-
Nature Jan 2011Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway... (Review)
Review
Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy - the 'autophagy proteins' - orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.
Topics: Animals; Autophagy; Cell Membrane; Humans; Immunity; Immunity, Innate; Infections; Inflammation; Phagosomes
PubMed: 21248839
DOI: 10.1038/nature09782 -
Current Biology : CB Feb 2023Cutting up food into small pieces is well known to improve digestion. New work now shows that this concept also applies in the cellular world, by demonstrating that...
Cutting up food into small pieces is well known to improve digestion. New work now shows that this concept also applies in the cellular world, by demonstrating that phagolysosome vesiculation promotes cell corpse degradation in Caenorhabditis elegans blastomeres.
Topics: Animals; Phagocytosis; Phagosomes; Blastomeres; Cadaver; Caenorhabditis elegans
PubMed: 36854271
DOI: 10.1016/j.cub.2023.01.017 -
Frontiers in Immunology 2023Bacterial infections still impose a significant burden on humanity, even though antimicrobial agents have long since been developed. In addition to individual severe... (Review)
Review
Bacterial infections still impose a significant burden on humanity, even though antimicrobial agents have long since been developed. In addition to individual severe infections, the f fatality rate of sepsis remains high, and the threat of antimicrobial-resistant bacteria grows with time, putting us at inferiority. Although tremendous resources have been devoted to the development of antimicrobial agents, we have yet to recover from the lost ground we have been driven into. Looking back at the evolution of treatment for cancer, which, like infectious diseases, has the similarity that host immunity eliminates the lesion, the development of drugs to eliminate the tumor itself has shifted from a single-minded focus on drug development to the establishment of a treatment strategy in which the de-suppression of host immunity is another pillar of treatment. In infectious diseases, on the other hand, the development of therapies that strengthen and support the immune system has only just begun. Among innate immunity, the first line of defense that bacteria encounter after invading the host, the molecular mechanisms of the phagolysosome pathway, which begins with phagocytosis to fusion with lysosome, have been elucidated in detail. Bacteria have a large number of strategies to escape and survive the pathway. Although the full picture is still unfathomable, the molecular mechanisms have been elucidated for some of them, providing sufficient clues for intervention. In this article, we review the host defense mechanisms and bacterial evasion mechanisms and discuss the possibility of host-directed therapy for bacterial infection by intervening in the phagolysosome pathway.
Topics: Humans; Bacterial Infections; Immunity, Innate; Anti-Infective Agents; Bacteria; Phagosomes; Communicable Diseases
PubMed: 37841276
DOI: 10.3389/fimmu.2023.1227467 -
International Journal of Molecular... Jan 2019Epidemiological data from the Center of Disease Control (CDC) and the World Health Organization (WHO) statistics in 2017 show that 10.0 million people around the world... (Review)
Review
Epidemiological data from the Center of Disease Control (CDC) and the World Health Organization (WHO) statistics in 2017 show that 10.0 million people around the world became sick with tuberculosis. (MTB) is an intracellular parasite that mainly attacks macrophages and inhibits their apoptosis. It can become a long-term infection in humans, causing a series of pathological changes and clinical manifestations. In this review, we summarize innate immunity including the inhibition of antioxidants, the maturation and acidification of phagolysosomes and especially the apoptosis and autophagy of macrophages. Besides, we also elaborate on the adaptive immune response and the formation of granulomas. A thorough understanding of these escape mechanisms is of major importance for the prevention, diagnosis and treatment of tuberculosis.
Topics: Animals; Apoptosis; Autophagy; Humans; Immune Evasion; Mycobacterium tuberculosis; Oxidative Stress; Phagosomes
PubMed: 30650615
DOI: 10.3390/ijms20020340 -
Immunological Reviews Mar 2015Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they... (Review)
Review
Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti-microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti-microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well-adapted facultative intracellular bacterium, has learned during evolution to counter-balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host-pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi-resistance of M. tuberculosis against conventional antibiotics.
Topics: Animals; Cell Communication; Host-Pathogen Interactions; Humans; Immunity, Innate; Lysosomes; Macrophage Activation; Macrophages; Metals; Mycobacterium tuberculosis; Phagocytes; Phagocytosis; Phagosomes; Tuberculosis
PubMed: 25703560
DOI: 10.1111/imr.12266 -
Biochemical Society Symposium 2007Interconversions of phosphoinositides play a pivotal role during phagocytosis and at the subsequent stages of phagosomal maturation into the phagolysosome. Several model... (Review)
Review
Interconversions of phosphoinositides play a pivotal role during phagocytosis and at the subsequent stages of phagosomal maturation into the phagolysosome. Several model systems have been used to study the role of phosphoinositides in phagosomal membrane remodelling. These include phagosomes formed by inanimate objects such as latex beads, or pathogenic bacteria, e.g. Mycobacterium tuberculosis. The latter category provides naturally occurring tools to dissect membrane trafficking processes governing phagolysosome biogenesis. M. tuberculosis persists in infected macrophages by blocking Rab conversion and affecting Rab effectors. One of the major Rab effectors involved in this process is the type III phosphatidylinositol 3-kinase hVPS34. The lipid kinase hVPS34 and its enzymatic product PtdIns3P are critical for the default pathway of phagosomal maturation into phagolysosomes. Mycobacteria block PtdIns3P production and thus arrest phagosomal maturation. PtdIns3P is also critical for the process of autophagy, recently recognized as an effector of innate immunity defenses. Induction of autophagy by pharmacological, physiological, or immunological means, overcomes mycobacterial phagosome maturation block in a PtdIns3P generation dependent manner and eliminates intracellular M. tuberculosis. PtdIns3P and PtdIns3P-dependent processes represent an important cellular nexus where fundamental trafficking processes, disease causing host-pathogen interactions, and innate and adaptive immunity defense mechanisms meet.
Topics: Animals; Autophagy; Humans; Models, Biological; Mycobacterium tuberculosis; Phagocytosis; Phagosomes; Phosphatidylinositol Phosphates; Phosphatidylinositols
PubMed: 17233587
DOI: 10.1042/BSS0740141 -
Trends in Parasitology Aug 2007Leishmania amastigotes primarily proliferate within macrophages in the mammalian host. Genome-based metabolic reconstructions, combined with biochemical, reverse genetic... (Review)
Review
Leishmania amastigotes primarily proliferate within macrophages in the mammalian host. Genome-based metabolic reconstructions, combined with biochemical, reverse genetic and mRNA or protein profiling studies are providing new insights into the metabolism of this intracellular stage. We propose that the complex nutritional requirements of amastigotes have contributed to the tropism of these parasites for the amino acid-rich phagolysosome of macrophages. Amastigote metabolism in this compartment is robust because many metabolic mutants are capable of either growing normally or persisting long term in susceptible animals. New approaches for measuring amastigote metabolism in vivo are discussed.
Topics: Animals; Biological Transport; Cell Division; Gene Expression; Gene Expression Profiling; Host-Parasite Interactions; Humans; Leishmania; Macrophages; Membrane Transport Proteins; Phagosomes
PubMed: 17606406
DOI: 10.1016/j.pt.2007.06.009 -
Nature Cell Biology Oct 2019Phosphoinositides have a pivotal role in the maturation of nascent phagosomes into microbicidal phagolysosomes. Following degradation of their contents, mature...
Phosphoinositides have a pivotal role in the maturation of nascent phagosomes into microbicidal phagolysosomes. Following degradation of their contents, mature phagolysosomes undergo resolution, a process that remains largely uninvestigated. Here we studied the role of phosphoinositides in phagolysosome resolution. Phosphatidylinositol-4-phosphate (PtdIns(4)P), which is abundant in maturing phagolysosomes, was depleted as they tubulated and resorbed. Depletion was caused, in part, by transfer of phagolysosomal PtdIns(4)P to the endoplasmic reticulum, a process mediated by oxysterol-binding protein-related protein 1L (ORP1L), a RAB7 effector. ORP1L formed discrete tethers between the phagolysosome and the endoplasmic reticulum, resulting in distinct regions with alternating PtdIns(4)P depletion and enrichment. Tubules emerged from PtdIns(4)P-rich regions, where ADP-ribosylation factor-like protein 8B (ARL8B) and SifA- and kinesin-interacting protein/pleckstrin homology domain-containing family M member 2 (SKIP/PLEKHM2) accumulated. SKIP binds preferentially to monophosphorylated phosphoinositides, of which PtdIns(4)P is most abundant in phagolysosomes, contributing to their tubulation. Accordingly, premature hydrolysis of PtdIns(4)P impaired SKIP recruitment and phagosome resolution. Thus, resolution involves phosphoinositides and tethering of phagolysosomes to the endoplasmic reticulum.
Topics: ADP-Ribosylation Factors; Animals; CRISPR-Cas Systems; Endoplasmic Reticulum; Gene Editing; Gene Expression Regulation; Humans; Mice; Monocytes; Phagocytosis; Phagosomes; Phosphatidylinositol Phosphates; Primary Cell Culture; Proteolysis; RAW 264.7 Cells; RNA, Small Interfering; Receptors, Steroid; Signal Transduction; Vesicular Transport Proteins; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins
PubMed: 31570833
DOI: 10.1038/s41556-019-0394-2 -
Immunity Aug 2023STING (stimulator of interferon genes) exerts protective cellular responses to viral infection via induction of interferon production and autophagy. Here, we report the...
STING (stimulator of interferon genes) exerts protective cellular responses to viral infection via induction of interferon production and autophagy. Here, we report the role of STING in modulating the immune responses toward fungal infection. Upon Candida albicans stimulation, STING transited alongside the endoplasmic reticulum (ER) to the phagosomes. In phagosomes, STING directly bound with Src via the N-terminal 18 amino acids of STING, and this binding prevented Src from recruiting and phosphorylating Syk. Consistently, Syk-associated signaling and production of pro-inflammatory cytokines and chemokines were increased in mouse BMDCs (bone-marrow-derived dendritic cells) lacking STING with fungal treatment. STING deficiency improved anti-fungal immunity in systemic C. albicans infection. Importantly, administration of the N-terminal 18-aa (amino acid) peptide of STING improved host outcomes in disseminated fungal infection. Overall, our study identifies a previously unrecognized function of STING in negatively regulating anti-fungal immune responses and offers a potential therapeutic strategy for controlling C. albicans infection.
Topics: Animals; Mice; Cytokines; Immunity, Innate; Interferons; Nucleotides; Phagosomes; Signal Transduction
PubMed: 37379835
DOI: 10.1016/j.immuni.2023.06.002 -
Critical Reviews in Microbiology 1997Survival or destruction of intramacrophage pathogen Leishmania depends in part on modulation of their host cell phagosome, capabilities of the infected macrophages to... (Review)
Review
Survival or destruction of intramacrophage pathogen Leishmania depends in part on modulation of their host cell phagosome, capabilities of the infected macrophages to present parasite antigen to the host's immune system. Macrophages house these parasites as amastigotes in the acidic phagolysosomal compartment. Leishmania phagolysosome is the potential site for processing and presentation of its antigen as well as being the target site for chemotherapy in leishmaniasis. It is thought that the parasites are killed from macrophage activation by lymphokines secreted from either helper T1 cells or CD8+ T cells. Characterization of both the host and parasite molecules in the compartment in the context of biogenesis of Leishmania-phagolysosome and processing of the parasite antigen by this compartment are discussed. Trafficking of different drugs and new agents through this compartment and their role in chemotherapy and necessity of developing new drug carrier are also stressed.
Topics: Animals; Antigens, Protozoan; Antiprotozoal Agents; Biological Transport; Leishmania; Phagosomes
PubMed: 9347223
DOI: 10.3109/10408419709115139