Search

Reversal reactions (RRs) in leprosy are characterized by a reduction in the number of bacilli in lesions associated with an increase in cell-mediated immunity against the intracellular bacterium Mycobacterium leprae, the causative pathogen of leprosy. To identify the mechanisms that contribute to cell-mediated immunity in leprosy, we measured changes in the whole blood-derived transcriptome of patients with leprosy before, during and after RR. We identified an 'RR signature' of 1017 genes that were upregulated at the time of the clinical diagnosis of RR. Using weighted gene correlated network analysis (WGCNA), we detected a module of 794 genes, bisque4, that was significantly correlated with RR, of which 434 genes were part of the RR signature. An enrichment for both IFN-γ and IFN-β downstream gene pathways was present in the RR signature as well as the RR upregulated genes in the bisque4 module, including those encoding proteins of the guanylate binding protein (GBP) family that contributes to antimicrobial responses against mycobacteria. Specifically, GBP1, GBP2, GBP3 and GBP5 mRNAs were upregulated in the RR peripheral blood transcriptome, with GBP1, GBP2 and GBP5 mRNAs also upregulated in the RR disease lesion transcriptome. These data indicate that RRs involve a systemic upregulation of IFN-γ downstream genes including GBP family members as part of the host antimicrobial response against mycobacteria. [ABSTRACT FROM AUTHOR]

Cells damaged by mechanical or infectious injury release proinflammatory mitochondrial DNA (mtDNA) fragments into the circulation. We evaluated the relation between plasma levels of mtDNA fragments in obese type 2 diabetes mellitus (T2DM) patients and measures of chronic inflammation and insulin resistance. In 10 obese T2DM patients and 12 healthy control (HC) subjects, we measured levels of plasma cell-free mtDNA with quantitative real-time polymerase chain reaction, and mtDNA damage in skeletal muscle with quantitative alkaline Southern blot. Also, markers of systemic inflammation and oxidative stress in skeletal muscle were measured. Plasma levels of mtDNA fragments, mtDNA damage in skeletal muscle and plasma tumor necrosis factor α levels were greater in obese T2DM patients than HC subjects. Also, the abundance of plasma mtDNA fragments in obese T2DM patients levels positively correlated with insulin resistance. To the best of our knowledge, this is the first published evidence that elevated level of plasma mtDNA fragments is associated with mtDNA damage and oxidative stress in skeletal muscle and correlates with insulin resistance in obese T2DM patients. Plasma mtDNA may be a useful biomarker for predicting and monitoring insulin resistance in obese patients. [ABSTRACT FROM AUTHOR]

Network coupled cells, such as astrocytes, regulate their cellular homeostasis via Ca2+ signals spread between the cells through gap junctions. Intracellular Ca2+ release is controlled by different signaling pathways that can be stimulated by ATP, glutamate and serotonin (5-HT). Based on our findings, all these pathways are influenced by inflammatory agents and must be restored to fully recover the Ca2+ signaling network. An ultralow concentration of the local anesthetic agent bupivacaine reduced 5-HT-evoked intracellular Ca2+ release, and an ultralow concentration of the phosphodiesterase-5 inhibitor sildenafil in combination with vitamin D3 reduced ATP-evoked intracellular Ca2+ release. Combinations of these three substances downregulated 5-HT-, glutamate- and ATP-evoked intracellular Ca2+ release to a more normal Ca2+ signaling state. Furthermore, inflammatory Toll-like receptor 4 expression decreased with a combination of these three substances. Substance P receptor neurokinin (NK)-1 expression was reduced by ultralow concentrations of bupivacaine. Here, bupivacaine and sildenafil (at extremely low concentrations) combined with vitamin D3 have potential anti-inflammatory properties. According to the present study, drug combinations at the right concentrations, especially extremely low concentrations of bupivacaine and sildenafil, affect different cellular biochemical mechanisms and represent a potential solution for downregulating inflammatory parameters, thereby restoring cells or networks to normal physiological homeostasis. [ABSTRACT FROM AUTHOR]

Middle East respiratory syndrome-coronavirus (MERS-CoV) is an emerging virus that causes severe disease with fatal outcomes; however, there are currently no approved vaccines or specific treatments against MERS-CoV. Here, we developed a novel bivalent vaccine against MERS-CoV and rabies virus (RV) using the replication-incompetent P-gene-deficient RV (RVΔP), which has been previously established as a promising and safe viral vector. MERS-CoV spike glycoprotein comprises S1 and S2 subunits, with the S1 subunit being a primary target of neutralizing antibodies. Recombinant RVΔP, which expresses S1 fused with transmembrane and cytoplasmic domains together with 14 amino acids from the ectodomains of the RV-glycoprotein (RV-G), was developed using a reverse genetics method and named RVΔP-MERS/S1. Following generation of RVΔP-MERS/S1 and RVΔP, our analysis revealed that they shared similar growth properties, with the expression of S1 in RVΔP-MERS/S1-infected cells confirmed by immunofluorescence and western blot, and the immunogenicity and pathogenicity evaluated using mouse infection experiments. We observed no rabies-associated signs or symptoms in mice inoculated with RVΔP-MERS/S1. Moreover, virus-specific neutralizing antibodies against both MERS-CoV and RV were induced in mice inoculated intraperitoneally with RVΔP-MERS/S1. These findings indicate that RVΔP-MERS/S1 is a promising and safe bivalent-vaccine candidate against both MERS-CoV and RV. [ABSTRACT FROM AUTHOR]

Type I interferons (IFNs) play a critical role in host defense against influenza virus infection, and the mechanism of influenza virus to evade type I IFNs responses remains to be fully understood. Here, we found that progranulin (PGRN) was significantly increased both in vitro and in vivo during influenza virus infection. Using a PGRN knockdown assay and PGRN-deficient mice model, we demonstrated that influenza virus-inducing PGRN negatively regulated type I IFNs production by inhibiting the activation of NF-κB and IRF3 signaling. Furthermore, we showed that PGRN directly interacted with NF-κB essential modulator (NEMO) via its Grn CDE domains. We also verified that PGRN recruited A20 to deubiquitinate K63-linked polyubiquitin chains on NEMO at K264. In addition, we found that macrophage played a major source of PGRN during influenza virus infection, and PGRN neutralizing antibodies could protect against influenza virus-induced lethality in mice. Our data identify a PGRN-mediated IFN evasion pathway exploited by influenza virus with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of PGRN in innate immunity. [ABSTRACT FROM AUTHOR]

Introduction: In addition to their role in facilitating leukocyte-mediated inflammation, platelets can dampen leukocyte pro-inflammatory responses in some contexts. Consequently, platelets are increasingly appreciated as regulators of inflammation. Together, platelets and neutrophils play a role in inflammation through Toll-like receptor (TLR) expression, although we do not fully understand how platelets shape neutrophil responses to TLR stimulation. Here, we aimed to determine the extent to which platelets can modulate neutrophil function in response to in vitro stimulation with TLR4, TLR2/1, and TLR2/6 agonists. Methods: Neutrophils from 10 healthy individuals were cultured alone or with autologous platelets. Neutrophils ± platelets were left unstimulated or were stimulated with 1 or 100 ng/mL lipopolysaccharide (LPS; a TLR4 agonist), Pam3CSK4 (a TLR2/1 agonist) and fibroblast-stimulating lipopeptide (FSL)-1 (a TLR2/6 agonist). Neutrophil activation and phagocytic activity were assessed by flow cytometry, and elastase and interleukin-8 secretion were assessed by ELISA. Results: The addition of platelets attenuated neutrophil CD66b and CD11b expression in response to various doses of Pam3CSK4 and FSL-1. Furthermore, platelet co-culture was associated with higher CD62L expression (indicating reduced CD62L shedding) in response to these TLR agonists. Platelets also reduced elastase secretion in unstimulated cultures and in response to low-dose TLR stimulation. Conversely, platelet co-culture increased neutrophil phagocytosis in unstimulated cultures and in response to low-dose Pam3CSK4 and FSL-1. Platelets also increased IL-8 secretion in response to low-dose LPS. Conclusion: Platelets are complex immunomodulators that can attenuate some, and simultaneously augment other, neutrophil functions. This modulation can occur both in the absence and presence of TLR stimulation. [ABSTRACT FROM AUTHOR]

Oral herpes is a highly prevalent infection caused by herpes simplex virus 1 (HSV-1). After an initial infection of the oral cavity, HSV-1 remains latent in sensory neurons of the trigeminal ganglia. Episodic reactivation of the virus leads to the formation of mucocutaneous lesions (cold sores), but asymptomatic reactivation accompanied by viral shedding is more frequent and allows virus spread to new hosts. HSV-1 DNA has been detected in many oral tissues. In particular, HSV-1 can be found in periodontal lesions and several studies associated its presence with more severe periodontitis pathologies. Since gingival fibroblasts may become exposed to salivary components in periodontitis lesions, we analyzed the effect of saliva on HSV-1 and -2 infection of these cells. We observed that human gingival fibroblasts can be infected by HSV-1. However, pre-treatment of these cells with saliva extracts from some but not all individuals led to an increased susceptibility to infection. Furthermore, the active saliva could expand HSV-1 tropism to cells that are normally resistant to infection due to the absence of HSV entry receptors. The active factor in saliva was partially purified and comprised high molecular weight complexes of glycoproteins that included secretory Immunoglobulin A. Interestingly, we observed a broad variation in the activity of saliva between donors suggesting that this activity is selectively present in the population. The active saliva factor, has not been isolated, but may lead to the identification of a relevant biomarker for susceptibility to oral herpes. The presence of a salivary factor that enhances HSV-1 infection may influence the risk of oral herpes and/or the severity of associated oral pathologies. [ABSTRACT FROM AUTHOR]

Objective: Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model. Method: Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues. Results: In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice. Conclusions: Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation. [ABSTRACT FROM AUTHOR]

Aims: Alcohol use is associated with both positive and negative effects on individual cardiovascular risk factors, depending upon which risk factor is assessed. The present analysis uses a summative multisystem index of biologic risk, known as allostatic load (AL), to evaluate whether the overall balance of alcohol-associated positive and negative cardiovascular risk factors may be favorable or unfavorable. Methods: This analysis included 1255 adults from the Midlife in the United States (MIDUS) biomarker substudy. Participants, average age 54.5 (±11) years, were divided into 6 alcohol-use categories based on self-reported drinking habits. Current non-drinkers were classified as lifelong abstainers and former light drinkers, former moderate drinkers, or former heavy drinkers. Current alcohol users were classified as light, moderate, or heavy drinkers. A total AL score was calculated using 24 biomarkers grouped into 7 physiologic systems including cardiovascular, inflammation, glucose metabolism, lipid metabolism, sympathetic and parasympathetic nervous systems, and the hypothalamic-pituitary-adrenal axis. Mixed-effects regression models were fit to determine the relationship between alcohol use categories and AL with controls for covariates that may influence the relationship between alcohol use and AL. Results: 468 (37.6%) individuals were current non-drinkers while 776 (62.4%) were current drinkers. In adjusted mixed-effects regression models, all 3 groups of current drinkers had significantly lower average AL scores than the lifelong abstainer/former light drinker group (light: -0.23, 95% CI -0.40, -0.07, p < 0.01; moderate: -0.20, 95% CI -0.38, -0.02, p < 0.05; heavy: -0.30, 95% CI -0.57, -0.04, p < 0.05), while the average AL scores of former moderate and former heavy drinkers did not differ from the lifelong abstainer/former light drinker group. Conclusions: Current alcohol use is associated cross-sectionally with a favorable multisystem physiologic score known to be associated with better long-term health outcomes, providing evidence in support of long-term health benefits related to alcohol consumption. [ABSTRACT FROM AUTHOR]

Swine influenza virus (SIVs) infections cause a significant economic impact to the pork industry. Moreover, pigs may act as mixing vessel favoring genome reassortment of diverse influenza viruses. Such an example is the pandemic H1N1 (pH1N1) virus that appeared in 2009, harboring a combination of gene segments from avian, pig and human lineages, which rapidly reached pandemic proportions. In order to confront and prevent these possible emergences as well as antigenic drift phenomena, vaccination remains of vital importance. The present work aimed to evaluate a new DNA influenza vaccine based on distinct conserved HA-peptides fused with flagellin and applied together with Diluvac Forte as adjuvant using a needle-free device (IntraDermal Application of Liquids, IDAL®). Two experimental pig studies were performed to test DNA-vaccine efficacy against SIVs in pigs. In the first experiment, SIV-seronegative pigs were vaccinated with VC4-flagellin DNA and intranasally challenged with a pH1N1. In the second study, VC4-flagellin DNA vaccine was employed in SIV-seropositive animals and challenged intranasally with an H3N2 SIV-isolate. Both experiments demonstrated a reduction in the viral shedding after challenge, suggesting vaccine efficacy against both the H1 and H3 influenza virus subtypes. In addition, the results proved that maternally derived antibodies (MDA) did not constitute an obstacle to the vaccine approach used. Moreover, elevated titers in antibodies both against H1 and H3 proteins in serum and in bronchoalveolar lavage fluids (BALFs) was detected in the vaccinated animals along with a markedly increased mucosal IgA response. Additionally, vaccinated animals developed stronger neutralizing antibodies in BALFs and higher inhibiting hemagglutination titers in sera against both the pH1N1 and H3N2 influenza viruses compared to unvaccinated, challenged-pigs. It is proposed that the described DNA-vaccine formulation could potentially be used as a multivalent vaccine against SIV infections. [ABSTRACT FROM AUTHOR]

Acute appendicitis is one of the major causes for emergency surgery in childhood and adolescence. Appendectomy is still the therapy of choice, but conservative strategies are increasingly being studied for uncomplicated inflammation. Diagnosis of acute appendicitis remains challenging, especially due to the frequently unspecific clinical picture. Inflammatory blood markers and imaging methods like ultrasound are limited as they have to be interpreted by experts and still do not offer sufficient diagnostic certainty. This study presents a method for automatic diagnosis of appendicitis as well as the differentiation between complicated and uncomplicated inflammation using values/parameters which are routinely and unbiasedly obtained for each patient with suspected appendicitis. We analyzed full blood counts, c-reactive protein (CRP) and appendiceal diameters in ultrasound investigations corresponding to children and adolescents aged 0–17 years from a hospital based population in Berlin, Germany. A total of 590 patients (473 patients with appendicitis in histopathology and 117 with negative histopathological findings) were analyzed retrospectively with modern algorithms from machine learning (ML) and artificial intelligence (AI). The discovery of informative parameters (biomarker signatures) and training of the classification model were done with a maximum of 35% of the patients. The remaining minimum 65% of patients were used for validation. At clinical relevant cut-off points the accuracy of the biomarker signature for diagnosis of appendicitis was 90% (93% sensitivity, 67% specificity), while the accuracy to correctly identify complicated inflammation was 51% (95% sensitivity, 33% specificity) on validation data. Such a test would be capable to prevent two out of three patients without appendicitis from useless surgery as well as one out of three patients with uncomplicated appendicitis. The presented method has the potential to change today’s therapeutic approach for appendicitis and demonstrates the capability of algorithms from AI and ML to significantly improve diagnostics even based on routine diagnostic parameters. [ABSTRACT FROM AUTHOR]

The evidence that exposure to ozone air pollution causes acute cardiovascular effects is mixed. We postulated that exposure to ambient levels of ozone would increase blood markers of systemic inflammation, prothrombotic state, oxidative stress, and vascular dysfunction in healthy older subjects, and that absence of the glutathione S-transferase Mu 1 (GSTM1) gene would confer increased susceptibility. This double-blind, randomized, crossover study of 87 healthy volunteers 55–70 years of age was conducted at three sites using a common protocol. Subjects were exposed for 3 h in random order to 0 parts per billion (ppb) (filtered air), 70 ppb, and 120 ppb ozone, alternating 15 min of moderate exercise and rest. Blood was obtained the day before, approximately 4 h after, and approximately 22 h after each exposure. Linear mixed effect and logistic regression models evaluated the impact of exposure to ozone on pre-specified primary and secondary outcomes. The definition of statistical significance was p<0.01. There were no effects of ozone on the three primary markers of systemic inflammation and a prothrombotic state: C-reactive protein, monocyte-platelet conjugates, and microparticle-associated tissue factor activity. However, among the secondary endpoints, endothelin-1, a potent vasoconstrictor, increased from pre- to post-exposure with ozone concentration (120 vs 0 ppb: 0.07 pg/mL, 95% confidence interval [CI] 0.01, 0.14; 70 vs 0 ppb: -0.03 pg/mL, CI -0.09, 0.04; p = 0.008). Nitrotyrosine, a marker of oxidative and nitrosative stress, decreased with increasing ozone concentrations, with marginal significance (120 vs 0 ppb: -41.5, CI -70.1, -12.8; 70 vs 0 ppb: -14.2, CI -42.7, 14.2; p = 0.017). GSTM1 status did not modify the effect of ozone exposure on any of the outcomes. These findings from healthy older adults fail to identify any mechanistic basis for the epidemiologically described cardiovascular effects of exposure to ozone. The findings, however, may not be applicable to adults with cardiovascular disease. [ABSTRACT FROM AUTHOR]

Introduction: Studying the role of the immune system in the interaction between mental and physical health is challenging. To study individuals with an intensive, longitudinal study design that requires repetitive sampling in their daily life, non-invasive sampling techniques are a necessity. Urine can be collected in a non-invasive way, but this may be demanding for participants and little is known about fluctuation of inflammatory markers in urine over time. The aim of this study was to investigate the feasibility of non-invasive sampling, and to explore intra-individual differences in inflammatory markers in urine. Materials & methods: Ten healthy individuals collected 24-hour urine for 63 consecutive days. In a pilot analysis, 39 inflammatory markers were examined for detectability in urine, stability over time and under storage conditions, and daily fluctuations. Multiplex analyses were used to quantify levels of eight selected markers: C-reactive protein (CRP), Fractalkine, Interleukin-1 receptor-antagonist (IL-1RA), interferon-α (IFNα), interferon-γ (IFNγ), Interferon gamma-induced protein 10 (IP10), Macrophage inflammatory protein-1β (MIP-1β), and Vascular Endothelial Growth Factor (VEGF). Cross-correlations were calculated between the overnight and 24-hour samples were calculated, to examine whether 24-hour urine could be replaced by the overnight portion for better feasibility. We examined intra- and interindividual differences in the levels of inflammatory markers in urine and the fluctuations thereof. Results: This study showed that levels of selected inflammatory markers can be detected in urine. Cross-correlation analyses showed that correlations between levels of inflammatory markers in the night portion and the 24-hour urine sample varied widely between individuals. In addition, analyses of time series revealed striking inter- and intra-individual variation in levels of inflammatory markers and their fluctuations. Conclusion: We show that the assessment of urinary inflammatory markers is feasible in an intensive day-to-day study in healthy individuals. However, 24-hour urine cannot be replaced by an overnight portion to alleviate the protocol burden. Levels of inflammatory markers show substantial variation between and within persons. [ABSTRACT FROM AUTHOR]

Objectives: Traits of metabolic syndrome (MetS) and biomarkers of inflammation and endothelial dysfunction were examined. We investigated the differences of various biomarkers among individuals with or without Mets in a gender-specific manner. The gender-specific associations between E-selectin and MetS were further evaluated. Methods: A total of 205 patients were recruited from the outpatient clinics of Tri-Service General Hospital, Taipei, Taiwan. Inclusion criteria were age between 20–75 years and BMI < 35 kg/m2. Demographic, anthropometric and MetS index data were compared between genders. Markers of inflammation and endothelial dysfunction were compared between individuals with or without MetS by gender. Results: Age-adjusted E-selectin values showed significant positive correlations with BMI, waist-hip ratio, fasting plasma glucose, systolic and diastolic blood pressure, triglycerides, TNF-α, hsCRP and ICAM-1, and inverse correlation with HDL cholesterol. E-selectin levels were positively correlated with numbers of MetS components in females (P < 0.001) but not in males (P = 0.125). Conclusions: Increased E-selectin levels are significantly associated with increased MetS risk in females, but not in males. [ABSTRACT FROM AUTHOR]

Introduction: Mucosal immune activation, in the context of sexual transmission of HIV-1 infection, is crucial, as the increased presence of activated T cells enhance susceptibility to infection. In this regard, it has been proposed that immunomodulatory compounds capable of modulating immune activation, such as Vitamin D (VitD) may reduce HIV-1 transmission and might be used as a safe and cost-effective strategy for prevention. Considering this, we examined the in vitro effect of the treatment of peripheral blood mononuclear cells (PBMCs) with the active form of VitD, calcitriol, on cellular activation, function and susceptibility of CD4+ T cells to HIV-1 infection. Methods: We treated PBMCs from healthy HIV unexposed individuals (Co-HC) and frequently exposed, HIV-1 seronegative individuals (HESNs) from Colombia and from healthy non-exposed individuals from Canada (Ca-HC) with calcitriol and performed in vitro HIV-1 infection assays using X4- and R5-tropic HIV-1 strains respectively. In addition, we evaluated the activation and function of T cells and the expression of viral co-receptors, and select antiviral genes following calcitriol treatment. Results: Calcitriol reduced the frequency of infected CD4+ T cells and the number of viral particles per cell, for both, X4- and R5-tropic viruses tested in the Co-HC and the Ca-HC, respectively, but not in HESNs. Furthermore, in the Co-HC, calcitriol reduced the frequency of polyclonally activated T cells expressing the activation markers HLA-DR and CD38, and those HLA-DR+CD38-, whereas increased the subpopulation HLA-DR-CD38+. Calcitriol treatment also decreased production of granzyme, IL-2 and MIP-1β by T cells and increased the transcriptional expression of the inhibitor of NF-kB and the antiviral genes cathelicidin (CAMP) and APOBEC3G in PBMCs from Co-HC. Conclusion: Our in vitro findings suggest that VitD treatment could reduce HIV-1 transmission through a specific modulation of the activation levels and function of T cells, and the production of antiviral factors. In conclusion, VitD remains as an interesting potential strategy to prevent HIV-1 transmission that should be further explored. [ABSTRACT FROM AUTHOR]

Background: Zika virus (ZIKV) and Dengue virus (DENV) are often co-endemic. The high protein-sequence homology of flaviviruses renders IgG induced by and directed against them highly cross-reactive against their antigen(s), as observed on a large set of sera, leading to poorly reliable sero-diagnosis. Methods: We selected Domain III of the ZIKV Envelope (ZEDIII) sequence, which is virus specific. This recombinant domain was expressed and purified for the specific detection of ZEDIII-induced IgG by ELISA from ZIKV-RT-PCR-positive, ZIKV-IgM-positive, flavivirus-positive but ZIKV-negative, or flavivirus-negative sera. We also assessed the reactivity of ZEDIII-specific human antibodies against EDIII of DENV serotype 4 (D4EDIII) as a specific control. Sera from ZEDIII-immunized mice were also tested. Results: Cross-reactivity of IgG from 5,600 sera against total inactivated DENV or ZIKV was high (71.0% [69.1; 72.2]), whereas the specificity and sensitivity calculated using a representative cohort (242 sera) reached 90% [84.0; 95.8] and 92% [84.5; 99.5], respectively, using a ZEDIII-based ELISA. Moreover, purified human IgG against D2EDIII or D4EDIII did not bind to ZEDIII and we observed no D4EDIII reactivity with ZIKV-induced mouse polyclonal IgGs. Conclusions: We developed a ZEDIII-based ELISA that can discriminate between past or current DENV and ZIKV infections, allowing the detection of a serological scar from other flaviviruses. This could be used to confirm exposure of pregnant women or to follow the spread of an endemic disease. [ABSTRACT FROM AUTHOR]

Recent studies have begun to elucidate a role for E3 ubiquitin ligases as important mediators of the innate immune response. Our previous work defined a role for the ubiquitin ligase natural killer lytic-associated molecule (NKLAM/RNF19b) in mouse and human innate immunity. Here, we present novel data describing a role for NKLAM in regulating the immune response to Sendai virus (SeV), a murine model of paramyxoviral pneumonia. NKLAM expression was significantly upregulated by SeV infection. SeV-infected mice that are deficient in NKLAM demonstrated significantly less weight loss than wild type mice. In vivo, Sendai virus replication was attenuated in NKLAM-/- mice. Autophagic flux and the expression of autophagy markers LC3 and p62/SQSTM1 were also less in NKLAM-/- mice. Using flow cytometry, we observed less neutrophils and macrophages in the lungs of NKLAM-/- mice during SeV infection. Additionally, phosphorylation of STAT1 and NFκB p65 was lower in NKLAM-/- than wild type mice. The dysregulated phosphorylation profile of STAT1 and NFκB in NKLAM-/- mice correlated with decreased expression of numerous proinflammatory cytokines that are regulated by STAT1 and/or NFκB. The lack of NKLAM and the resulting attenuated immune response is favorable to NKLAM-/- mice receiving a low dose of SeV; however, at a high dose of virus, NKLAM-/- mice succumbed to the infection faster than wild type mice. In conclusion, our novel results indicate that NKLAM plays a role in regulating the production of pro-inflammatory cytokines during viral infection. [ABSTRACT FROM AUTHOR]

Respiratory infection can be exacerbated by the high glucose concentration in the airway surface liquid (ASL). We investigated the effects of salbutamol and phlorizin on the pulmonary function, oxidative stress levels and SGLT1 activity in lung, pulmonary histopathological damages and survival rates of rats with sepsis. Sepsis was induced by cecal ligation and puncture surgery (CLP). Twenty-four hours after surgery, CLP rats were intranasally treated with saline, salbutamol or phlorizin. After 2 hours, animals were anesthetized and sacrificed. Sepsis promoted atelectasis and bronchial inflammation, and led to increased expression of SGLT1 on cytoplasm of pneumocytes. Salbutamol treatment reduced bronchial inflammation and promoted hyperinsuflation in CLP rats. The interferon-ɤ and Interleucin-1β concentrations in bronchoalveolar lavage (BAL) were closely related to the bronchial inflammation regulation. Salbutamol stimulated SGLT1 in plasma membrane; whereas, phlorizin promoted the increase of SGLT1 in cytoplasm. Phlorizin reduced catalase activity and induced a significant decrease in the survival rate of CLP rats. Taken together, sepsis promoted atelectasis and lung inflammation, which can be associated with SGLT1 inhibition. The loss of function of SGLT1 by phlorizin are related to the augmented disease severity, increased atelectasis, bronchial inflammation and a significant reduction of survival rate of CLP rats. Alternatively salbutamol reduced BAL inflammatory cytokines, bronchial inflammation, atelectasis, and airway damage in sepsis. These data suggest that this selective β2-adrenergic agonist may protect lung of septic acute effects. [ABSTRACT FROM AUTHOR]

Objective: To explore clinical factors associated with bacterial translocation in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: The data of 118 patients with T2DM were obtained from two previous clinical studies, and were retrospectively analyzed regarding the clinical parameters associated with bacterial translocation defined as detection of bacteremia and levels of plasma lipopolysaccharide binding protein (LBP), the latter of which is thought to reflect inflammation caused by endotoxemia. Results: LBP level was not significantly different between patients with and without bacteremia. No clinical factors were significantly correlated with the detection of bacteremia. On the other hand, plasma LBP level was significantly correlated with HbA1c (r = 0.312), fasting blood glucose (r = 0.279), fasting C-peptide (r = 0.265), body mass index (r = 0.371), high-density lipoprotein cholesterol (r = -0.241), and inflammatory markers (high-sensitivity C-reactive protein, r = 0.543; and interleukin-6, r = 0.456). Multiple regression analysis identified body mass index, HbA1c, high-sensitivity C-reactive protein, and interleukin-6 as independent determinants of plasma LBP level. Conclusion: The plasma LBP level was similar in patients with and without bacteremia. While both bacteremia and LBP are theoretically associated with bacterial translocation, the detection of bacteremia was not associated with LBP level in T2DM. [ABSTRACT FROM AUTHOR]

The ability of DENV2 to display different morphologies (hence different antigenic properties) complicates vaccine and therapeutics development. Previous studies showed most strains of laboratory adapted DENV2 particles changed from smooth to “bumpy” surfaced morphology when the temperature is switched from 29°C at 37°C. Here we identified five envelope (E) protein residues different between two alternative passage history DENV2 NGC strains exhibiting smooth or bumpy surface morphologies. Several mutations performed on the smooth DENV2 infectious clone destabilized the surface, as observed by cryoEM. Molecular dynamics simulations demonstrated how chemically subtle substitution at various positions destabilized dimeric interactions between E proteins. In contrast, three out of four DENV2 clinical isolates showed a smooth surface morphology at 37°C, and only at high fever temperature (40°C) did they become “bumpy”. These results imply vaccines should contain particles representing both morphologies. For prophylactic and therapeutic treatments, this study also informs on which types of antibodies should be used at different stages of an infection, i.e., those that bind to monomeric E proteins on the bumpy surface or across multiple E proteins on the smooth surfaced virus. [ABSTRACT FROM AUTHOR]

Zika virus infection is associated with the development of Guillain-Barré syndrome (GBS), a neurological autoimmune disorder caused by immune recognition of gangliosides and other components at nerve membranes. Using a high-throughput ELISA, we have analyzed the anti-glycolipid antibody profile, including gangliosides, of plasma samples from patients with Zika infections associated or not with GBS in Salvador, Brazil. We have observed that Zika patients that develop GBS present higher levels of anti-ganglioside antibodies when compared to Zika patients without GBS. We also observed that a broad repertoire of gangliosides was targeted by both IgM and IgG anti-self antibodies in these patients. Since Zika virus infects neurons, which contain membrane gangliosides, antigen presentation of these infected cells may trigger the observed autoimmune anti-ganglioside antibodies suggesting direct infection-induced autoantibodies as a cause leading to GBS development. Collectively, our results establish a link between anti-ganglioside antibodies and Zika-associated GBS in patients. [ABSTRACT FROM AUTHOR]

Neutrophils play a critical role in host defense against Pseudomonas aeruginosa infection. Mechanisms underlying the negative regulation of neutrophil function in bacterial clearance remain incompletely defined. Here, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a negative regulator of P. aeruginosa clearance by neutrophils. PTP1B-deficient neutrophils display greatly enhanced bacterial phagocytosis and killing, which are accompanied by increased Toll-like receptor 4 (TLR4) signaling activation and nitric oxide (NO) production following P. aeruginosa infection. Interestingly, PTP1B deficiency mainly upregulates the production of IL-6 and IFN-β, leads to enhanced TLR4-dependent STAT1 activation and iNOS expression by neutrophils following P. aeruginosa infection. Further studies reveal that PTP1B and STAT1 are physically associated. These findings demonstrate a negative regulatory mechanism in neutrophil underlying the elimination of P. aeruginosa infection though a PTP1B-STAT1 interaction. [ABSTRACT FROM AUTHOR]

Laboratory assays for identifying recent HIV-1 infections are widely used for estimating incidence in cross-sectional population-level surveys in global HIV-1surveillance. Adequate assay and laboratory performance are required to ensure accurate incidence estimates. The NIAID-supported External Quality Assurance Program Oversight Laboratory (EQAPOL) established a proficiency testing program for the most widely-used incidence assay, the HIV-1 Limiting Antigen Avidity EIA (LAg), with US Centers for Disease Control and Prevention (CDC)-approved kits manufactured by Sedia Biosciences Corporation and Maxim Biomedical. The objective of this program is to monitor the performance of participating laboratories. Four rounds of blinded external proficiency (EP) panels were distributed to up to twenty testing sites (7 North American, 5 African, 4 Asian, 2 South American and 2 European). These panels consisted of ten plasma samples: three blinded well-characterized HIV-1-seropositive samples that were included as replicates and an HIV-negative control. The seropositive samples spanned the dynamic range of the assay and are categorized as either recent or long-term infection. Participating sites performed the assay according to manufacturers’ instructions and completed an online survey to gather information on kit manufacturer, lot of kit used, laboratory procedures and the experience of technicians. On average, fifteen sites participated in each round of testing, with an average of four sites testing with only the Maxim assay, seven testing with only the Sedia assay and five sites utilizing both assays. Overall, the Sedia and Maxim assays yielded similar infection status categorization across the laboratories; however, for most of the nine HIV+ samples tested, there were significant differences in the optical density readouts, ODn (N = 8) and OD (N = 7), between LAg kit manufacturers (p < 0.05 based on mixed effects models. The EQAPOL LAg program is important for monitoring laboratory performance as well as detecting variations between manufacturers of HIV-1incidence assays. [ABSTRACT FROM AUTHOR]

The present study investigates the wound healing potential of three chitosan-based topical preparations loaded with either tea tree essential oil, rosemary essential oil or a mixture of both oils in vivo. Essential oils of M. alternifolia and R. officinalis were analyzed using GC/MS. Essential oil-loaded chitosan topical preparations were formulated. Wound healing potential was evaluated in vivo using an excision wound model in rats. GC/MS analysis of M. alternifolia and R. officinalis essential oils revealed richness in oxygenated monoterpenes, representing 51.06% and 69.61% of the total oil composition, respectively. Topical application of chitosan-based formulation loaded with a mixture of tea tree and rosemary oils resulted in a significant increase in wound contraction percentage compared to either group treated with individual essential oils and the untreated group. Histopathological examination revealed that topical application of tea tree and rosemary oil combination demonstrated complete re-epithelialization associated with activated hair follicles. The high percentage of oxygenated monoterpenes in both essential oils play an important role in the antioxidant and wound healing potential observed herein. Incorporation of tea tree and rosemary essential oils in chitosan-based preparations in appropriate combination could efficiently promote different stages of wound healing. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection in a high percentage of the population worldwide. CMV induces the strongest and most durable CD8+ T cell response known in human clinical medicine. Due to its unique properties, the virus represents a promising candidate vaccine vector for the induction of persistent cellular immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) expressing an MHC-I restricted epitope from influenza A virus (IAV) H1N1 within the immediate early 2 (ie2) gene. Only mice that were immunized intranasally (i.n.) were capable of controlling IAV infection, despite the greater potency of the intraperitoneally (i.p.) vaccination in inducing a systemic IAV-specific CD8+ T cell response. The protective capacity of the i.n. immunization was associated with its ability to induce IAV-specific tissue-resident memory CD8+ T (CD8TRM) cells in the lungs. Our data demonstrate that the protective effect exerted by the i.n. immunization was critically mediated by antigen-specific CD8+ T cells. CD8TRM cells promoted the induction of IFNγ and chemokines that facilitate the recruitment of antigen-specific CD8+ T cells to the lungs. Overall, our results showed that locally applied MCMV vectors could induce mucosal immunity at sites of entry, providing superior immune protection against respiratory infections. [ABSTRACT FROM AUTHOR]

The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage. [ABSTRACT FROM AUTHOR]

Introduction: End-stage renal disease (ESRD) strongly associates with cardiovascular disease (CVD) risk. This risk is not completely mitigated by renal replacement therapy. Endothelial dysfunction (ED) and low-grade inflammation (LGI) may contribute to the increased CVD risk. However, data on serum biomarkers of ED and LGI during the transition to renal replacement therapy (dialysis and kidney transplantation) are scarce. Methods: We compared serum biomarkers of ED and LGI between 36 controls, 43 participants with chronic kidney disease (CKD) stage 5 non-dialysis (CKD5-ND), 20 participants with CKD stage 5 hemodialysis (CKD5-HD) and 14 participants with CKD stage 5 peritoneal dialysis (CKD5-PD). Further, in 34 and 15 participants repeated measurements were available during the first six months following dialysis initiation and kidney transplantation, respectively. Serum biomarkers of ED (sVCAM-1, E-selectin, P-selectin, thrombomodulin, sICAM-1, sICAM-3) and LGI (hs-CRP, SAA, IL-6, IL-8, TNF-α) were measured with a single- or multiplex array detection system based on electro-chemiluminescence technology. Results: In linear regression analyses adjusted for potential confounders, participants with ESRD had higher levels of most serum biomarkers of ED and LGI than controls. In addition, in CKD5-HD levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, in CKD5-PD levels of biomarkers of ED were higher than in CKD5-ND and CKD5-HD. Similarly, in linear mixed model analyses sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 increased after PD initiation. In contrast, incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α, but a decline of hs-CRP, SAA and IL-6. Further, following kidney transplantation sVCAM-1, thrombomodulin, sICAM-3 and TNF-α were lower at three months post-transplantation and remained stable in the three months thereafter. Conclusions: Levels of serum biomarkers of ED and LGI were higher in ESRD as compared with controls. In addition, PD initiation and, less convincingly, HD initiation may increase levels of selected serum biomarkers of ED and LGI on top of uremia per se. In contrast to dialysis, several serum biomarkers of ED and LGI markedly declined following kidney transplantation. [ABSTRACT FROM AUTHOR]

Mother-to-child-transmission (MTCT) of human T-cell lymphotropic virus type-1(HTLV-1) contributes disproportionately to the burden of HTLV-1 associated diseases. All preventive measures to avoid MTCT rely on the identification of infected mothers. However, the impact of pregnancy on HTLV-1 diagnosis has not been clearly assessed. Paired samples from 21 HTLV-1 infected women taken during pregnancy and while not pregnant were analysed by CMIA and PCR. The signal-to-cut-off values (S/CO) were higher during pregnancy than in the paired non-pregnant samples. HTLV-1 proviral load did not alter significantly by pregnant state. S/CO positively correlated with HTLV proviral load. Pregnancy does not impair the diagnosis of HTLV-1/2, by either immunological (CMIA) or molecular (qPCR/nPCR) tests. [ABSTRACT FROM AUTHOR]

Background: Rift Valley fever (RVF) is one of the main vector borne zoonotic diseases that affects a wide range of ruminants and human beings in Africa and the Arabian Peninsula. A rapid and specific test for RVF diagnosis at the site of a suspected outbreak is crucial for the implementation of control measures. Methodology/Principal findings: A first-line lateral flow immunochromatographic strip test (LFT) was developed for the detection of the nucleoprotein (N) of the RVF virus (RVFV). Its diagnostic performance characteristics were evaluated using reference stocks isolates recovered from different hosts and in geographic regions mimicking clinical specimens and from known RVF negative serum samples. A high level of diagnostic accuracy (DSe (35/35), DSp (167/169)) was observed, including the absence of cross-reactivity with viruses belonging to different genera. Conclusion/Significance: The fact no specialized reagents and laboratory equipment are needed, make this assay a valuable, first-line diagnostic tool in resource-poor diagnostic territories for on-site RVFV detection, however the staff require training. [ABSTRACT FROM AUTHOR]

Background: The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis).Methods and Findings: This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (β: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (β: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs.Conclusions: In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D.Trial Registration: The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481. [ABSTRACT FROM AUTHOR]

Introduction: The primary rational for using mesenchymal stromal cells (MSCs) to rejuvenate damaged tissue is mostly based on their capacity to trans-differentiate and repair injured organs. However, previous studies have demonstrated that MSCs are beneficial even at very early stages, before differentiation and proliferation can be expected. The aim of the current study was to investigate the multifaceted immunological effects of systemically administrating MSCs in the setting of acute kidney injury (AKI) induced by ischemic-reperfusion (I/R). Methods: A rat model of I/R induced AKI was used. The rats underwent a unilateral nephrectomy with simultaneously clamping the contralateral kidney for 60 minutes. Four treatment groups received intravenously, increasing doses of human MSCs and after 48 hours, the rats were sacrificed. Blood was taken to evaluate renal functions and to measure systemic inflammatory markers. Kidneys were taken for histopathologic examinations and evaluations of intra-renal complement activation and inflammatory mediators. Results: Renal functions improved in U shaped dose dependent manner. Mean serum creatinine levels were 4.5, 2.9, 2.6, 1.7 and 4.1 mg/dL in I/R + placebo, I/R + 150x103 cells, I/R + 250x103 cells, I/R + 500x103 cells and I/R + 1,000x103 cells respectfully (p-values<0.05). Urea demonstrated consistent results with the same U shape improvement manner. The extensive activation of the complement system was ameliorated in the MSCs treatment groups. In addition, MSCs significantly decreased intra-renal levels of IL-1β and TNF-α. It should be noted that the highest doses of MSCs induced renal hypoxia, marked by the Hypoxy-probe staining. Conclusions: The early beneficial effect of MSCs in the setting of AKI may be attributed to their immunomodulatory effects. Safe treatment with MSCs can block the deleterious activation of the complement cascade and alleviate the hazardous inflammatory mediator-related cascade. [ABSTRACT FROM AUTHOR]

Purpose: To determine the characteristics of diabetic macular edema (DME) patients refractory to intravitreal bevacizumab (IVB) treatments and an additional dexamethasone implant. Methods: We classified 119 DME patients according to whether or not they are responsive to 3 consecutive monthly anti-VEGF treatments and/or an additional dexamethasone implant. We compared their concentrations of IL (interleukin)-1β, IL-8, IL-10, IL-17, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) in the aqueous humor as well as their optical coherence tomography (OCT) findings, and baseline characteristics. We used logistic regression analyses to identify preoperative factors related to refractoriness to treatments. Results: Of 119 treatment-naïve DME patients, 50 (42.02%) patients showed responsiveness [central subfield thickness (CST) < 300μm] after 3 IVBs, and 59 (49.58%) patients showed responsiveness after an additional dexamethasone implant, but 10 (8.40%) patients showed CST 300 ≥ μm even after both treatments. Refractory DME patients showed significantly higher number of hyperreflective foci (HF) in the OCT and higher average level of aqueous IL-1β at baseline (p<0.001 and p = 0.042, respectively). In the logistic regression analysis, higher number of HF in the OCT was associated with the refractoriness to both treatments (odds ratio [OR]: 7.03, p = 0.007) Conclusions: Higher number of HF in the OCT at the initial visit was associated with poor responses to IVBs and an additional dexamethasone implant. [ABSTRACT FROM AUTHOR]

Multi-marker tests hold promise for identifying symptomatic women at risk of imminent preterm delivery (PTD, <37 week’s gestation). This study sought to determine the relationship of inflammatory mediators and metabolites in cervicovaginal fluid (CVF) with spontaneous PTD (sPTD) and delivery within 14 days of presentation with symptoms of preterm labour (PTL). CVF samples from 94 (preterm = 19, term = 75) singleton women with symptoms of PTL studied between 19+0–36+6 weeks’ gestation were analysed for cytokines/chemokines by multiplexed bead-based immunoassay, while metabolites were quantified by enzyme-based spectrophotometry in a subset of 61 women (preterm = 16, term = 45). Prevalence of targeted vaginal bacterial species was determined for 70 women (preterm = 14, term = 66) by PCR. Overall, 10 women delivered within 14 days of sampling. Predictive capacities of individual biomarkers and cytokine-metabolite combinations for sPTD and delivery within 14 days of sampling were analysed by logistic regression models and area under the receiver operating characteristic curve. Fusobacterium sp., Mubiluncus mulieris and Mycoplasma hominis were detected in more preterm-delivered than term women (P<0.0001), while, M. curtisii was found in more term-delivered than preterm women (P<0.0001). RANTES (0.91, 0.65–1.0), IL-6 (0.79, 0.67–0.88), and Acetate/Glutamate ratio (0.74, 0.61–0.85) were associated with delivery within 14 days of sampling (AUC, 95% CI). There were significant correlations between cytokines and metabolites, and several cytokine-metabolite combinations were associated with sPTD or delivery within 14 days of sampling (e.g. L/D-lactate ratio+Acetate/Glutamate ratio+IL-6: 0.84, 0.67–0.94). Symptomatic women destined to deliver preterm and within 14 days of sampling express significantly higher pro-inflammatory mediators at mid to late gestation. In this cohort, IL-6, Acetate/Glutamate ratio and RANTES were associated with delivery within 14 days of sampling, consistent with their roles in modulating infection-inflammation-associated preterm labour in women presenting with symptoms of preterm birth. Replication of these observations in larger cohorts of women could show potential clinical utility. [ABSTRACT FROM AUTHOR]

Vaccines that elicit broadly cross-neutralizing antibodies, including antibodies that target the conserved stem of hemagglutinin (HA), are being developed as a strategy for next-generation influenza vaccines that protect against influenza across multiple years. However, efficient induction of cross-neutralizing antibodies remains a challenge, and potential escape mutations have not been well characterized. Here we elicited cross-neutralizing antibodies by immunizing animals with the hemagglutinins from H5 and H9 subtype influenza A viruses that are sensitive to neutralization by stem antibodies. We further isolated and characterized an HA stem monoclonal antibody 4C2 that broadly neutralizes group 1 influenza viruses and identified HA mutations that reduced sensitivity to stem antibodies. Our results offer insights for next-generation influenza vaccine strategies for inducing cross-neutralizing antibodies. [ABSTRACT FROM AUTHOR]

Background: Different psychiatric diagnostic groups have been reported to have cytokine levels deviating from healthy controls. In acute clinical settings however, the specific challenging symptoms and signs are more important than a diagnostic group. Thus, exploration of cytokines and immune activity and their role in specific symptoms is important. Reports in this field so far are sparse. Objective: In the present study, we aimed to examine the association between immune activity measured as levels of cytokines and agitation (independent of diagnostic group) in patients admitted to an acute psychiatric inpatient department. Methods: A total of 316 patients admitted to an acute psychiatric inpatient department were included. Thirty-nine patients with psychosis were subject to subgroup analyses. Agitation was assessed by the Positive and Negative Syndrome Scale, Excitement Component (PANSS-EC). Based on PANNS-EC patients were stratified into two groups: 67 agitated patients and 249 non-agitated patients. Serum concentrations of the following immune markers were measured: interleukin (IL) -1β, IL-4, IL-6, IL-10, tumor necrosis factor (TNF) -α, interferon (IFN) -γ and transforming growth factor (TGF) -β. Results: Serum levels of TNF-α were significantly higher in patients with agitation compared to those without, both when all patients were included in the analyses (p = 0.004) and in the psychosis group (p = 0.027). After correcting for multiple testing, only the findings in the total population remained significant. Conclusions: Our findings suggest an association between TNF-α and agitation in an acute psychiatric population. A similar trend was reproduced to the psychosis subgroup. This suggests that agitation might be an independent entity associated with cytokines across different diagnostic groups. [ABSTRACT FROM AUTHOR]

Bacterial type IV secretion systems (T4SS) are a highly diversified but evolutionarily related family of macromolecule transporters that can secrete proteins and DNA into the extracellular medium or into target cells. It was recently shown that a subtype of T4SS harboured by the plant pathogen Xanthomonas citri transfers toxins into target cells. Here, we show that a similar T4SS from the multi-drug-resistant opportunistic pathogen Stenotrophomonas maltophilia is proficient in killing competitor bacterial species. T4SS-dependent duelling between S. maltophilia and X. citri was observed by time-lapse fluorescence microscopy. A bioinformatic search of the S. maltophilia K279a genome for proteins containing a C-terminal domain conserved in X. citri T4SS effectors (XVIPCD) identified twelve putative effectors and their cognate immunity proteins. We selected a putative S. maltophilia effector with unknown function (Smlt3024) for further characterization and confirmed that it is indeed secreted in a T4SS-dependent manner. Expression of Smlt3024 in the periplasm of E. coli or its contact-dependent delivery via T4SS into E. coli by X. citri resulted in reduced growth rates, which could be counteracted by expression of its cognate inhibitor Smlt3025 in the target cell. Furthermore, expression of the VirD4 coupling protein of X. citri can restore the function of S. maltophilia ΔvirD4, demonstrating that effectors from one species can be recognized for transfer by T4SSs from another species. Interestingly, Smlt3024 is homologous to the N-terminal domain of large Ca2+-binding RTX proteins and the crystal structure of Smlt3025 revealed a topology similar to the iron-regulated protein FrpD from Neisseria meningitidis which has been shown to interact with the RTX protein FrpC. This work expands our current knowledge about the function of bacteria-killing T4SSs and increases the panel of effectors known to be involved in T4SS-mediated interbacterial competition, which possibly contribute to the establishment of S. maltophilia in clinical and environmental settings. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a metabolic disease with a group of metabolic derangements and inflammatory reactants in the serum. Despite the substantial public health implications, markers of diabetes progression with abdominal obesity are still needed to facilitate early detection and treatment. In this study, we performed a proteomic approach to identify differential target proteins underlying diabetes progression in patients with abdominal obesity. Proteomic differences were investigated in the serum of controls and patients with prediabetes or diabetes with or without abdominal obesity by 2-DE combined with MALDI-TOF-MS. Proteomics data were validated by western blot analyses and major protein-protein interactions were assessed using a network analysis with String database. Among 245 matched protein spots, 36 exhibited marked differences in normal patients with abdominal obesity, prediabetes, and diabetes compared to levels in normal patients without abdominal obesity. Seven (Alpha-1-antichymotrypsin, Alpha-1-antitrypsin, Apolipoprotein A-I, haptoglobin, retinol-binding protein 4, transthyretin, and zinc-alpha2-glycoprotein) of these spots exhibited significant differences between normal and prediabetes/diabetes patients. After a network analysis, functional annotation using Gene Ontology indicated that most of the identified proteins were involved in lipid transport, lipid localization, and the regulation of serum lipoprotein particle levels. Our results indicated that variation in the levels of these identified protein biomarkers has been reported in normal, prediabetes and diabetic Assessment of the levels of these biomarkers may contribute to the development of biomarkers for not only early diagnosis but also in prognosis of diabetes mellitus type 2. [ABSTRACT FROM AUTHOR]

HIV envelope protein (Env) is the sole target of broadly neutralizing antibodies (BNAbs) that are capable of neutralizing diverse strains of HIV. While BNAbs develop spontaneously in a subset of HIV-infected patients, efforts to design an envelope protein-based immunogen to elicit broadly neutralizing antibody responses have so far been unsuccessful. It is hypothesized that a primary barrier to eliciting BNAbs is the fact that HIV envelope proteins bind poorly to the germline-encoded unmutated common ancestor (UCA) precursors to BNAbs. To identify variant forms of Env with increased affinities for the UCA forms of BNAbs 4E10 and 10E8, which target the Membrane Proximal External Region (MPER) of Env, libraries of randomly mutated Env variants were expressed in a yeast surface display system and screened using fluorescence activated cell sorting for cells displaying variants with enhanced abilities to bind the UCA antibodies. Based on analyses of individual clones obtained from the screen and on next-generation sequencing of sorted libraries, distinct but partially overlapping sets of amino acid substitutions conferring enhanced UCA antibody binding were identified. These were particularly enriched in substitutions of arginine for highly conserved tryptophan residues. The UCA-binding variants also generally exhibited enhanced binding to the mature forms of anti-MPER antibodies. Mapping of the identified substitutions into available structures of Env suggest that they may act by destabilizing both the initial pre-fusion conformation and the six-helix bundle involved in fusion of the viral and cell membranes, as well as providing new or expanded epitopes with increased accessibility for the UCA antibodies. [ABSTRACT FROM AUTHOR]

Of the fast ionotropic synapses, glycinergic synapses are the least well understood, but are vital for the maintenance of inhibitory signaling in the brain and spinal cord. Glycinergic signaling comprises half of the inhibitory signaling in the spinal cord, and glycinergic synapses are likely to regulate local nociceptive processing as well as the transmission to the brain of peripheral nociceptive information. Here we have investigated the rapid and prolonged potentiation of glycinergic synapses in the superficial dorsal horn of young male and female mice after brief activation of NMDA receptors (NMDARs). Glycinergic inhibitory postsynaptic currents (IPSCs) evoked with lamina II-III stimulation in identified GABAergic neurons in lamina II were potentiated by bath-applied Zn2+ and were depressed by the prostaglandin PGE2, consistent with the presence of both GlyRα1- and GlyRα3-containing receptors. NMDA application rapidly potentiated synaptic glycinergic currents. Whole-cell currents evoked by exogenous glycine were also readily potentiated by NMDA, indicating that the potentiation results from altered numbers or conductance of postsynaptic glycine receptors. Repetitive depolarization alone of the postsynaptic GABAergic neuron also potentiated glycinergic synapses, and intracellular EGTA prevented both NMDA-induced and depolarization-induced potentiation of glycinergic IPSCs. Optogenetic activation of trpv1 lineage afferents also triggered NMDAR-dependent potentiation of glycinergic synapses. Our results suggest that during peripheral injury or inflammation, nociceptor firing during injury is likely to potentiate glycinergic synapses on GABAergic neurons. This disinhibition mechanism may be engaged rapidly, altering dorsal horn circuitry to promote the transmission of nociceptive information to the brain. [ABSTRACT FROM AUTHOR]

Background: Pathogens causing acute fever, with the exception of malaria, remain largely unidentified in sub-Saharan Africa, given the local unavailability of diagnostic tests and the broad differential diagnosis. Methodology: We conducted a cross-sectional study including outpatient acute undifferentiated fever in both children and adults, between November 2015 and June 2016 in Kinshasa, Democratic Republic of Congo. Serological and molecular diagnostic tests for selected arboviral infections were performed on blood, including PCR, NS1-RDT, ELISA and IFA for acute, and ELISA and IFA for past infections. Results: Investigation among 342 patients, aged 2 to 68 years (mean age of 21 years), with acute undifferentiated fever (having no clear focus of infection) revealed 19 (8.1%) acute dengue–caused by DENV-1 and/or DENV-2 –and 2 (0.9%) acute chikungunya infections. Furthermore, 30.2% and 26.4% of participants had been infected in the past with dengue and chikungunya, respectively. We found no evidence of acute Zika nor yellow fever virus infections. 45.3% of patients tested positive on malaria Rapid Diagnostic Test, 87.7% received antimalarial treatment and 64.3% received antibacterial treatment. Discussion: Chikungunya outbreaks have been reported in the study area in the past, so the high seroprevalence is not surprising. However, scarce evidence exists on dengue transmission in Kinshasa and based on our data, circulation is more important than previously reported. Furthermore, our study shows that the prescription of antibiotics, both antibacterial and antimalarial drugs, is rampant. Studies like this one, elucidating the causes of acute fever, may lead to a more considerate and rigorous use of antibiotics. This will not only stem the ever-increasing problem of antimicrobial resistance, but will–ultimately and hopefully–improve the clinical care of outpatients in low-resource settings. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

Gender differences in Human immunodeficiency virus (HIV) disease progression and comorbidities have been extensively reported. Using the simian immunodeficiency virus (SIV) infected rhesus macaque model, we show that these differences are apparent very early during the course of infection. Though there were no major changes in the proportions of CD4 T cells or its subsets, central memory CD4 T cells from female macaques were found to differentially regulate a significantly larger number of genes at day 4 post-infection (PI) as compared to males. Pathway analysis revealed divergence of both canonical and biological pathways that persisted at day 10 PI. Changes in gene expression profiles were accompanied by a significant increase in plasma levels of pro-inflammatory mediators such as MCP-1/CCL2, I-TAC/CXCL11, and MIF. Though plasma levels of IFNα did not differ between male and female macaques, the expression levels of IFNα subtype-14, 16, IFNβ, and IFNω were significantly upregulated in the lymph nodes of female macaques at day 10 PI as compared to male macaques. Our results suggest that the pathogenic sequelae seen during chronic infection may be shaped by gender differences in immune responses induced very early during the course of HIV infection. [ABSTRACT FROM AUTHOR]

Background: Inflammation has been associated with increased morbidity and mortality in HIV-positive patients. We compared inflammatory biomarkers with dual therapy using lopinavir/ritonavir plus lamivudine (LPV/r+3TC) versus triple therapy using LPV/r plus two nucleoside reverse transcriptase inhibitors (LPV/r+2NRTIs) in treatment-naïve HIV-positive adults. Methods: This was a substudy among Argentinian participants in the randomized trial GARDEL. We measured hsCRP, IL-6, MCP-1, TNF, D-dimer and sCD14 from plasma collected at baseline, week 24 and week 48. Generalized estimating equations with an identity/logit link were used to model the average impact of dual versus triple therapy on each biomarker over time, controlling for baseline levels. Additional models estimated the average effect of virologic suppression on biomarker levels over time, adjusting for age, sex, and baseline CD4 count. Results: Of 191 trial participants enrolled in Argentina, 172 had baseline and follow-up measurements and were included. Median (IQR) age was 35.5 (28.5, 45) years and CD4 cell count was 310 (219, 414) cells/mm3. Dual therapy was not associated with significantly different biomarker levels over 48 weeks relative to triple therapy. Virologic suppression was associated with statistically significant decreases in MCP-1, TNF and D-dimer levels and an unexpected increase in sCD14 levels. No change was observed in hsCRP or the proportion of participants with undetectable IL-6 levels. Conclusions: In addition to having virologic non-inferiority, LPV/r+3TC dual therapy is generally associated with similar inflammatory biomarker levels over 48 weeks compared to LPV/r+2NRTIs triple therapy in treatment-naïve adults. Further study of dual treatment regimens is warranted. [ABSTRACT FROM AUTHOR]

Antibodies are essential to functional immunity, yet the epitopes targeted by antibody repertoires remain largely uncharacterized. To aid in characterization, we developed a generalizable strategy to predict antibody-binding epitopes within individual proteins and entire proteomes. Specifically, we selected antibody-binding peptides for 273 distinct sera out of a random library and identified the peptides using next-generation sequencing. To predict antibody-binding epitopes and the antigens from which these epitopes were derived, we tiled the sequences of candidate antigens into short overlapping subsequences of length k (k-mers). We used the enrichment over background of these k-mers in the antibody-binding peptide dataset to predict antibody-binding epitopes. As a positive control, we used this approach, termed K-mer Tiling of Protein Epitopes (K-TOPE), to predict epitopes targeted by monoclonal and polyclonal antibodies of well-characterized specificity, accurately recovering their known epitopes. K-TOPE characterized a commonly targeted antigen from Rhinovirus A, predicting four epitopes recognized by antibodies present in 87% of sera (n = 250). An analysis of 2,908 proteins from 400 viral taxa that infect humans predicted seven enterovirus epitopes and five Epstein-Barr virus epitopes recognized by >30% of specimens. Analysis of Staphylococcus and Streptococcus proteomes similarly predicted 22 epitopes recognized by >30% of specimens. Twelve of these common viral and bacterial epitopes agreed with previously mapped epitopes with p-values < 0.05. Additionally, we predicted 30 HSV2-specific epitopes that were 100% specific against HSV1 in novel and previously reported antigens. Experimentally validating these candidate epitopes could help identify diagnostic biomarkers, vaccine components, and therapeutic targets. The K-TOPE approach thus provides a powerful new tool to elucidate the organisms, antigens, and epitopes targeted by human antibody repertoires. [ABSTRACT FROM AUTHOR]

Sex-based differences in susceptibility have been reported for a number of neovascular ocular diseases. We quantified corneal neovascularization, induced by superficial silver nitrate cautery, in male and female inbred albino Sprague-Dawley, inbred albino Fischer 344, outbred pigmented Hooded Wistar and inbred pigmented Dark Agouti rats of a range of ages. Corneal neovascular area was quantified on haematoxylin-stained corneal flatmounts by image analysis. Pro-and anti-angiogenic gene expression was measured early in the neovascular response by quantitative real-time polymerase chain reaction. Androgen and estrogen receptor expression was assessed by immunohistochemistry. Male rats from all strains, with or without ocular pigmentation, exhibited significantly greater corneal neovascular area than females: Sprague-Dawley males 43±12% (n = 8), females 25±5% (n = 12), p = 0.001; Fischer 344 males 38±10% (n = 12) females 27±8% (n = 8) p = 0.043; Hooded Wistar males 32±6% (n = 8) females 22±5% (n = 12) p = 0.002; Dark Agouti males 37±11% (n = 9) females 26±7% (n = 9) p = 0.015. Corneal vascular endothelial cells expressed neither androgen nor estrogen receptor. The expression in cornea post-cautery of Cox-2, Vegf-a and Vegf-r2 was significantly higher in males compared with females and Vegf-r1 was significantly lower in the cornea of males compared to females, p<0.001 for each comparison. These data suggest that male corneas are primed for angiogenesis through a signalling nexus involving Cox-2, Vegf-a, and Vegf receptors 1 and 2. Our findings re-enforce that pre-clinical animal models of human diseases should account for sex-based differences in their design and highlight the need for well characterized and reproducible pre-clinical studies that include both male and female animals. [ABSTRACT FROM AUTHOR]

Background: Recent studies are suggesting a U-shaped relationship between antenatal iron exposure and birth outcomes. Little is known about the iron status and associated birth outcomes of pregnant women in South Africa. Our aim was to assess iron status at early, mid- and late pregnancy, and to determine associations with gestational age and birth weight in women in Johannesburg, South Africa. Methods: In this prospective study of 250 pregnant women, we measured haemoglobin, biomarkers of iron status and inflammation at <18, 22 and 36 weeks of gestation, plus birth weight and gestational age at delivery. Associations of anaemia and iron status with birth outcomes were determined using regression models adjusted for confounders. Results: At enrolment, the prevalence of anaemia, iron depletion (ID) and iron deficiency erythropoiesis (IDE) was 29%, 15% and 15%, respectively, and increased significantly with pregnancy progression. Anaemia and ID at 22 weeks, as well as IDE at 36 weeks were associated with higher birth weight (β = 135.4; 95% CI: 4.8, 266.1 and β = 205.4; 95% CI: 45.6, 365.1 and β = 178.0; 95% CI: 47.3, 308.7, respectively). Women in the lowest ferritin quartile at 22 weeks gave birth to babies weighing 312 g (95% CI: 94.8, 528.8) more than those in the highest quartile. In contrast, IDE at 22 weeks was associated with a higher risk for premature birth (OR: 3.57, 95% CI: 1.24, 10.34) and women in lower haemoglobin quartiles at <18 weeks had a shorter gestation by 7 days (β = -6.9, 95% CI: -13.3, -0.6) compared to those in the highest quartile. Conclusion: Anaemia, ID and IDE prevalence increased during pregnancy despite routine iron supplementation. ID and anaemia at mid-pregnancy were associated with higher birth weight, while IDE was associated with premature birth. These results suggest that current antenatal screening and supplementation practices in South Africa need to be revisited. [ABSTRACT FROM AUTHOR]

Background: Evaluation of therapeutic response in chronic Chagas disease is a major challenge, due to prolonged persistence of Trypanosoma cruzi-specific antibodies, lack of sensitivity of parasitological tests, and need for long-term follow-up to observe negative seroconversion of conventional serological tests (CS). The objective of this study was to evaluate F2/3-ELISA serology, a promising early biomarker of therapeutic response, and T.cruzi Polymerase chain reaction (PCR) for T. cruzi Deoxyribonucleic acid (DNA), for neonatal diagnosis and evaluation of parasitemia after treatment. Methods: Prospective cohort study, with three-year clinical, serological and parasitological follow-up of pediatric Chagas disease patients treated with benznidazole. Serology was evaluated by Enzyme-Linked ImmunoSorbent Assay (ELISA), Indirect hemagglutination (IHA) and F2/3-ELISA; Parasitemia by microhematocrit (MH) and PCR. Results: A cohort of 107 pediatric patients treated with benznidazole was enrolled in the study. ELISA and IHA were initially reactive in 100% of patients, F2/3-ELISA serology was reactive in 80% (86/107) and 91% (97/107) had detectable parasitemia. Seventy-six (71%) patients completed at least 36 months of serological follow up after treatment. Although a similar decreasing linear trend was observed for all serological tests, F2/3-ELISA presented earlier, age dependent, negative seroconversion compared to CS. All patients reaching undetectable CS titers had previously seroreverted by F2/3-ELISA. All patients with persistently decreasing antibody titers had negative PCRs throughout the follow up period. No new cardiological lesions were observed during the 3 years follow-up period. Conclusions: The data reported here, using CS, F2/3 ELISA and PCR provide support for the efficacy of benznidazole in congenital Chagas diseases. These results provide support for scaling up of screening, diagnosis and access to benznidazole treatment. Trial registration: ClinicalTrials.gov 0028/04 in the Research Council, Secretary of Health Buenos Aires city Goberment. [ABSTRACT FROM AUTHOR]

Objective: Previous studies indicate a role for Oncostatin M (OSM) in atherosclerosis and other chronic inflammatory diseases for which inhibitory antibodies are in development. However, to date no intervention studies with OSM have been performed, and its relation to coronary heart disease (CHD) has not been studied. Approach and results: Gene expression analysis on human normal arteries (n = 10) and late stage/advanced carotid atherosclerotic arteries (n = 127) and in situ hybridization on early human plaques (n = 9) showed that OSM, and its receptors, OSM receptor (OSMR) and Leukemia Inhibitory Factor Receptor (LIFR) are expressed in normal arteries and atherosclerotic plaques. Chronic OSM administration in APOE*3Leiden.CETP mice (n = 15/group) increased plasma E-selectin levels and monocyte adhesion to the activated endothelium independently of cholesterol but reduced the amount of inflammatory Ly-6CHigh monocytes and atherosclerotic lesion size and severity. Using aptamer-based proteomics profiling assays high circulating OSM levels were shown to correlate with post incident CHD survival probability in the AGES-Reykjavik study (n = 5457). Conclusions: Chronic OSM administration in APOE*3Leiden.CETP mice reduced atherosclerosis development. In line, higher serum OSM levels were correlated with improved post incident CHD survival probability in patients, suggesting a protective cardiovascular effect. [ABSTRACT FROM AUTHOR]

Antibody titers against a viral pathogen are typically measured using an antigen binding assay, such as an enzyme-linked immunosorbent assay (ELISA), which only measures the ability of antibodies to identify a viral antigen of interest. Neutralization assays measure the presence of virus-neutralizing antibodies in a sample. Traditional neutralization assays, such as the plaque reduction neutralization test (PRNT), are often difficult to use on a large scale due to being both labor and resource intensive. Here we describe an Ebola virus fluorescence reduction neutralization assay (FRNA), which tests for neutralizing antibodies, that requires only a small volume of sample in a 96-well format and is easy to automate. The readout of the FRNA is the percentage of Ebola virus-infected cells measured with an optical reader or overall chemiluminescence that can be generated by multiple reading platforms. Using blinded human clinical samples (EVD survivors or contacts) obtained in Liberia during the 2013–2016 Ebola virus disease outbreak, we demonstrate there was a high degree of agreement between the FRNA-measured antibody titers and the Filovirus Animal Non-clinical Group (FANG) ELISA titers with the FRNA providing information on the neutralizing capabilities of the antibodies. [ABSTRACT FROM AUTHOR]

Moreover, nonvaccine serotypes and NESp prevalence have markedly increased since the introduction of pneumococcal vaccines [[5],[6]]. Altogether, the current risk of NESp-associated invasive disease is minimal, with only 1% to 15% of IPD cases associated with NESp depending on the region, but selective pressures and NESp persistence are slowly establishing a suitable environment for a devastating rise in invasive disease [[8]]. Reductions in vaccine serotypes cause propagation of nonvaccine serotypes (pink and purple) and nonencapsulated pneumococci (blue and green). Teal = vaccine serotypes; purple = antibiotic-susceptible nonvaccine serotypes; pink = antibiotic-resistant nonvaccine serotypes; green = antibiotic-susceptible NESp; blue = antibiotic-resistant NESp. [Extracted from the article]

Zika virus (ZIKV) is a newly-identified infectious cause of congenital disease. Transplacental transfer of maternal IgG to the fetus plays an important role in preventing many neonatal infections. However, antibody transfer may also have negative consequences, such as mediating enhancement of flavivirus infections in early life, or trafficking of virus immune complexes to the fetal compartment. ZIKV infection produces placental pathology which could lead to impaired IgG transfer efficiency as occurs in other maternal infections, such as HIV-1 and malaria. In this study, we asked whether ZIKV infection during pregnancy impairs transplacental transfer of IgG. We enrolled pregnant women with fever or rash in a prospective cohort in Vitoria, Brazil during the recent ZIKV epidemic. ZIKV and dengue virus (DENV)-specific IgG, ZIKV and DENV neutralizing antibodies, and routine vaccine antigen-specific IgG were measured in maternal samples collected around delivery and 20 paired cord blood samples. We concluded that 8 of these mothers were infected with ZIKV during pregnancy and 12 were ZIKV-uninfected. The magnitude of flavivirus-specific IgG, neutralizing antibody, and vaccine-elicited IgG were highly correlated between maternal plasma and infant cord blood in both ZIKV-infected and -uninfected mother-infant pairs. Moreover, there was no difference in the magnitude of plasma flavivirus-specific IgG levels between mothers and infants regardless of ZIKV infection status. Our data suggests that maternal ZIKV infection during pregnancy does not impair the efficiency of placental transfer of flavivirus-specific, functional, and vaccine-elicited IgG. These findings have implications for the neonatal outomes of maternal ZIKV infection and optimal administration of antibody-based ZIKV vaccines and therapeutics. [ABSTRACT FROM AUTHOR]