Natural History of Tuberculosis: Duration and Fatality of Untreated Pulmonary Tuberculosis in HIV Negative Patients: A Systematic Review

Background The prognosis, specifically the case fatality and duration, of untreated tuberculosis is important as many patients are not correctly diagnosed and therefore receive inadequate or no treatment. Furthermore, duration and case fatality of tuberculosis are key parameters in interpreting epidemiological data. Methodology and Principal Findings To estimate the duration and case fatality of untreated pulmonary tuberculosis in HIV negative patients we reviewed studies from the pre-chemotherapy era. Untreated smear-positive tuberculosis among HIV negative individuals has a 10-year case fatality variously reported between 53% and 86%, with a weighted mean of 70%. Ten-year case fatality of culture-positive smear-negative tuberculosis was nowhere reported directly but can be indirectly estimated to be approximately 20%. The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be similar for smear-positive and smear-negative tuberculosis. Conclusions Current models of untreated tuberculosis that assume a total duration of 2 years until self-cure or death underestimate the duration of disease by about one year, but their case fatality estimates of 70% for smear-positive and 20% for culture-positive smear-negative tuberculosis appear to be satisfactory

Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria

Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20–40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection. In addition, acquisition of cholesterol was identified across the bacterial species. This detailed reference dataset has been established as an open resource to support discovery and translational research

Human Plasminogen Exacerbates Clostridioides difficile Enteric Disease and Alters the Spore Surface

Background & Aims: The protease plasmin is an important wound healing factor, but it is not clear how it affects gastrointestinal infection–mediated damage, such as that resulting from Clostridioides difficile. We investigated the role of plasmin in C difficile–associated disease. This bacterium produces a spore form that is required for infection, so we also investigated the effects of plasmin on spores. Methods: C57BL/6J mice expressing the precursor to plasmin, the zymogen human plasminogen (hPLG), or infused with hPLG were infected with C difficile, and disease progression was monitored. Gut tissues were collected, and cytokine production and tissue damage were analyzed by using proteomic and cytokine arrays. Antibodies that inhibit either hPLG activation or plasmin activity were developed and structurally characterized, and their effects were tested in mice. Spores were isolated from infected patients or mice and visualized using super-resolution microscopy; the functional consequences of hPLG binding to spores were determined. Results: hPLG localized to the toxin-damaged gut, resulting in immune dysregulation with an increased abundance of cytokines (such as interleukin [IL] 1A, IL1B, IL3, IL10, IL12B, MCP1, MP1A, MP1B, GCSF, GMCSF, KC, TIMP-1), tissue degradation, and reduced survival. Administration of antibodies that inhibit plasminogen activation reduced disease severity in mice. C difficile spores bound specifically to hPLG and active plasmin degraded their surface, facilitating rapid germination. Conclusions: We found that hPLG is recruited to the damaged gut, exacerbating C difficile disease in mice. hPLG binds to C difficile spores, and, upon activation to plasmin, remodels the spore surface, facilitating rapid spore germination. Inhibitors of plasminogen activation might be developed for treatment of C difficile or other infection-mediated gastrointestinal diseases.Full Tex

Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining

Chromosome missegregation into a micronucleus can cause complex and localized genomic rearrangements known as chromothripsis, but the underlying mechanisms remain unresolved. Here we developed an inducible Y centromere-selective inactivation strategy by exploiting a CENP-A/histone H3 chimaera to directly examine the fate of missegregated chromosomes in otherwise diploid human cells. Using this approach, we identified a temporal cascade of events that are initiated following centromere inactivation involving chromosome missegregation, fragmentation, and re-ligation that span three consecutive cell cycles. Following centromere inactivation, a micronucleus harbouring the Y chromosome is formed in the first cell cycle. Chromosome shattering, producing up to 53 dispersed fragments from a single chromosome, is triggered by premature micronuclear condensation prior to or during mitotic entry of the second cycle. Lastly, canonical non-homologous end joining (NHEJ), but not homology-dependent repair, is shown to facilitate re-ligation of chromosomal fragments in the third cycle. Thus, initial errors in cell division can provoke further genomic instability through fragmentation of micronuclear DNAs coupled to NHEJ-mediated reassembly in the subsequent interphase.National Institutes of Health (U.S.) (Grant HG007852