The Listeria monocytogenes

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Definition of Innate Immune system and its importance to defend human body against intracellular invaders. Be as concise as possible, because a good essay focuses on the question, and doesn't rewrite the text books. You will need to explain the function of the cells (dendritic and macroph).

Definition of Microbial Virulence and its importance to occur disease or infection in human body. Again, focus on L.monocytogenes and its virulence factors, such as listeriolysin and internalin, and important mechanisms such as lysosomal escape and how cells are infected (listeriopods). Who gets disease.....

The aim of this essay is to see the function of Macrophage and Dendritic cells how they could play critical role to control and defence human body as initial immune system. Have you found any papers yet? Most are mouse models, so you need to show that you are aware that they are a compromise to the real situation (infection by food) whereas mouse models are intravenous, septic models.

The aim of this essay is to illustrate L.monocytogenes's virulence as a tool for escaping from Macrophage cells and Dendritic cells. And any differences between these cells in how they handle l.monocytogenes (that's actually the important part).

Describe the role dendritic cells and macrophage cells play in the control and escape of Listeria monocytogenes.


The purpose of this essay is to illustrate Listeria monocytogenes's virulence as a tool for escaping from phagosome vacuole of Macrophage and Dendritic cells. The parameters of this essay will be illustrative rather than being deep investigation. In other word, from the questions that will be answered later, how do L.monocytogene become resistance or have the ability to escape from phagosome before fusion with lysosome vacuole? Another question is that what makes L.monocytogene virulence? Firstly, the relationship between Dendritic and Macrophage will be explained. Secondly, this essay will search deeply inside the contents of cell to discover what the differences between these antigenic presenting cells in relation to response to infection of L.monocytogene as intracellular invader? Thirdly, some mode of action of virulence factors of L.monocytogene will be mentioned. Last but certainly not least, some suggestions for controlling of L.monocytogene escaping will be given.

Glance of innate immune system

The immune system plays a critical role to protect human body from spread out L.monocytogenes into neighboring cells or organs (Zenewicz, L.A, 2007). Innate immune cells consist of different cells with respect to function and shape. There are two immune cells play important defence against any invader germ directly. These cells are dendritic cell and macrophage cell. A macrophage cell, which is found in tissues and organs e.g. lung and brain, is derived originally from monocyte, which is found in blood stream. Dendritic cell can be found in, as well, in many organs. It plays important roles in innate immunity to eliminate microbes as well as, macrophages. All of these two cells called Antigenic Presenting Cells (APC) due to present microbial products after phagocytic mechanism and degrading microbe's protein into peptides, and demonstrate peptides on Major Histocompatibility Complex (MHC I,II) 'for recognition by the T cells' (Abbas, et al, 2007: p.116).

However, there are many microorganisms have adapted themselves in order to invade human body and occur infectious disease through intracellular pathogenic mechanism by virulence factors which might be toxin secretions and many factors. Virulence factors can invert the balance of battle between bacteria and APCs for bacteria. One of those intracellular microbes, which is interested by this essay, is Listeria monocytogenes. This bacterium is a Gram-positive rod and it causes Listeriosis in humans and animals, in addition, the infection by this bacterium is possibly by "subcutaneous inoculation and feeding" (Liu. D, 2008: p.99).

Intracellular immune reaction of L. monocytogenes

Phagocytosis mechanism

Any of these cells within APCs has the ability to engulf foreign body to its cytoplasm surrounded by vacuole which is very important to keep the microbe from escaping into cytoplasm. The Phagocytosis process has been explained by Abbas, et al, (2007: p.11) in details by following steps. The first step, microbes are recognised in surface of APCs by many receptors e.g. scavenger, mannose and Toll-like receptors. The next step, APCs membrane 'zips up around microbe' and engulf it in vacuole. This vacuole could be divided into two vacuoles regarding phagosome development in PH levels and GTPase. Lastly step, the early endosome and late endosome, which is more acidosis than the first one to set for fusion with lysosome, according to Shaughnessy, et al, 2007. These GTPase are Rab5a (early) and Rab7 (late). It has been demonstrated by Shaughnessy, et al, (2007) and Abbas, et al, (2007: p.35) that Rab5a is crucial for subsequent process to fusion lysosome with phagosome vacuole in order to kill microbe by reactive oxygen species (ROS) and nitrogen intermediates (nitric oxide NO) and proteolytic enzymes such as oxidase. Therefore, in case of engulfing L.monocytogenes, that GTPase become involve in (Myers, et al, 2000).

The problem is L.monocytogenes has been demonstrated to avoid late endosome and lysosome; also it has been found that in its early vacuole in macrophages has not possessed Rab5a. Thus, excluded Rab5a could interrupt phagosomal maturation (Shaughnessy, et al, 2007).

Dendritic & Macrophage cells correlation

The most one possible importance different between DCs and macrophages is that DCs play an important role in adaptive immunity to eliminate viruses and tumour cells. In contrast, one important similarity between them, the effector cells (Naive T CD4+ cells) are stimulated and activated by DCs and macrophage with IL-12, IL-1 that leads to activation macrophage by those effector cells to kill the phagocytic microbe (adaptive immunity). Moreover, IFN-? is secreted by certain cells e.g. Natural Killer cell (NK) that contact with intracellular pathogens directly or by recognizing MHC I molecules in non-phagocytic infected cells. Thus, that action leads to release IFN-? (Champoux, et al, 2004: p.121 and Abbas, et al, 2007: p.117 and Shaughnessy, et al, 2007).

Macrophage cells could be indirectly activated to kill the phagocytic microbe by other non-phagocyte cells. The fact that is DCs the only one cell in immune system has two distinct complex classes MHC I, II molecules. In addition, it has the ability to phagocyte microbes and present their products attach with these classes. Therefore, T cells CD8+ (Cytotoxic) can be stimulated by DCs via TCR binds to MHC I molecule. That action allows CD8+ cells to produce TNF and IFN-?. This IFN-? can activate macrophages to become listericidal activity to kill microorganisms by fusion phagosome with lysosome vacuole (Abbas, et al, 2007: p.294). In addition, TNF-a, which considers the importance factor in resistance to enteric L.monocytogenes, is produced and "mediated growth control" when the flagellin of it attaches with Toll-like receptor-5 (TLR5) in DCs and other cells (Dons, L., et al, 2004).

Moreover, CTLs bind directly with non-phagocytic lineage cells, which has been infected by L.monocytogenes, with MHC I that has the cytosolic antigens of listeria products when L.monocytogenes escaped from phagosome to the cytoplasm. These products are lysed by proteasome into antigenic epitopes. As a result of biding CTLs with non-phagocytic lineage cells, lysing infected cells through perforin and granzymes (apoptotic) that leads to L.monocytogenes becomes extracellular for a moment that could allow the macrophages to capture it, according to Zenewicz, L.A, et al, (2007) and Liu. D. (2008: p.432-435).

Therefore, macrophages possibly kill L.monocytogenes by two ways. The first way is by CTLs when it destroys non-phagocyte infected cells by recognizing MHC I molecule. The second way is by NK cells that act the same as CTLs or kill L.monocytogenes, when it becomes extracellular, and release Interferon gamma as essential interferon for clearance intracellular pathogen. However, the correlation of DCs and macrophage could be indirectly for clearance L.monocytogenes via CTLs.

Dendritic cells

DCs are vital cells to connect between innate and adaptive immunity (Zenewicz, L.A, et al, 2007). In addition, DCs play crucial function in the first and regulation of immune responses. DCs are able to phagocyte microbes even intracellular bacteria e.g. L.monocytogenes and infected cells and then there are many steps could do. One of them, mobilization and migration into lymph node to present those foreign antigens on its surface with MHC II for assisting recognise T-helper cells CD4+ to differentiate (Paschen, et al, 2000). DCs are activated by signalling cascade of TLRs result in product of specific recognition of pathogen Zenewicz, L.A, et al, 2007).

The opsonisation of L.monocytogenes by DCs through mediating Fc receptor may depend on human immunoglobulin's (Antibodies) for L.monocytogenes antigens (Kolb-Mäurer, A., et al, 2003). It has been suggested by Kolb-Mäurer, A., et al, (2003) that some DCs unable to kill L.monocytogenes in phagosome vacuole consequence of a distinct bacterial killing volume of their phagosome vacuoles.

It has been reported by Paschen, A., et al, (2000) many intracellular bacteria such as L.monocytogenes 'inhibit CD4+ T cell responses' by interference with inducing antigen specific antagonism in murine APC MHC II.

As Paschen, A., et al, (2000) says mature DCs has lost the efficiency of capturing listeria (Phagocytosis), however, immature DCs has the ability to phagocyte L.monocytogenes that escapes in short time from phagosome vacuole and that leads to morphological changes of DCs to present listeria antigens for CD4+ T cells. Moreover, the data has not been shown that mature DCs have high level of expression MHC II without intracellular listeria, however, immature DCs have low level of expression MHC II binding with antigen (Kolb-Mäurer, A., et al, 2003 and Paschen, et al, 2000).

Nevertheless, it has been observed by Paschen. A., et al, (2000) that human DCs have the efficiency against 'cytolytic activity of listeriolysin'.

Inflammatory Cytokines

As can be seen from the function of IFN-?, considers the most important cytokine for clearance L.monocytogenes. This bacterium benefits from induction of type I interferons, which is very important for clearance viral infection, to enhance its growth and escaping into cytosol (Zenwicz, L.A., et al, 2007). According to Zenwicz, L.A., et al, (2007) this interferon to be induced by listeria recognition pathway is independent to many receptors, for example, Toll-like receptor 2,4 and receptor interaction protein 2 (RIP-2), in contrast, it depend on 'the transcription factor IFN regulatory factor 3 (IRF3) and serine-threonine kinase TNFR-associated NF-kB kinase (TANK)-binding kinase 1 (TBK1).

Listeria monocytogenes


As mentioned before the way of entry pathway for this microbe is probably two ways. The first is direct pathway via enterocytes invasion coating microvilli absorptive epithelium by specific receptor reaction which has been thought by Liu, D, (2008: p.100) that would happen only in intestinal host cells e.g. humans or guinea pig, that express listeria invader 'susceptible' receptors isoform. The second pathway is by Intestinal translocation mechanism. Therefore, L.monocytogenes spreads out into spleen and liver from mesenteric lymph nodes distribution and makes hepatitis and splenitis (Liu, D., 2008: p.100).

This microbe is able to be engulfed by DCs, macrophages and M cells etc which is located in Peyer's patches. By specific surface protein in L.monocytogenes called internalin, this intracellular bacterium encourage epithelial cell for invasion (Champoux, J. J., et al, 2004: p.303). Once this bacterium becomes engulfed, its virulence factors assist it to escape from phagosome vacuole. These virulence factors will be discussed later.

Surprisingly, L.monocytogenes also could survive with high virulence in the protozoan Acanthamoeba by mimic the same as pathogenesis in APCs (Zhou, X., et al, 2007).

Virulence factors

Listeriolysin O (LLO)

L.monocytogenes releases cholesterol-dependent cytolysin (CDC), listeriolysin O (LLO) which is crucial for L.monocytogenes virulence. In addition, this factor is considered the responsible enzyme for L.monocytogenes escaping to cytoplasm by lysing phagosome vacuole before fusion with lysosome vacuole to become phagolysosome vacuole also it is RBCs haemolysin ( Shaughnessy, L. M., et al, 2007 and Liu, D., 2008: p.108). Gamma-interferon-inducible lysosomal thiol reductase (GILT) is the key factor to activate LLO (Singh, R., et al, 2008). Therefore, it has been observed by Singh, R., et al, (2008) that L.monocytogenes LLO becomes active to formation hales on phagocytic vacuole membrane when active GILT is present. In addition, in case of absence the LLO, according to Henry, R., et al, (2006) the fate of escaping is fail.

IFN-ß can be secreted in response to L.monocytogenes infection; in contrast, it could be considered one of the factors that raise the ability of LLO to be more efficiently. It has also been suggested that that INF-ß enhance the phagosomal vacuole acidity to be more acidic, by phagosomal membrane, to activate LLO (Zwaferink, H., et al, 2009).

It has been stated by Liu. D. (2008: p.109) and Henry, R., et al, (2006) that LLO becomes active between PH 5.5-6.0. As Henry, R., et al, (2006) demonstrate listeriolysin O could be inactivated by deficient of Rab5a (GTPase) that is essential for early endosome vacuole in APCs. Thus, the escaping might be prevented. However, it has been discovered that L.monocytogenes does not affect 'Rab5 exchange' (Henry, R., et al, 2006). The optimum active of LLO obtains in the late endosome of which by Rab7-positive could help escaping L.monocytogenes (Henry, R., et al, 2006).

However, there is a gene where found in L.monocytogenes is considered the main responsible for escaping this bacterium from cytosolic vacuoles it is called hly gene for listeriolysin O (Zhou, X., et al, 2007). Therefore, it has been mentioned that gene speeds up 'fusion with early endosomes' and postpones 'fusion with lysosomes' (Henry, R., et al, 2006).

Actin filament polymerization (Actin-based motility)

When L.monocytogenes escape from phagocytic vacuole leads to formation of actin filaments as covering and surrounding the bacterium and becomes arrangement to form big "tail" (Tilney, L. G., et al, 1989 and Liu, D., 2008: p.113). This tail filament becomes at one pole, and helps L.monocytogenes to escape from APCs cytoplasm to another cell cytoplasm (Liu, D., 2008: p.113). By that way, L.monocytogenes could infect other cells by jumping from infected macrophage to another intact macrophage. This process would first, be movement intracellular bacterium to the host cell surface, and then spread out by forming "pseudopodal projection or large microvillus" (Tilney, L. G., et al, 1989).

Flagellin is the essential component of flagellar filament (Dons, L., et al, 2004). It has been suggested by Dons, L., et al, (2004) that consists of flagellar filament may react like "adhesions and mediate the binding to" targeted cell.

However, pseudopodal membrane and the phagocytic vacuole membrane of another APC is possibly dissolved (Tilney, L. G., et al, 1989).

There is a protein called ActA which is a "surface protein" capable of polymerizing actin and spread of bacterium, thus, it considers as sufficient protein to regulate actin filament on bacterium surface to move forwarding fast (Liu, D., 2008: p.113).

Phosphoinositde-specific phospholipase C (PI-PLC)

Broad-range phospholipase (PC-PLC)


  • Dons, L., Eriksson, E., Jin, Y.X., Rottenberg, M.E., Kristensson, K., Larsen, C.N., Bresciani, J. & Olsen, J.E. 2004, "Role of flagellin and the two-component CheA/CheY system of Listeria monocytogenes in host cell invasion and virulence", Infection and immunity, vol. 72, no. 6, pp. 3237-3244.