How Pathogens Manipulate Host Intracellular Pathways to Promote Infection

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At any moment, the human immune system is assaulted with a multitude of bacteria, most occurring without clinical symptoms or recognition. Both bacteria and humans have an accumulation of traits shaped from constant pressure to survive, thrive and pass on genetic material, resulting in an evolutionary arms race. With additional exposure to bacteria, and with each ‘success’ of the human immune system, bacteria have an added chance to evolve new virulence tactics to propagate their genetic information.  Many bacteria have techniques to avoid and defeat the immune system, including evasion, invasion, and manipulation, and an exceptional technique that bacteria have evolved is their manipulation of host immune intracellular pathways. Bacterial species such as Bacillus anthracis, Listeria monocytogenes, and Salmonella have engineered manipulation techniques of the host,leading to severe effects due to their success of promoting infection.

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 The host immune system has many functions and pathways in order to defend itself upon oncoming insults and attacks from bacteria, viruses, and parasites. Included in the immune regulation is the innate immune system, which functions to recognize pathogens non-specifically and immediately to inform the host of an incident. Pathogens have certain attributes, called pathogen associated molecular patterns (PAMPs), that are recognized through receptors on host cells in order to recognize them as foreign, termed pathogen recognition receptors (PRRs) (Athman and Philpott,2004). Upon recognition via PRRs, the host cell begins an intracellular cascade in order to release cytokines or undergo apoptosis to remove the pathogen. Recognition of a bacterial component can occur specifically via Toll-like receptors (TLR), e.g., TLR4, an example of a PRR. The binding of the pathogen results in association of various molecules within the cytosol, such as MyD88 (Athman and Philpott,2004). Association of MyD88 causes phosphorylation of the intracellular component IRAK1, which in turn causes phosphorylation of TRAF6. TRAF6 then further activated TAK1 within the cell, causing phosphorylation of the mitogen-activated protein kinase (MAPK) pathway system within cells (Athman and Philpott,2004). The phosphorylation pathway results in translocation of MAPK into the nucleus of the host cell, allowing the phosphorylation of p38, and consequently activating transcription factors of the NFκB (Athman and Philpott,2004). These transcription factors primarily target the release of cytokines to inform the immune system of a threat, as well as initiating apoptosis of the infected cell in normal signal transduction in order to control the infection and alert the immune system of the insult (Athman and Philpott,2004). Thus, the host innate immune system has several tools in order to defeat incoming pathogens through intracellular signalling pathwyas.

 Bacillus anthracis is a well studied bacterium that takes advantage of host intracellular pathways in order to succeed the immune responses of the host. Bacillus anthracis is the causative agent of Anthrax which results in severe clinical effects if inhaled and, due to the immediate and fatal agents of Anthrax, has been used as a weapon of biowarfare (Pile et al., 1998). Bacillus anthracis produces toxins that invade the host, termed protective antigen (PA), edema factor (EF), and lethal factor (LF). The PA binds to a receptor naturally present on host cells (ANTXR1) and is soon cleaved by a cell surface protease (furin). Upon cleavage, the PA is now activated nPA and forms a heptameric pore through oligomerization, allowing the binding of EF and LF. Once these toxins are bound they are endocytosed into the host cell through an acidic vesicle and are subsequently translocated into the cytoplasm of the host cell (Kintzer et al., 2009; van der Goot and Young, 2009). The edema Factor (EF) is a calmodulin-activated adenylyl cyclase (AC) which causes an increased activity of cyclic adenosine monophosphate (cAMP) activity through hydrolyzation of adenosine-5’triphosphate (ATP). This signaling cascade causes dysregulation of cellular ion channels, including sodium, potassium, and chloride, resulting in a net influx of water and cellular edema. Cellular edema affects the cellular metabolism within the affected cells, and thus inhibits phagocytosis due to the elevation of cAMP (Collier and Young, 2003). In addition to EF, lethal factor (LF) of Bacillus anthracis is also responsible for manipulating the host intracellular pathways in a lethal manner. The combination of LF and EF creates a ‘lethal toxin’ (LT) that has a strong manipulation of the host’s natural immune defense against pathogens.  The LT enzymatically cleaves the MAPK-kinase1 and 2 (MAPKK1/2) at the amino terminus, rendering it unable to phosphorylate MAPK and translocation of MAP into the nucleus is unable to occur (Park et al., 2002). This ingenious technique employed by Bacillus anthracis not only inhibits chemokine transcription such as IL-1β and TNF-α, thus inhibiting chemotactic signaling for more proinflammatories, but also results in a regulated cell-death for the infected cell death, as to not alarm the body of the bacterial and cellular invasion (Park et al., 2002). Bacillus anthracis effectively manipulates the intracellular pathway resulting in transduction of chemokines to propagate itself within the host cell and spread to additional cells and through the body.

 Listeria monocytogenes is another bacterium that manoeuvres the host’s innate immune system, allowing for survival and replication of the bacterium. Listeria monocytogenes is ingested through contamination of food, and once within the host can mount an attack on the host immune system. The bacterium has many tools to succeed within the cell, including rearrangement of the host cytoskeleton to move around the cell via actin polymerization, and manipulation of intracellular pathways by secreted proteins. Several of the Listeria monocytogenes’ secreted toxins have manipulative effects on the host cell, including lysteriolysin O (LLO) and internalins A-C (InlA, InlB, InlC) (Gouin et al., 2010). Listeria monocytogenes is a facultative intracellular bacterium, and can manipulate the host to replicate within macrophages, and interestingly can induce local inflammation, resulting in an attraction of monocytes, which Listeria monocytogenes is able to invade, commandeer, and utilize to spread within the host. Specifically, Listeria monocytogenes releases internalins not only to enter the cell, but also to affect the transcription of cytokines within the host cell which normally acts to attract a robust immune response (Gouin et al., 2010). The Listeria monocytogenes bacterium overrides the same end-product gene, NFκB, as in Bacillus anthracis however through a different mechanism. Similar to Anthrax there is a balance, however Listeria monocytogenes balances attraction of macrophages through the induction of cytokine signalling and dampening the proinflammatory response in order to survive and replicate without a mass influx of other inflammatory cells intent on phagocytosing Listeria monocytogenes. Listeria monocytogenes accomplishes this balance by differentially expressing toxins in specific cells (Gouin et al., 2010). For instance, increased presence of LLO within macrophages, resulting in an increased expression of NFκB and influx of more macrophages to infect and replicate within, however expressing more internalins in other phagocytic cells that decrease the expression of NFκB (Kuhn and Goebel, 1998; Gouin et al., 2010).  Specifically, InlC interacts with the cytoplasmic factor IKKα, thus impairing the downstream phosphorylation of IκBα. In a normal bacterial infection, IκB is an inhibitor of NFκB and is bound and unable to inhibit NFκB. In the presence of Listeria monocytogenes, IκB can associate with cytoplasmic NFκB, therefore inhibiting the translocation into the nucleus and unable to affect transcription of cytokine genes required for inflammatory signaling, such as IL-1β (Gouin et al., 2010). Listeria monocytogenes skillfully manipulates the host intracellular signaling pathways, whether to propagate itself within macrophages and inducing amplified signaling of chemoattractant for macrophages or reducing proinflammatory cytokines to survive efficiently within host cells.

 In addition to Listeria monocytogenes and Anthrax, Salmonella intercepts and inhibits the NFκB signalling pathway as illustrated above, however Salmonella additionally manipulates the intracellular apoptotic pathway. Salmonella releases an effector toxin termed AvrA derived from the pathogenicity island SPI-1 (Schleker et al., 2012). AvrA has many actions within the host cell, acting to both suppress apoptosis as well as release of inflammatory cytokines. AvrA acts similarly to Listeria monocytogenes in the suppressing the inhibitory effects of IκBα, as described above. However, AvrA also exerts its effects on the cytoplasmic p38 and MAPK, resulting in similar effects of Bacillus anthracis in that the NFκB pathway resulting in transcription of proinflammatory signals is inhibited (Schelker et al., 2012). Differing from Listeria monocytogenes and Anthrax, Salmonella also exerts its effects on the pro-apoptotic c-Jun NH2-terminal kinase (JNK) pathway.  In contrast to Anthrax and Listeria monocytogenes, Salmonella causes the phosphorylation of MKK4/7 specifically, which activates via dual phosphorylation of JNK1/2, and enables JNK1/2 to phosphorylate p53 proteins at Ser6 (Kawai and Akira, 2006). Apoptosis of the cell results due to p53 as the transcription factor is responsible for genes related to apoptotic pathways, including growth arrest, cytochrome-c and caspase related apoptosis (Jones et al., 2008; Kawai and Akira, 2006; Schelker et al., 2012). Salmonella’s effector toxin AvrA however, intercepts the JNK apoptotic pathway at the level of MKK4/7, wherein AvrA has an acetyltransferase capability, that renders MKK4/7’s phosphorylation abilities void. The inability of JNK1/2 to be inhibited results in a reduction in apoptosis. Thus, AvrA acts as a antiapoptotic toxin, allowing survival of Salmonella within the host (Jones et al., 2008; Schelker et al., 2012). Similar to Bacillus anthracis and Listeria monocytogenes, Salmonella functions to balance the effect on anti-inflammatories through reduction of cytokine signaling with antiapoptotic effects to facilitate survival of the bacterium within the host.

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 Bacterial species such as Bacillus anthracis, Listeria monocytogenes, and Salmonella manipulate the host’s intracellular pathway mechanisms to exploit the host’s natural immune defense and facilitate survival and replication of the bacteria within the host. Anthrax toxin (Bacillus anthracis) have evolved to invade cells and release toxins that inhibit the activity of NFκB transcription factor, resulting in a decrease in pro-inflammatory cytokines. Listeria monocytogenes also exploits the production of the NFκB, however through the activity of IKKα. In concert with the pathways influenced by Bacillus anthracis and Listeria monocytogenes, Salmonella influences the affected cell to inhibit the pro-apoptotic mechanisms, in order to effectively survive within the cell. These ingenious techniques that bacteria have evolved to utilize, have arisen from constant contact with the host’s immune system. This persistent interaction of the immune system’s techniques opposed against the techniques of the bacteria have resulted in an infinite co-evolution and arms race of whichever has the more proliferative and successive techniques. The understanding of the techniques that bacteria have evolved to use can lead to a greater understanding of how society can counteract the devastating effects that these bacteria have on human health and survival.

REFERENCES

At any moment, the human immune system is assaulted with a multitude of bacteria, most occurring without clinical symptoms or recognition. Both bacteria and humans have an accumulation of traits shaped from constant pressure to survive, thrive and pass on genetic material, resulting in an evolutionary arms race. With additional exposure to bacteria, and with each ‘success’ of the human immune system, bacteria have an added chance to evolve new virulence tactics to propagate their genetic information.  Many bacteria have techniques to avoid and defeat the immune system, including evasion, invasion, and manipulation, and an exceptional technique that bacteria have evolved is their manipulation of host immune intracellular pathways. Bacterial species such as Bacillus anthracis, Listeria monocytogenes, and Salmonella have engineered manipulation techniques of the host,leading to severe effects due to their success of promoting infection.

 The host immune system has many functions and pathways in order to defend itself upon oncoming insults and attacks from bacteria, viruses, and parasites. Included in the immune regulation is the innate immune system, which functions to recognize pathogens non-specifically and immediately to inform the host of an incident. Pathogens have certain attributes, called pathogen associated molecular patterns (PAMPs), that are recognized through receptors on host cells in order to recognize them as foreign, termed pathogen recognition receptors (PRRs) (Athman and Philpott,2004). Upon recognition via PRRs, the host cell begins an intracellular cascade in order to release cytokines or undergo apoptosis to remove the pathogen. Recognition of a bacterial component can occur specifically via Toll-like receptors (TLR), e.g., TLR4, an example of a PRR. The binding of the pathogen results in association of various molecules within the cytosol, such as MyD88 (Athman and Philpott,2004). Association of MyD88 causes phosphorylation of the intracellular component IRAK1, which in turn causes phosphorylation of TRAF6. TRAF6 then further activated TAK1 within the cell, causing phosphorylation of the mitogen-activated protein kinase (MAPK) pathway system within cells (Athman and Philpott,2004). The phosphorylation pathway results in translocation of MAPK into the nucleus of the host cell, allowing the phosphorylation of p38, and consequently activating transcription factors of the NFκB (Athman and Philpott,2004). These transcription factors primarily target the release of cytokines to inform the immune system of a threat, as well as initiating apoptosis of the infected cell in normal signal transduction in order to control the infection and alert the immune system of the insult (Athman and Philpott,2004). Thus, the host innate immune system has several tools in order to defeat incoming pathogens through intracellular signalling pathwyas.

 Bacillus anthracis is a well studied bacterium that takes advantage of host intracellular pathways in order to succeed the immune responses of the host. Bacillus anthracis is the causative agent of Anthrax which results in severe clinical effects if inhaled and, due to the immediate and fatal agents of Anthrax, has been used as a weapon of biowarfare (Pile et al., 1998). Bacillus anthracis produces toxins that invade the host, termed protective antigen (PA), edema factor (EF), and lethal factor (LF). The PA binds to a receptor naturally present on host cells (ANTXR1) and is soon cleaved by a cell surface protease (furin). Upon cleavage, the PA is now activated nPA and forms a heptameric pore through oligomerization, allowing the binding of EF and LF. Once these toxins are bound they are endocytosed into the host cell through an acidic vesicle and are subsequently translocated into the cytoplasm of the host cell (Kintzer et al., 2009; van der Goot and Young, 2009). The edema Factor (EF) is a calmodulin-activated adenylyl cyclase (AC) which causes an increased activity of cyclic adenosine monophosphate (cAMP) activity through hydrolyzation of adenosine-5’triphosphate (ATP). This signaling cascade causes dysregulation of cellular ion channels, including sodium, potassium, and chloride, resulting in a net influx of water and cellular edema. Cellular edema affects the cellular metabolism within the affected cells, and thus inhibits phagocytosis due to the elevation of cAMP (Collier and Young, 2003). In addition to EF, lethal factor (LF) of Bacillus anthracis is also responsible for manipulating the host intracellular pathways in a lethal manner. The combination of LF and EF creates a ‘lethal toxin’ (LT) that has a strong manipulation of the host’s natural immune defense against pathogens.  The LT enzymatically cleaves the MAPK-kinase1 and 2 (MAPKK1/2) at the amino terminus, rendering it unable to phosphorylate MAPK and translocation of MAP into the nucleus is unable to occur (Park et al., 2002). This ingenious technique employed by Bacillus anthracis not only inhibits chemokine transcription such as IL-1β and TNF-α, thus inhibiting chemotactic signaling for more proinflammatories, but also results in a regulated cell-death for the infected cell death, as to not alarm the body of the bacterial and cellular invasion (Park et al., 2002). Bacillus anthracis effectively manipulates the intracellular pathway resulting in transduction of chemokines to propagate itself within the host cell and spread to additional cells and through the body.

 Listeria monocytogenes is another bacterium that manoeuvres the host’s innate immune system, allowing for survival and replication of the bacterium. Listeria monocytogenes is ingested through contamination of food, and once within the host can mount an attack on the host immune system. The bacterium has many tools to succeed within the cell, including rearrangement of the host cytoskeleton to move around the cell via actin polymerization, and manipulation of intracellular pathways by secreted proteins. Several of the Listeria monocytogenes’ secreted toxins have manipulative effects on the host cell, including lysteriolysin O (LLO) and internalins A-C (InlA, InlB, InlC) (Gouin et al., 2010). Listeria monocytogenes is a facultative intracellular bacterium, and can manipulate the host to replicate within macrophages, and interestingly can induce local inflammation, resulting in an attraction of monocytes, which Listeria monocytogenes is able to invade, commandeer, and utilize to spread within the host. Specifically, Listeria monocytogenes releases internalins not only to enter the cell, but also to affect the transcription of cytokines within the host cell which normally acts to attract a robust immune response (Gouin et al., 2010). The Listeria monocytogenes bacterium overrides the same end-product gene, NFκB, as in Bacillus anthracis however through a different mechanism. Similar to Anthrax there is a balance, however Listeria monocytogenes balances attraction of macrophages through the induction of cytokine signalling and dampening the proinflammatory response in order to survive and replicate without a mass influx of other inflammatory cells intent on phagocytosing Listeria monocytogenes. Listeria monocytogenes accomplishes this balance by differentially expressing toxins in specific cells (Gouin et al., 2010). For instance, increased presence of LLO within macrophages, resulting in an increased expression of NFκB and influx of more macrophages to infect and replicate within, however expressing more internalins in other phagocytic cells that decrease the expression of NFκB (Kuhn and Goebel, 1998; Gouin et al., 2010).  Specifically, InlC interacts with the cytoplasmic factor IKKα, thus impairing the downstream phosphorylation of IκBα. In a normal bacterial infection, IκB is an inhibitor of NFκB and is bound and unable to inhibit NFκB. In the presence of Listeria monocytogenes, IκB can associate with cytoplasmic NFκB, therefore inhibiting the translocation into the nucleus and unable to affect transcription of cytokine genes required for inflammatory signaling, such as IL-1β (Gouin et al., 2010). Listeria monocytogenes skillfully manipulates the host intracellular signaling pathways, whether to propagate itself within macrophages and inducing amplified signaling of chemoattractant for macrophages or reducing proinflammatory cytokines to survive efficiently within host cells.

 In addition to Listeria monocytogenes and Anthrax, Salmonella intercepts and inhibits the NFκB signalling pathway as illustrated above, however Salmonella additionally manipulates the intracellular apoptotic pathway. Salmonella releases an effector toxin termed AvrA derived from the pathogenicity island SPI-1 (Schleker et al., 2012). AvrA has many actions within the host cell, acting to both suppress apoptosis as well as release of inflammatory cytokines. AvrA acts similarly to Listeria monocytogenes in the suppressing the inhibitory effects of IκBα, as described above. However, AvrA also exerts its effects on the cytoplasmic p38 and MAPK, resulting in similar effects of Bacillus anthracis in that the NFκB pathway resulting in transcription of proinflammatory signals is inhibited (Schelker et al., 2012). Differing from Listeria monocytogenes and Anthrax, Salmonella also exerts its effects on the pro-apoptotic c-Jun NH2-terminal kinase (JNK) pathway.  In contrast to Anthrax and Listeria monocytogenes, Salmonella causes the phosphorylation of MKK4/7 specifically, which activates via dual phosphorylation of JNK1/2, and enables JNK1/2 to phosphorylate p53 proteins at Ser6 (Kawai and Akira, 2006). Apoptosis of the cell results due to p53 as the transcription factor is responsible for genes related to apoptotic pathways, including growth arrest, cytochrome-c and caspase related apoptosis (Jones et al., 2008; Kawai and Akira, 2006; Schelker et al., 2012). Salmonella’s effector toxin AvrA however, intercepts the JNK apoptotic pathway at the level of MKK4/7, wherein AvrA has an acetyltransferase capability, that renders MKK4/7’s phosphorylation abilities void. The inability of JNK1/2 to be inhibited results in a reduction in apoptosis. Thus, AvrA acts as a antiapoptotic toxin, allowing survival of Salmonella within the host (Jones et al., 2008; Schelker et al., 2012). Similar to Bacillus anthracis and Listeria monocytogenes, Salmonella functions to balance the effect on anti-inflammatories through reduction of cytokine signaling with antiapoptotic effects to facilitate survival of the bacterium within the host.

 Bacterial species such as Bacillus anthracis, Listeria monocytogenes, and Salmonella manipulate the host’s intracellular pathway mechanisms to exploit the host’s natural immune defense and facilitate survival and replication of the bacteria within the host. Anthrax toxin (Bacillus anthracis) have evolved to invade cells and release toxins that inhibit the activity of NFκB transcription factor, resulting in a decrease in pro-inflammatory cytokines. Listeria monocytogenes also exploits the production of the NFκB, however through the activity of IKKα. In concert with the pathways influenced by Bacillus anthracis and Listeria monocytogenes, Salmonella influences the affected cell to inhibit the pro-apoptotic mechanisms, in order to effectively survive within the cell. These ingenious techniques that bacteria have evolved to utilize, have arisen from constant contact with the host’s immune system. This persistent interaction of the immune system’s techniques opposed against the techniques of the bacteria have resulted in an infinite co-evolution and arms race of whichever has the more proliferative and successive techniques. The understanding of the techniques that bacteria have evolved to use can lead to a greater understanding of how society can counteract the devastating effects that these bacteria have on human health and survival.

REFERENCES

  • ATHMA, R., PHILPOTT, D. (2004) Innate immunity via Toll-like receptors and Nod proteins. Current opinion in microbiology. 7(1), 25-32.
  • COLLIER, R., YOUNG, J. (2003) Anthrax toxin. Annual review of cell and developmental biology. 19, 45-70.
  • GOUIN, E., ADIB-CONQUY, M., BALESTRINO, D., NAHORI, M., VILLIERS, V., COLLAND, F., DRAMSI, S., DUSSUERGET, O., COSSART, P. (2010) The Listeria monocytogenes InlC protein interferes with innate immune responses by targeting IκB kinase subunit IKKα. Proceedings of the national academy of sciences. 107(40), 17333-17338.
  • JONES, R., WU, H., WENTWORTH, C., LUO, L., COLLIER-HYAMS, L., NEISH, A. (2008) Salmonella AvrA coordinates suppression of host immune apoptotic defenses via JNK pathway blockade. Cell host & microbe. 3(4), 233-244.
  • KINTZER, A., THOREN, K., STERLING, H., DONG, K., FELD, G., TANG, I., ZHANG, T., WILLIAMS, E., BERGER, J., KRANTZ, B. (2009) The protective antigen component of anthrax toxin forms functional octameric complexes. Journal of molecular biology, 392(3), 614-629.
  • KUHN, M., GOEBEL, W., (1998) Host cell signalling during Listeria monocytogenes infection. Trends in microbiology. 6(1), 11-15.  
  • PARK, J., GRETEN, F., LI, Z., KARIN, M. (2002) Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science, 297, 2048-2051.
  • PILE, J., MALONE, J., EITZEN, E., FRIEDLANDER, A. (1998) Anthrax as a potential biological warfare agent. Archives of internal medicine, 158(5), 429-434.
  • SCHLEKER, S., SUN, J., RAGHAVAN, B., SRNEC, M., MÜLLER, N., KOEPFINGER, M., MURTHY, L., ZHAO, Z., KLEIN-SEETHARAMAN, J. (2012) The current Salmonella-host interactome. PROTEOMICS- clinical applications. 6(1-2), 117-133.
  • VAN DER GOOT, G., YOUNG, J. (2009) Receptors of anthrax toxin and cell entry. Molecular aspects of medicine. 30(6), 406-412.

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