Streptococcus pneumoniae is a major cause of pneumonia in infants and the elderly. Innate defenses are essential to the control of pneumococcal infections, and deficient responses can trigger disease ...in susceptible individuals. Here we showed that flagellin can locally activate innate immunity and thereby increase the resistance to acute pneumonia. Flagellin mucosal treatment improved S. pneumoniae clearance in the lungs and promoted increased survival of infection. In addition, lung architecture was fully restored after the treatment of infected mice, indicating that flagellin allows the reestablishment of steady-state conditions. Using a flagellin mutant that is unable to signal through Toll-like receptor 5 (TLR5), we established that TLR5 signaling is essential for protection. In the respiratory tract, flagellin induced neutrophil infiltration into airways and upregulated the expression of genes coding for interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), CXCL1, CXCL2, and CCL20. Using depleting antibodies, we demonstrated that neutrophils are major effectors of protection. Further, we found that B- and T-cell-deficient SCID mice clear S. pneumoniae challenge to the same extent as immunocompetent animals, suggesting that these cell populations are not required for flagellin-induced protection. In conclusion, this study emphasizes that mucosal stimulation of innate immunity by a TLR not naturally engaged by S. pneumoniae can increase the potential to cure pneumococcal pneumonia.
Current Perspectives on Gastric Cancer Marqués-Lespier, Juan M; González-Pons, María; Cruz-Correa, Marcia
Gastroenterology clinics of North America,
09/2016, Letnik:
45, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Gastric cancer (GC) is third leading cause of cancer-related death. Only 28.3% of new GC cases survive more than 5 years. Although incidence has declined in the United States, an increase is ...estimated for 2016. Risk factors include sex (risk is higher in men), Helicobacter pylori infection, heredity, and lifestyle. GC is usually diagnosed between the ages of 60-80 years. Prognosis of GC is largely dependent on the tumor stage at diagnosis and classification as intestinal or diffuse type; diffuse-type GC has worse prognosis. Chemoprevention has been shown to decrease risk, but is currently not used clinically.
Summary
Despite the efficacy of current immune‐chemotherapy for treatment of B‐cell non‐Hodgkin lymphoma, a substantial proportion of patients relapse, highlighting the need for new therapeutic ...modalities. The use of live microorganisms to develop anti‐tumoural therapies has evolved since Coley's toxin and is now receiving renewed attention. Salmonella Typhimurium has been shown to be highly effective as an anti‐tumour agent in many solid cancer models, but it has not been used in haemato‐oncology. Here, we report that intra‐tumoural administration of LVR01 (attenuated S. Typhimurium strain with safety profile) elicits local and systemic anti‐tumour immunity, resulting in extended survival in a lymphoma model. LVR01 induces intra‐tumoural recruitment of neutrophils and activated CD8+ T cells, as well as increasing the natural killer cell activation status. Furthermore, a systemic specific anti‐tumour response with a clear T helper type 1 profile was observed. This approach is an alternative therapeutic strategy for lymphoma patients that could be easily moved into clinical trials.
A series of experiments on stratified Taylor–Couette flow in short aspect ratio wide-gap annuli found an intriguing and not-well-understood dynamics: nonlinear coherent structures appearing and ...disappearing periodically, along with density layering reminiscent of staircase profiles. A detailed numerical study is presented of the nonlinear dynamics near onset of instability in this setting, which explains most of the characteristics found in the experiments. The simulations show that centrifugal instability of the boundary layer on the inner rotating cylinder produces jets of angular momentum forming Taylor cells that are compressed axially due to the strong stratification. These cells are not axisymmetric from the onset, but are in fact two sets of Taylor cells displaced axially that meet in localized azimuthal defect regions where the cells are patched together; the whole structure is a rotating wave with azimuthal wavenumber $m=1$. The presence of endwalls in this short aspect ratio annulus is critical for the understanding of the dynamics. Their impact cannot be accounted for in idealized axially periodic models. Another key ingredient is the role played by the symmetries of the system. Although the axial reflection symmetry is weakly broken by centrifugal buoyancy effects, following instability there are various branches of solutions corresponding to the different ways the system's symmetries may be broken.
Abstract Acute pneumonia caused by Streptococcus pneumoniae is a major cause of child mortality. Antibodies are considered the main effectors of protection in this clinical presentation of ...pneumococcal invasive disease. To get new insights into the mechanisms involved in the protective immunity, we established a murine experimental model of protection against acute pneumococcal pneumonia and then evaluated the transcriptional, humoral and cellular responses in protected and non-protected animals. We found that intranasal inoculation of a sublethal dose of S. pneumoniae serotype 1 conferred complete protection against a subsequent challenge with a lethal dose of the same strain. Sublethal infection elicited a strong IgM and IgG antibody response against the capsular polysaccharide, as assessed one week later, and an exacerbated influx of neutrophils into the lungs immediately after the lethal challenge. Genome-wide microarray-based transcriptional analysis of whole lungs showed 149 differentially expressed genes among which we found upregulation of Il17a , Ifng and several IL-17A- and IFN-γ-related genes in protected versus non-protected mice. Kinetics analysis showed higher expression levels of Il17a in protected animals at all time points whereas Ifng was upregulated early in the protected mice and later in the non-protected animals. Intracelluar cytokine staining demonstrated that CD4+ T cells account for a great proportion of the IL-17A produced in the lungs of protected animals. Overall, these results showed that an upregulation of IL-17A- and a timely regulation of IFN-γ-related gene expression, together with development of a Th17 response, are relevant characteristics of the protective immunity against S. pneumoniae acute pneumonia.
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