Macrophage-specific responses to human -and animal- adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation

The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. The host and pathogen determinants underlying host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection, and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed blood-derived primary human and bovine macrophages (hMϕ or bMϕ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMϕ whereas both Mbv and Mtb efficiently replicate in bMϕ. Specifically, we show that out of the four infection combinations, only the infection of bMϕ with Mbv promoted the formation of multinucleated giant cells (MNGCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMϕ promote macrophage multinucleation. Importantly, we extended our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNGCs. Our findings implicate MNGC formation in the contrasting pathology between Mtb and Mbv for the bovine host and identify MPB70 from Mbv and extracellular vesicles from bMϕ as mediators of this process

A Rab20-dependent membrane trafficking pathway controls M. tuberculosis replication by regulating phagosome spaciousness and integrity

The intracellular pathogen Mycobacterium tuberculosis (Mtb) lives within phagosomes and also disrupts these organelles to access the cytosol. The host pathways and mechanisms that contribute to maintaining Mtb phagosome integrity have not been investigated. Here, we examined the spatiotemporal dynamics of Mtb-containing phagosomes and identified an interferon-gamma-stimulated and Rab20-dependent membrane trafficking pathway in macrophages that maintains Mtb in spacious proteolytic phagolysosomes. This pathway functions to promote endosomal membrane influx in infected macrophages, and is required to preserve Mtb phagosome integrity and control Mtb replication. Rab20 is specifically and significantly upregulated in the sputum of human patients with active tuberculosis. Altogether, we uncover an immune-regulated cellular pathway of defense that promotes maintenance of Mtb within intact membrane-bound compartments for efficient elimination

Short flashes and continuous light have similar photoinhibitory efficiency in intact leaves

Lincomycin-treated pumpkin leaves were illuminated with either continuous light or saturating single-turnover xenon flashes to study the dependence of photoinactivation of photosystem II (PSII) on the mode of delivery of light. The flash energy and the time interval between the flashes were varied between the experiments, and photoinactivation was measured with oxygen evolution and the ratio of variable to maximum fluorescence (Fv/Fm). The photoinhibitory efficiency of saturating xenon flashes was found to be directly proportional to flash energy and independent of the time interval between the flashes. These findings indicate that a low-light-specific mechanism, based on charge recombination between PSII electron acceptors and the oxygen-evolving complex, is not the main cause of photoinactivation caused by short flashes in vivo. Furthermore, the relationship between the rate constant of photoinactivation and photon flux density was similar for flashes and continuous light when Fv/Fm was used to quantify photoinactivation, suggesting that continuous-light photoinactivation has a mechanism in which the quantum yield does not depend on the mode of delivery of light. A similar quantum yield of photoinhibition for flashes and continuous light is compatible with the manganese-based photoinhibition mechanism and with mechanisms in which singlet oxygen, produced via a direct photosensitization reaction, is the agent of damage. However, the classical acceptor-side and donor-side mechanisms do not predict a similar quantum yield for flashes and continuous light

Structure-based design of MptpB inhibitors that reduce multi-drug-resistant mycobacterium tuberculosis survival and infection burden in vivo

Mycobacterium tuberculosis protein-tyrosine-phosphatase B (MptpB) is a secreted virulence factor that subverts antimicrobial activity in the host. We report here the structure-based design of selective MptpB inhibitors that reduce survival of multidrug-resistant tuberculosis strains in macrophages and enhance killing efficacy by first-line antibiotics. Monotherapy with an orally bioavailable MptpB inhibitor reduces infection burden in acute and chronic guinea pig models and improves the overall pathology. Our findings provide a new paradigm for tuberculosis treatmen

Nostrum, nostrum est Romanum Imperium : la presence de Rome dans l´exercice du pouvoir du Saint-Empire romain germanique

Schnettger Matthias. Nostrum, nostrum est Romanum Imperium. La présence de Rome dans l'exercice du pouvoir du Saint-Empire romain germanique. In: L'imperium Romanum en perspective. Les savoirs d'empire dans la République romaine et leur héritage dans l'Europe médiévale et moderne. Besançon : Institut des Sciences et Techniques de l'Antiquité, 2014. pp. 341-354. (Collection « ISTA », 1302