Molecular determinants of multidrug-resistant tuberculosis in Sierra Leone.

Unlabelled: Multidrug-resistant tuberculosis (MDR-TB) management has become a serious global health challenge. Understanding its epidemic determinants on the regional level is crucial for developing effective control measures. We used whole genome sequencing data of 238 of complex (MTBC) strains to determine drug resistance profiles, phylogeny, and transmission dynamics of MDR/rifampicin-resistant (RR) MTBC strains from Sierra Leone.

Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo.

Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils.

Survival of hypoxia-induced dormancy is not a common feature of all strains of the Mycobacterium tuberculosis complex.

While persistence in a dormant state is crucial for the life cycle of Mycobacterium tuberculosis, no investigation regarding dormancy survival of different strains across different lineages was performed so far. We analyzed responses to oxygen starvation and recovery in terms of growth, metabolism, and transcription. All different strains belonging to the Euro-American lineage (L4) showed similar survival and resuscitation characteristics.

Strategies to Improve Vaccine Efficacy against Tuberculosis by Targeting Innate Immunity.

The global tuberculosis epidemic is the most common cause of death after infectious disease worldwide. Increasing numbers of infections with multi- and extensively drug-resistant variants of the complex, resistant even to newly discovered and last resort antibiotics, highlight the urgent need for an efficient vaccine. The protective efficacy to pulmonary tuberculosis in adults of the only currently available vaccine, BCG, is unsatisfactory and geographically diverse.

Targeting neutrophils for host-directed therapy to treat tuberculosis.

M. tuberculosis is one of the prime killers from infectious diseases worldwide. Infections with multidrug-resistant variants counting for almost half a million new cases per year are steadily on the rise.

M. tuberculosis-Induced Necrosis of Infected Neutrophils Promotes Bacterial Growth Following Phagocytosis by Macrophages.

Neutrophils represent the main infected cell population in the lungs of active tuberculosis patients. Efficient removal of infected and dying neutrophils is required to protect the surrounding tissue from bioactive neutrophil molecules and subsequent pathological sequelae. While the removal of apoptotic M.

Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis.

Background: Axonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis. Here, we assessed the amount of Wallerian degeneration in brain tissue of multiple sclerosis patients in relation to demyelinating lesion activity and asked whether a transient blockade of Wallerian degeneration decreases axonal loss and clinical disability in a mouse model of inflammatory demyelination.

Methods: Wallerian degeneration and acute axonal damage were determined immunohistochemically in the periplaque white matter of multiple sclerosis patients with early actively demyelinating lesions, chronic active lesions, and inactive lesions.

Neutrophils in tuberculosis--first line of defence or booster of disease and targets for host-directed therapy?

Necrotizing granulomas, exacerbating pathogenesis and neutrophil influx at the site of infection are hallmarks of active pulmonary tuberculosis (TB) in humans. The role of polymorphonuclear neutrophils (PMN) in host defence and TB pathogenesis has recently attracted broader interest. Association of infiltrating PMN, enhanced mycobacterial load and disease exacerbation in both, mice susceptible to experimental TB as well as in TB patients, link PMN to exacerbated pathology.

Infection of human neutrophils to study virulence properties of Mycobacterium tuberculosis.

Polymorphonuclear neutrophils (PMN) are professional phagocytes and the first line of defense against invading microbes. Upon infection with Mycobacterium tuberculosis, PMN are attracted to the site of infection along an interleukin 8 gradient. In patients with active tuberculosis, PMN comprise the predominant population in the lung and carry the main mycobacterial load suggesting a minor role for PMN in protective host defense against M.

Immunomagnetic isolation of pathogen-containing phagosomes and apoptotic blebs from primary phagocytes.

Macrophages and polymorphonuclear neutrophils are professional phagocytes essential in the initial host response against intracellular pathogens such as Mycobacterium tuberculosis. Phagocytosis is the first step in phagocyte-pathogen interaction, where the pathogen is engulfed into a membrane-enclosed compartment termed a phagosome. Subsequent effector functions of phagocytes result in killing and degradation of the pathogen by promoting phagosome maturation, and, terminally, phago-lysosome fusion.

Assessment of lesion pathology in a new animal model of MS by multiparametric MRI and DTI.

Magnetic resonance imaging (MRI) is the gold standard for the detection of multiple sclerosis (MS) lesions. However, current MRI techniques provide little information about the structural features of a brain lesion with inflammatory cell infiltration, demyelination, gliosis, acute axonal damage and axonal loss. To identify methods for a differentiation of demyelination, inflammation, and axonal damage we developed a novel mouse model combining cuprizone-induced demyelination and experimental autoimmune encephalomyelitis.

Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis.

Axonal loss is a major component of the pathology of multiple sclerosis (MS) and the morphological basis of permanent clinical disability. It occurs in demyelinating plaques but also in the so-called normal-appearing white matter (NAWM). However, the contribution of Wallerian degeneration to axonal pathology is not known.