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The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like ‘homing’ motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed αVβ3 integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (ΔΨm), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.Cell Death and Differentiation (2007) 14, 422–435. doi:10.1038/sj.cdd.4402018; published online 4 August 2006 [ABSTRACT FROM AUTHOR]

Three strains of mice (Swiss albinos, C57BL/6,C3H/OuJ) were injected intravenously with 3.7 x 106 colony forming units (CFU) of M. tuberculosis. H37RV, sensitive and resistant to antibiotics (90% of bacilli sensitive, 9% resistant lo Streptomycin and 0.9% resistant to Kanamycin). Two weeks later, chemotherapy was started 6 days a week for a 6-month period with isoniazid (INH) and rifampicin (RMP). Twenty mice of each strain were killed at the end of the chemotherapy and the others were kept without antibiotics for a second 6-month follow-up period before being killed. The early multiplication of bacilli during the first 2 weeks following infection and before chemotherapy, was similar in the three strains of mice. Chemotherapy had the same apparent efficacy in the three strains of mice, nearly all the mice being cured as assessed by a negative spleen culture on Lowenstein-Jensen medium at the end of chemotherapy. But after the 6-month follow-up period, the C3H strain presented a statistically significantly higher level of positive spleen culture ('relapse') than seen in the C57BL/6 strain, and an increased number of mycobacteria per relapsing mouse spleen. It has been estimated with the help of resistant and sensitive bacilli that the relapses were due in most of the cases to the regrowth of one or very few bacilli. giving a clone. It seems that the C3H strain of mice, known to carry the Bcg-r allele of the Beg gene, might be less able to develop a specific acquired resistance capable of stopping the delayed development of a highly virulent strain of mycobacteria. [ABSTRACT FROM AUTHOR]

Context: The spread of drug-resistant Streptococcus pneumoniae in the community is a public health problem in developed and developing nations, but whether antibiotic use is responsible for the increase in drug resistance is not known.Objective: To analyze the relationship between penicillin-resistant S pneumoniae (PRSp) pharyngeal carriage and characteristics of beta-lactam use.Design: Observational study of children attending 20 randomly sampled schools.Setting: The Loiret, in the center of France.Participants: A total of 941 children, 3 to 6 years old.Main Outcome Measure(s): Pharyngeal carriage of S pneumoniae, antibiotic use, and medical events during the preceding 30 days. Pneumococcal penicillin G sodium minimal inhibitory concentrations and serotyping were performed.Results: Medical illnesses and the use of antibiotics were not associated with PRSp carriage. However, oral beta-lactam use was associated with an increased risk of PRSp carriage (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.1-8.3; P=.03). Children treated by low daily doses of an oral beta-lactam (defined as lower than clinical recommendations) had an increased risk of PRSp carriage, as compared with children who did not (OR, 5.9; 95% CI, 2.1-16.7; P=.002). A treatment of long duration (>5 days) with a beta-lactam was associated with an increased risk of PRSp carriage (OR, 3.5; 95% CI, 1.3-9.8; P=.02).Conclusions: Our results suggest that a low daily dose and a long duration of treatment with an oral beta-lactam contribute to the selective pressure in promoting pharyngeal carriage of PRSp. [ABSTRACT FROM AUTHOR]

The resistance to Mycobacteriurn boils (BCG) of lines of mice selected for high (H) or low (L) antibody responsiveness was estimated from the rate of BCG multiplication in the organs. During the first 2 weeks after i.v. infection with 5 × 106 CFU. BCG multiplied faster in the spleens of H than of L mice. Afterwards there was a more drastic reduction of viable BCG counts in H mice than in L mice so that the residual BCG counts were significant N lower in H mice than in L mice, not only in the spleen but also in the liver and lungs. On the 14th day of infection, the spleen and liver enlargement and the increase of phagocytic activity were similar in the two lines. suggesting an identical T lymphokine release. In contrast with BCG. during the first 2 weeks after infection with 7 × 105 CFU, M. tuberculosis (H37Rv) multiplied in the spleens of L mice at a similar or a slightly faster rate than in the spleens of H mice. On the 4th week, the viable H37Rv counts were reduced in H mice whereas L mice did not survive the infection, in mice vaccinated with BCG 5 months before virulent challenge, the multiplication of H37Rv was inhibited in the H and L lines. The protective effect of BCG is therefore stronger in L mice taking into account their higher innate susceptibility to H37Rv. This might be due to the higher level of living BCG found in L mice at the time of challenge. [ABSTRACT FROM AUTHOR]

Dans la méthode prospective SYSPAHMM, élaborée à l’INRA, nous construisons des microscénarios du futur à partir d’une description fouillée de la situation d’état du système étudié. Pour cela nous commençons par considérer que l’environnement socio-économique et écologique du système étudié est stable. Or, nous savons que cela est faux. Pour remédier à ce problème et sur l’exemple des protéines végétales et animales, nous avons, à partir d’hypothèses sur les modes de gouvernance mondiale, construit des macroscénarios du monde qui se caractérisent par six ensemble de variables. Nous étudions alors leurs effets sur le devenir des microscénarios et réciproquement. De cette manière, il est possible, au bout de quelques années, de comprendre le sens d’évolution générale du système étudié et, en actualisant les hypothèses qui ont servi à construire les microscénarios, de réécrire, sans recommencer tout le travail de prospective, des microscénarios plus adaptés à leur environnement. Celui-ci est décrit par le macroscénario dont la situation mondiale s’est rapprochée. L’exemple des protéines permet d’illustrer la démarche.

Intracellular parasites have evolved intricate strategies to subvert host cell functions for their own survival. These strategies are particularly damaging to the host if the infection involves immune cells, as illustrated by protozoan parasites of the genus Leishmania that thrive inside mononuclear phagocytic cells, causing devastating immunopathologies. While the impact of Leishmania infection on host cell phenotype and functions has been well documented, the regulatory mechanisms underlying host cell subversion were only recently investigated. Here we summarize the current knowledge on how Leishmania infection affects host nuclear activities and propose thought-provoking new concepts on the reciprocal relationship between epigenetic and transcriptional regulation in host cell phenotypic plasticity, its potential subversion by the intracellular parasite, and its relevance for host-directed therapy., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Leishmania spp. are obligate intracellular parasites that infect phagocytes, notably macrophages. No information is available on how Leishmania parasites respond to pyroptosis of their host cell, which is known to limit microbial infection. Here, we analyzed the pyroptotic process and the fate of intracellular amastigotes at the single-cell level using high-content real-time imaging. Bone marrow-derived macrophages were infected with virulent Leishmania amazonensis amastigotes and sequentially treated with lipopolysaccharide and ATP to induce pyroptosis. Real-time monitoring identified distinct pyroptotic phases, including rapid decay of the parasitophorous vacuole (PV), progressive cell death and translocation of the luminal PV membrane to the cell surface in 40% of macrophages, resulting in the extracellular exposure of amastigotes that remained anchored to PV membranes. Electron microscopy analyses revealed an exclusive polarized orientation of parasites, with the anterior pole exposed toward the extracellular milieu, and the parasite posterior pole attached to the PV membrane. Exposed parasites retained their full infectivity towards naïve macrophages suggesting that host cell pyroptosis may contribute to parasite dissemination., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)