Macrophage activation and human immunodeficiency virus infection: HIV replication directs macrophages towards a pro-inflammatory phenotype while previous activation modulates macrophage susceptibility to infection and viral production

AbstractMacrophages are pivotal for the regulation of immune and inflammatory responses, but whether their role in HIV infection is protective or deleterious remains unclear. In this study, we investigated the effect of pro- and anti-inflammatory stimuli on macrophage sensitivity to two different aspects of HIV infection: their susceptibility to infection stricto sensu, which we measured by endpoint titration method, and their ability to support virus spread, which we measured by using an RT activity assay in infection kinetics. We show a partially protective role for pro-inflammatory agents as well as for IL-4. We also illustrate that various different stimuli display differential effects on macrophage susceptibility to HIV and on virus replication that occurs thereafter. On the other hand, HIV replication strongly repressed CD206 and CD163 expression, thus clearly orientating macrophages towards a pro-inflammatory phenotype, but independently of TNF. Taken together, our results emphasize that HIV infection of macrophages sets up inflammation at the cell level but through unexpected mechanisms. This may limit target susceptibility and participate in virus clearance but may also result in tissue damage

Combined CD4 T-Cell and Antibody Response to Human Minor Histocompatibility Antigen DBY After Allogeneic Stem-Cell Transplantation

Antibody responses to HY antigens in male recipients are frequent after transplantation of stem cells from female donors (Miklos et al., Blood 2005; 105: 2973; Miklos et al., Blood 2004; 103: 353). However, evidence that this B-cell immunity is accompanied by T-cell responses to the cognate antigens is scarce. Here, we examined T- and B-cell responses to DBY antigen in a male patient who received hematopoietic stem cells from a human leukocyte antigen-identical female sibling

Type I interferon-mediated autoinflammation due to DNase II deficiency

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans

Activations classiques et alternatives des macrophages et des cellules microgliales dans l'infection à VIH (implications pour l'inflammation et la neurotoxicité)

Les troubles neurologiques souvent observés au stade avancés du SIDA constituent une complication importante de la maladi et peuvent mener à lamort du patient. Les macrophages et la microglie sont les seules cellules capables de supporter une infection productive dans le cerveau. Ces cellules sont connues pour leurs propriétés neurotoxiques, via la production de médiateurs pro-inflammatoires et le relarguage de divers neurotoxines, parmi lesquelles le glutamate. Cependant, des études récentes suggèrent également des propriétés neuroprotectrices pour les macrophages et la microglie, qui expriment les transporteurs du glutamate et peuvent donc limiter sa concentration dans la fente synaptique. Dans cette étude, nous avons caractérisé les activations pro- et anti-inflammatoires des macrophages et étudiés leurs effets sur le comportement de ces cellules vis-à-vis de l'infection. Ensuite, les conséquences de l'environnement inflammatoire sur les propriétés neuroprotectrices des macrophages, via la détoxification du glutamate, ont été évaluées. Ce travail met en évidence les interrelations entre les macrophages, l'inflammation et le métabolisme du glutamate, ainsi que les conséquences sur le stress oydant généré lors de l'infection.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

LA PRATIQUE DE L'ELECTROCONVULSIVOTHERAPIE

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

GroEL (Hsp60) of Clostridium difficile is involved in cell adherence.

International audiencePrevious results have demonstrated that adherence of Clostridium difficile to tissue culture cells is augmented by various stresses; this study focussed on whether the GroEL heat shock protein is implicated in this process. The 1940 bp groESL operon of C. difficile was isolated by PCR. The 1623 bp groEL gene is highly conserved between various C. difficile isolates as determined by RFLP-PCR and DNA sequencing, and the operon is present in one copy on the bacterial chromosome. The 58 kDa GroEL protein was expressed in Escherichia coli in fusion with glutathione S:-transferase and the fusion protein was purified from IPTG-induced bacterial lysates by affinity chromatography on glutathione-Sepharose. A polyclonal, monospecific antiserum was obtained for GroEL which established by immunoelectron microscopy, indirect immunofluorescence and immunoblot analysis that GroEL is released extracellularly after heat shock and can be surface associated. Cell fractionation experiments suggest that GroEL is predominantly cytoplasmic and membrane bound. GroEL-specific antibodies as well as the purified protein partially inhibited C. difficile cell attachment and expression of the protein was induced by cell contact, suggesting a role for GroEL in cell adherence