Macrophages in tuberculosis: friend or foe Guirado, Evelyn; Schlesinger, Larry S.; Kaplan, Gilla
Seminars in immunopathology,
09/2013, Letnik:
35, Številka:
5
Journal Article
Recenzirano
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Tuberculosis (TB) remains one of the greatest threats to human health. The causative bacterium,
Mycobacterium tuberculosis
(Mtb), is acquired by the respiratory route. It is exquisitely human adapted ...and a prototypic intracellular pathogen of macrophages, with alveolar macrophages (AMs) being the primary conduit of infection and disease. The outcome of primary infection is most often a latently infected healthy human host, in whom the bacteria are held in check by the host immune response. Such individuals can develop active TB later in life with impairment in the immune system. In contrast, in a minority of infected individuals, the host immune response fails to control the growth of bacilli, and progressive granulomatous disease develops, facilitating spread of the bacilli via infectious aerosols coughed out into the environment and inhaled by new hosts. The molecular details of the Mtb–macrophage interaction continue to be elucidated. However, it is clear that a number of complex processes are involved at the different stages of infection that may benefit either the bacterium or the host. Macrophages demonstrate tremendous phenotypic heterogeneity and functional plasticity which, depending on the site and stage of infection, facilitate the diverse outcomes. Moreover, host responses vary depending on the specific characteristics of the infecting Mtb strain. In this chapter, we describe a contemporary view of the behavior of AMs and their interaction with various Mtb strains in generating unique immunologic lung-specific responses.
Macrophages are a first line of defense against pathogens. However, certain invading microbes modify macrophage responses to promote their own survival and growth. Mycobacterium tuberculosis (M.tb) ...is a human-adapted intracellular pathogen that exploits macrophages as an intracellular niche. It was previously reported that M.tb rapidly activates cAMP Response Element Binding Protein (CREB), a transcription factor that regulates diverse cellular responses in macrophages. However, the mechanism(s) underlying CREB activation and its downstream roles in human macrophage responses to M.tb are largely unknown. Herein we determined that M.tb-induced CREB activation is dependent on signaling through MAPK p38 in human monocyte-derived macrophages (MDMs). Using a CREB-specific inhibitor, we determined that M.tb-induced CREB activation leads to expression of immediate early genes including COX2, MCL-1, CCL8 and c-FOS, as well as inhibition of NF-kB p65 nuclear localization. These early CREB-mediated signaling events predicted that CREB inhibition would lead to enhanced macrophage control of M.tb growth, which we observed over days in culture. CREB inhibition also led to phosphorylation of RIPK3 and MLKL, hallmarks of necroptosis. However, this was unaccompanied by cell death at the time points tested. Instead, bacterial control corresponded with increased colocalization of M.tb with the late endosome/lysosome marker LAMP-1. Increased phagolysosomal fusion detected during CREB inhibition was dependent on RIPK3-induced pMLKL, indicating that M.tb-induced CREB signaling limits phagolysosomal fusion through inhibition of the necroptotic signaling pathway. Altogether, our data show that M.tb induces CREB activation in human macrophages early post-infection to create an environment conducive to bacterial growth. Targeting certain aspects of the CREB-induced signaling pathway may represent an innovative approach for development of host-directed therapeutics to combat TB.
Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human ...angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.
Alveolar macrophages play a large role in the innate immune response of the lung. However, when these highly immune-regulatory cells are unable to eradicate pathogens, the adaptive immune system, ...which includes activated macrophages and lymphocytes, particularly T cells, is called upon to control the pathogens. This collection of immune cells surrounds, isolates and quarantines the pathogen, forming a small tissue structure called a granuloma for intracellular pathogens like Mycobacterium tuberculosis (Mtb). In the present work we develop a mathematical model of the dynamics of a granuloma by a system of partial differential equations. The 'strength' of the adaptive immune response to infection in the lung is represented by a parameter α, the flux rate by which T cells and M1 macrophages that immigrated from the lymph nodes enter into the granuloma through its boundary. The parameter α is negatively correlated with the 'switching time', namely, the time it takes for the number of M1 type macrophages to surpass the number of infected, M2 type alveolar macrophages. Simulations of the model show that as α increases the radius of the granuloma and bacterial load in the granuloma both decrease. The model is used to determine the efficacy of potential host-directed therapies in terms of the parameter α, suggesting that, with fixed dosing level, an infected individual with a stronger immune response will receive greater benefits in terms of reducing the bacterial load.
Granulomas are the hallmark of Mycobacterium tuberculosis (M.tb) infection and thus sit at the center of tuberculosis (TB) immunopathogenesis. TB can result from either early progression of a primary ...granuloma during the infection process or reactivation of an established granuloma in a latently infected person. Granulomas are compact, organized aggregates of immune cells consisting of blood-derived infected and uninfected macrophages, foamy macrophages, epithelioid cells (uniquely differentiated macrophages), and multinucleated giant cells (Langerhans cells) surrounded by a ring of lymphocytes. The granuloma's main function is to localize and contain M.tb while concentrating the immune response to a limited area. However, complete eradication does not occur since M.tb has its own strategies to persist within the granuloma and to reactivate and escape under certain conditions. Thus M.tb-containing granulomas represent a unique battlefield for dictating both the host immune and bacterial response. The architecture, composition, function, and maintenance of granulomas are key aspects to study since they are expected to have a profound influence on M.tb physiology in this niche. Granulomas are not only present in mycobacterial infections; they can be found in many other infectious and non-infectious diseases and play a crucial role in immunity and disease. Here we review the models currently available to study the granulomatous response to M.tb.
The impact of cellular apoptosis in controlling M. tuberculosis during tuberculosis (TB) infection remains unresolved. In this issue of Immunity, Stutz et al. provide compelling evidence that ...apoptosis controls M. tuberculosis infection in vivo and compounds that induce apoptosis limit M. tuberculosis growth in mice.
The impact of cellular apoptosis in controlling M. tuberculosis during tuberculosis (TB) infection remains unresolved. In this issue of Immunity, Stutz et al. provide compelling evidence that apoptosis controls M. tuberculosis infection in vivo and compounds that induce apoptosis limit M. tuberculosis growth in mice.
Lungs are directly exposed to the air, have enormous surface area, and enable gas exchange in air-breathing animals. They are constantly ‘attacked’ by microbes from both outside and inside and thus ...possess a unique, highly regulated local immune defense system which efficiently allows for microbial clearance while minimizing damaging inflammatory responses. As a prototypic host-adapted airborne pathogen, Mycobacterium tuberculosis traverses the lung and has several ‘interaction points’ (IPs) which it must overcome to cause infection. These interactions are critical, not only from a pathogenesis perspective but also in considering the effectiveness of therapies and vaccines in the lungs. Here we discuss emerging views on immunologic interactions occurring in the lungs for M. tuberculosis and their impact on infection and persistence.
Nuclear receptors (NRs) are ligand-activated transcription factors that are expressed in a variety of cells, including macrophages. For decades, NRs have been therapeutic targets because their ...activity can be pharmacologically modulated by specific ligands and small molecule inhibitors. NRs regulate a variety of processes, including those intersecting metabolic and immune functions, and have been studied in regard to various autoimmune diseases. However, the complex roles of NRs in host response to infection are only recently being investigated. The NRs peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptors (LXRs) have been most studied in the context of infectious diseases; however, recent work has also linked xenobiotic pregnane X receptors (PXRs), vitamin D receptor (VDR), REV-ERBα, the nuclear receptor 4A (NR4A) family, farnesoid X receptors (FXRs), and estrogen-related receptors (ERRs) to macrophage responses to pathogens. Pharmacological inhibition or antagonism of certain NRs can greatly influence overall disease outcome, and NRs that are protective against some diseases can lead to susceptibility to others. Targeting NRs as a novel host-directed treatment approach to infectious diseases appears to be a viable option, considering that these transcription factors play a pivotal role in macrophage lipid metabolism, cholesterol efflux, inflammatory responses, apoptosis, and production of antimicrobial byproducts. In the current review, we discuss recent findings concerning the role of NRs in infectious diseases with an emphasis on PPARγ and LXR, the two most studied. We also highlight newer work on the activity of emerging NRs during infection.
Highlights • The current rise in diabetes mellitus (DM) worldwide has led to the re-emerging importance of DM to tuberculosis control. • We review the impact of type 2 DM on every stage of the ...natural history of TB. • We postulate mechanisms by which DM increases the risk of TB development or its more adverse treatment outcomes. • Dysfunctional immunity in the poorly controlled DM patient is the best-characterized underlying factor for promoting TB.
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