. Swiss mice were immunized with BSA-NPs associated with total P. aeruginosa antigens (NPPa) or empty NPs (NPe). As positive and negative control, groups of animals were immunized with total antigens of P. aeruginosa ATCC 27853 and phosphate buffered saline, respectively. Immunized mice were infected via nasal route using P. aeruginosa PA14 strain. The survival after 48 h was evaluated and the lungs from animals were processed for quantification of bacterial load, cytokine expression and histopathological analysis. After infection with P. aeruginosa PA14, animals immunized with NPPa had the highest survival rate, the lowest bacterial lung load, a controlled production of cytokines and few histopathological changes. These results indicate that NPPa immunization protected mice from infection, contributing for the elimination of the bacteria from the lungs, which consequently reflected the survival of the animals. Therefore, this vaccine was able to induce a functional response in an animal model of lethal infection and thereby is a promising platform for P. aeruginosa vaccines.

Simvastatin does not reduce chemokine production in obesity without comorbidities.

Obesity is considered a subchronic inflammatory disease with high risk of comorbidity development. Obesity-associated inflammation originates from adipose tissue itself, which secretes a panel of inflammatory chemokines and cytokines. Therefore, we enrolled 23 obese women without comorbidity and evaluated if simvastatin 20 mg/day dose therapy for 6 weeks (n=15) may modulate plasma levels of inflammatory CXCL-10, CCL-2, CXCL-9, CXCL-8, and CCL-5. A significant decrease of cholesterol and its fractions, triglycerides, and high-sensitivity C-reactive protein (hsCRP) after simvastatin treatment was observed when compared to placebo (n=8). Chemokine plasma levels were unchanged by statin intake when compared to placebo. Although dyslipidemia biomarkers and hsCRP have been diminished by simvastatin, low chemokine amounts produced by healthy obese women do not seem to be altered by simvastatin anti-inflammatory activity.