What are the advantages of the intracellular lifestyle?
1 - Nutritional advantages: avoid competition for space and nutrients 2 - Protection from immune system: avoid a number of innate and humoral defenses. Lack of sterilization allows some bacteria to lay dormant for decades, only to emerge under immunosuppressive conditions. 3 - Protected dissemination around the body: Shigella can spread from cell to cell in epithelial monolayers. Salmonella can disseminate outside of the intestine to systemic sites inside phagocytes.
What are the two mechanisms of entry for intracellular bacteria?
Bacteria can be taken by professional and non-professional phagocytes by either a ZIPPER or a TRIGGER mechanism. In both cases, the reorganization of the actin cytoskeleton results in changes at the membrane surface, allowing uptake of bacteria.
What is the process of the zipper mechanism and what are some examples?
In the zipper model, a tight interaction between the bacterial cell surface ligands and the host cell receptors results in a closure of the host cell surface around the bacterium. Examples include: 1. PARASITE-INDUCED PHAGOCYTOSIS into non-professional phagocytes: Listeria monocytogenes into human epithelial cells. 2. RECEPTOR-MEDIATED PHAGOCYTOSIS of macrophages: the internalization of Mycobacterium tuberculosis into macrophages. 3. COILING PHAGOCYTOSIS: the internalization of Legionella pneumophila into macrophages.
What is the process of the trigger mechanism and what are some examples?
Trigger. In this model, bacterial products induce the cell surface to ruffle, projecting membrane extensions that surround the bacteria. Products secreted by type III secretory systems of Salmonella and Shigella induce this kind of uptake.
Describe the steps of the process by which phagocytic vesicles change and degrade bacteria or other absorbed substances. What are the main functions of this process?
After internalization of inert particles the membrane-bound PHAGOSOME modifies its composition by recycling plasma membrane proteins and by acquiring markers of early ENDOSOMES. Undisturbed phagosomes continue their maturation process and acquire markers of lysosomes. These changes contribute to the formation of the PHAGOLYSOSOME, which main function is to kill microbes, degrade complex molecules and present antigen to the acquired immune system.
What are three classes of antimicrobial defense in professional phagocytic cells?
NADPH oxidase Inducible nitric oxide synthase Oxygen-independent effector molecules
Summarize the NADPH oxidase reaction.
Phagocytosis of bacteria signal the assembly of cytosolic and membrane-bound components of the NADPH oxidase, activating the enzymatic reduction of oxygen to superoxide which gives rise to radicals known as reactive oxygen species.
How do Listeria, Legionella, and Salmonella each avoid degradation by the NADPH oxidase reaction?
Listeria escapes from the phagosomal vacuole to the cytosol where the NADPH oxidase cannot be assembled Legionella pneumophila inhibits the mobilization of cytosolic components of the NADPH oxidase to the membrane Salmonella uses superoxide dismutase and catalase for the detoxification of reactive oxygen species.
How does nitric oxide synthase degrade bacteria, and what is one of the common consequences of this system?
NO synthases produce nitric oxide. Human mononuclear phagocytes express inducible nitric oxide synthase and produce high amounts of nitric oxide. Nitric oxide targets many intracellular pathogens. Establishment of dormancy is one of the clinical consequences emanating from the continuous production of nitric oxide.
What are some of the oxygen independent pathways by which phagocytes degrade bacteria?
Reduced iron: Decreased expression of transferrin receptors with increased expression of iron storage proteins; activated phagocytes reduce the concentrations of iron available to intracellular pathogens to levels non compatible with life. (Anemia of Chronic Disease) pH: Intracellular pathogens also face the challenge of low pH attained within the phagolysosomes.
How does listeria invade cells, and how does it avoid the extracellular environment?
Escape: Listeria lyses the phagocytic vacuole, escaping into the cytosol. Intracellular movement: In the cytosol, Listeria polymerizes actin at one its poles, an event that propels the bacteria within the cytosol. These actin tails also allow bacteria to invade neighboring cells without ever being exposed to the extracellular environment.
What are the advantages and disadvantages of escaping the phagosome into the cytosol?
Advantages: By escaping into the cytosol, these intracellular pathogens have access to large amounts of nutrients, and minimize their exposure to antimicrobial defenses associated with vesicles. Disadvantages: Host defenses. Cytosolic antimicrobial peptides and cytosolic inducible nitric oxide synthase can target them. In addition, cytotoxic CD8 positive T cells can lyse infected cells expressing microbial peptides on their surface MHC class I molecules.
What is a non-fusogenic organism?
Intracellular pathogens that remain contained in membrane-bound compartments that avoid the degradation pathway linked to lysosomal fusion. In short, they prevent the fusion of phagosomes and lysosomes.
What are the advantages of a non-fusogenic strategy and what affect does this have on host immune defenses?
Advantages: Prevention of phagosome-lysosome fusion not only ensures that the bacteria can remain viable inside phagosome but also avoids the processing of bacterial antigens that would lead to activation of the immune system through presentation of such peptides by MHC class II molecules. Host defenses: Many of the non-fusogenic intracellular pathogens cause long-term infections by stimulating the formation of granulomas. These lesions develop over months after infection, and consist of activated macrophages and T cells. Granulomas contain these infectious agents by maintaining a balance between organism growth and antimicrobial host defenses.
What is the only intracellular pathogen to reside within a phagolysosome, and by what pathway does the vesicle progress?
Coxiella burnetii, an obligate intracellular Gram negative bacterium, is the only intracellular pathogen to reside within a phagolysosome. The nascent phagosome matures through the endocytic pathway, eventually acquiring the properties of lysosomes. The pathogen-containing vacuole acidifies. The organism is not cytopathic, reaching very high numbers within a single vacuole.
What genetic change separates facultative and obligate intracellular bacteria?
Facultative microorganisms are capable of both intra and extracellular growth. In contrast, obligate intracellular pathogens have established such an intimate relation with their host that they cannot reproduce outside of the intracellular environment. The lost of essential biosynthetic metabolic pathways underlies their obligate dependency of host cells
What types of cells does bartonella invade?
Bartonella seeks refuge inside red blood cells and endothelial cells. Some intracellular bacteria invade non-professional phagocytes such as endothelial cells, which have limited phagocytic and bactericidal activity, or even cells without lysosomes such as erythrocytes.
What are four factors that influence the intracellular activity of antibiotics?
(i) penetration of the eukaryotic membrane (ii) subcellular localization (iii) deleterious interactions with the intracellular milieu, including pH (iv) antibiotic susceptibility of the intracellular pathogen. The intracellular location of some microbes has been recognized as a critical aspect for the failure of some antibiotics for the treatment of such pathogens from infected hosts.
Why are aminoglycosides and macrolides poorly effective against intracellular pathogens?
Weak base antibiotics such as aminoglycosides and macrolides are concentrated within lysosomes by a pH-dependent mechanism. Their preferential localization within lysosomes and their partial inactivation by acidic pH represent major disadvantages.
How does rifampicin enter cells and does it collect in the cytosol or in lysosomes? Is it effective against intracellular bacteria?
Rifampicin enters cells via diffusion and accumulates equally in the cytosol and lysosomes. It is effective against a broad range of bacteria.