Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice.

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations are still not fully understood. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate that there is a correlation between ZIKV neurological complications with higher Gas6 levels and the downregulation of genes associated with anti-viral response, as type I IFN due to Socs1 upregulation. Also, Gas6 gamma-carboxylation is essential for ZIKV invasion and replication in monocytes, the main source of this protein, which was inhibited by warfarin. Conversely, Gas6 facilitates ZIKV replication in adult immunocompetent mice and enabled susceptibility to transplacental infection. Our data indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

Nontuberculous mycobacterial infections in a Brazilian pediatric population: a seven-year survey.

The aim of this study was to describe the frequency of nontuberculous mycobacteria (NTM) isolation and their related outcomes among pediatric patients of a Brazilian university hospital from 2012 to 2019. NTM were identified in different clinical samples by microbiological culture and molecular-based methods. NTM were isolated from 14 patients, out of whom four (27%) were infected and were treated accordingly. Two were infected with Mycobacterium avium complex (MAC), two with M. abscessus complex (MABSC) and one with M. intracellulare. Two patients had cystic fibrosis-related lung disease and improved after successful NTM eradication. One patient was HIV-positive and died. One patient had severe combined immunodeficiency (SCID)-related pneumonia and is currently being followed-up. We conclude that NTM frequency in our center was low among pediatric patients. Whether this is inherent to Brazilian patients, due to the broad coverage of the Bacille Calmette-Guérin (BCG) vaccine in Brazil, or a result of underdiagnosis remains to be elucidated.

Lymphocyte responses to Mycobacterium tuberculosis and Mycobacterium bovis are similar between BCG-vaccinated patients with cystic fibrosis and healthy controls.

BACKGROUND: The low rate of nontuberculous mycobacteria (NTM) among Brazilian patients with cystic fibrosis (CF) may be due to cross-reactive Bacille Calmette-Guérin (BCG) vaccination. In the present pilot study, we aimed to compare the lymphocyte responses against Mycobacterium tuberculosis(Mtb) and Mycobacterium bovis (BCG) in BCG-vaccinated CF patients and healthy controls. METHODS: The lymphocyte responses of CF patients (n = 10) and healthy controls (n = 10) were assessed in terms of lymphocyte proliferation index (LPI), using flow cytometry. Median rates of each cell subtype - CD4, CD8, γδ T cells and CD19 (B) cells - were also determined. RESULTS: Median LPIs (CF vs. controls) were 22.9% vs. 13.0% (p = 0.481) and 23.1% vs. 17.6% (p = 0.481), upon stimulation with Mtb and BCG, respectively. Both groups had a predominant CD4 T cell response to Mtb (median rate = 82.5% vs. 79.7%; p = 0.796) and BCG (LPI = 84.3% vs. 83.0%; p = 0.853), which were significantly higher than the CD8, CD19 and γδ responses within both groups. CF patients tended to have a higher CD8 T cell response upon stimulation with the phytohemagglutinin mitogen than healthy controls (median rate = 42.8% vs. 31.7%, p = 0.075). CONCLUSION: The responses of BCG-vaccinated CF patients to Mtb and BCG are at least similar to those of healthy individuals. These are probably memory responses elicited by the BCG vaccination, which can cross-react with NTM and may explain the low frequency of NTM lung infection in our CF center.

Antibody response against Pseudomonas aeruginosa and its relationship with immune mediators in the upper and lower airways of cystic fibrosis patients.

BACKGROUND: The upper airways (UAW) are a niche and a reservoir of Pseudomonas aeruginosa strains that cause chronic infection of the lower airways (LAW) in cystic fibrosis (CF). Here, we assessed the role of anti-P. aeruginosa immunoglobulin A (IgA) and IgG antibodies in upper and lower airway infections in cystic fibrosis patients. METHODS: Nasal lavage fluid and induced sputum samples of 40 CF patients were microbiologically cultured. We searched for correlations between anti-P. aeruginosa IgA and IgG levels, measured by enzyme-linked immunosorbent assay (optical density), and unspecific immune mediators in both specimens. RESULTS: Anti-P. aeruginosa IgA (median optical density: 0.953 vs 0.298) and IgG (0.120 vs 0.059) were significantly higher in nasal lavage than in sputum, but not significantly different between patients with and without chronic P. aeruginosa infection in UAW. Matrix metallopeptidase-9 (MMP-9) in nasal lavage and neutrophil elastase (NE) in sputum were predictors of IgA in nasal lavage and IgA in sputum, respectively. IgA was a predictor of myeloperoxidase (MPO) in nasal lavage. Tissue inhibitor of metalloproteinases-1 (TIMP-1) was a predictor of IgG in sputum. IgG, TIMP-1, and NE in sputum were predictors of IgG in nasal lavage. CONCLUSION: The anti-P. aeruginosa IgA response was more prominent in CF patients' UAW, indicating a lower degree of inflammatory responses. Proteases may play a role in the anti-P. aeruginosa humoral response in the upper and LAW, and anti-P. aeruginosa IgG may be involved in the crosstalk between upper and lower airways in cystic fibrosis patients.

Prevalence and clinical outcomes of nontuberculous mycobacteria in a Brazilian cystic fibrosis reference center.

Nontuberculous mycobacteria (NTM) have been well established as an opportunistic pathogenic bacterial group for cystic fibrosis (CF) patients, with a prevalence ranging from 3% to 23% worldwide. A myriad of factors can bias the prevalence rate in different CF centers, especially misdiagnosis as systematic screening for NTM are still lacking in a number of centers. Here, we evaluated the presence and clinical outcomes of NTM isolation in microbiological respiratory cultures from CF patients attending a Brazilian reference center after setting up a systematic diagnostic protocol. Of 117 patients with respiratory samples cultured for NTM research, we found seven patients (6%) with at least one positive result for NTM [four males (57.1%), median age = 21 years (9-58)]. These cases are reported one-by-one. Median FEV1 was 40%, all patients showed signs of lung deterioration, with a median number of pulmonary exacerbations of three per patient/year. However, the impact of NTM isolation remains unclear in our center as all patients were coinfected with other CF respiratory pathogens. Our NTM prevalence assimilates to the lowest levels reported in literature, which is possibly influenced by the routinely applied Bacille Calmette-Guérin vaccine.