The multifaceted role of chromosomal instability in cancer and its microenvironment

The major innate immune cell types involved in tuberculosis (TB) infection are macrophages, dendritic cells (DCs), neutrophils and natural killer (NK) cells. These immune cells recognize the TB-causing pathogen Mycobacterium tuberculosis (Mtb) through various pattern recognition receptors (PRRs), including but not limited to Toll-like receptors (TLRs), Nod-like receptors (NLRs) and C-type lectin receptors (CLRs). Upon infection by Mtb, the host orchestrates multiple signaling cascades via the PRRs to launch a variety of innate immune defense functions such as phagocytosis, autophagy, apoptosis and inflammasome activation. In contrast, Mtb utilizes numerous exquisite strategies to evade or circumvent host innate immunity. Here we discuss recent research on major host innate immune cells, PRR signaling, and the cellular functions involved in Mtb infection, with a specific focus on the host’s innate immune defense and Mtb immune evasion. A better understanding of the molecular mechanisms underlying host–pathogen interactions could provide a rational basis for the development of effective anti-TB therapeutics.

/pdf/innate-immunity-in-tuberculosis-host-defense-vs-pathogen-24fbve6gji.pdf

Innate immunity in tuberculosis: host defense vs pathogen evasion.

Granulomas are organized aggregates of macrophages, often with characteristic morphological changes, and other immune cells These evolutionarily ancient structures form in response to persistent particulate stimuli-infectious or noninfectious-that individual macrophages cannot eradicate Granulomas evolved as protective responses to destroy or sequester particles but are frequently pathological in the context of foreign bodies, infections, and inflammatory diseases We summarize recent findings that suggest that the granulomatous response unfolds in a stepwise program characterized by a series of macrophage activations and transformations that in turn recruit additional cells and produce structural changes We explore why different granulomas vary and the reasons that granulomas are protective and pathogenic Understanding the mechanisms and role of granuloma formation may uncover new therapies for the multitude of granulomatous diseases that constitute serious medical problems while enhancing the protective function of granulomas in infections

The Formation and Function of Granulomas.

Co-infection with Mycobacterium tuberculosis is the leading cause of death in individuals infected with HIV-1. It has long been known that HIV-1 infection alters the course of M. tuberculosis infection and substantially increases the risk of active tuberculosis (TB). It has also become clear that TB increases levels of HIV-1 replication, propagation and genetic diversity. Therefore, co-infection provides reciprocal advantages to both pathogens. In this Review, we describe the epidemiological associations between the two pathogens, selected interactions of each pathogen with the host and our current understanding of how they affect the pathogenesis of TB and HIV-1/AIDS in individuals with co-infections. We evaluate the mechanisms and consequences of HIV-1 depletion of T cells on immune responses to M. tuberculosis. We also discuss the effect of HIV-1 infection on the control of M. tuberculosis by macrophages through phagocytosis, autophagy and cell death, and we propose models by which dysregulated inflammatory responses drive the pathogenesis of TB and HIV-1/AIDS.

/pdf/pathogenesis-of-hiv-1-and-mycobacterium-tuberculosis-co-444to01uup.pdf

Pathogenesis of HIV-1 and Mycobacterium tuberculosis co-infection

Tumours with profound copy-number aberration elude molecular stratification due to their genomic complexity. By representing this complexity as a mixture of copy-number signatures, we provide molecular explanations for differing clinical outcomes. Here we present a method for copy-number signature identification, deriving eight signatures in 117 shallow whole-genome sequenced high-grade serous ovarian cancers (HGSOC), which validated on independent cohorts of 95 deep whole-genome sequenced, and 402 SNP array-profiled cases. Three copy-number signatures predicted longer overall survival, while the others predicted poorer outcome. We found evidence for the mutational processes giving rise to copy-number change for six of the eight signatures via correlations with other genomic features. Our results provide insights into the pathogenesis of HGSOC by uncovering multiple mutational processes that shape genomes following TP53 mutation. Importantly, our work shows that most HGSOC have a mixture of mutational processes suggesting that targeting a single mutator phenotype may be therapeutically suboptimal.

https://www.biorxiv.org/content/biorxiv/early/2017/09/04/174201.full.pdf

Copy-number signatures and mutational processes in ovarian carcinoma

DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas

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DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas