Why toxins are produced

For example, the bacteria Listeria monocytogenes , associated with food-borne illnesses, specifically targets cholesterol by producing a pore-forming toxin protein, listeriolysin O.

This exotoxin affects intracellular processes and creates unregulated pores within the cell membranes of the host. Another example of an exotoxin includes an enterotoxin produced by the bacteria Staphlycoccal aureus.

Upon activation of the immune system, the release of large amounts of cytokines, inflammatory related molecules, causes significant inflammation. Lastly, an example of an endotoxin, includes the protein lipopolysaccharide LPS produced by gram-negative bacteria. Upon destruction of the membrane by an immune response, the LPS is released and functions as a toxin.

However, bacterial toxins are also currently serving as new sources for potential drug development. Toxins have been shown to exhibit anticancer characteristics and fight again microbial virulence. The investigation of toxins as potential medicinal compounds is currently underway. Mycotoxins are the classes of toxins produced by fungi. Mycotoxins are numerous and production of a specific mycotoxin is not restricted to one specific species.

Mycotoxins are secondary metabolites that are toxic to humans and produced by fungi. There are various types of mycotoxins including, but not limited to, aflatoxins, ochratoxins, citrinin, and ergot alkaloids. Aflatoxins are a type of mycotoxin that are produced by certain strains of Aspergillus fungi. These strains are present in a wide range of agricultural commodities associated with tropic and subtropic zones.

These commodities include species of peanuts and corn. Altogether, available data indicate that ALO is not essential for B. Anthrax toxins originate from the association of three different protein components: a host cell receptor binding protein named protective antigen PA and two enzymatic proteins, edema factor EF and lethal factor LF Young and Collier, ; Figure 2.

Upon binding to its cell surface receptor, PA is proteolytically processed at its N-terminus by a furin-like protease and self-assembles forming an oligomeric prepore able to bind EF and LF. In endosomes, the toxin complex can also be sorted into intraluminal vesicles that undergo back fusion with the endosomal membrane allowing sequestered EF and LF to reach the cytosol Abrami et al.

Anthrax toxins cooperatively disable host innate immune response. Host cell intoxication by anthrax toxins involves interaction of protective antigen PA, 83 kDa with two cellular receptors [tumor endothelium marker 8 TEM8 , also known as anthrax toxin receptor 1 ANTXR1 and capillary morphogenesis protein 2 CMG2 also known as anthrax toxin receptor 2 ANTXR2 ], which are expressed by different cell types, including macrophages and neutrophils. Upon binding to the cell surface receptor, PA83 is proteolytically processed at its N-terminus by a furin-like protease yielding the C-terminal fragment PA63 that oligomerises into a heptameric prepore able to bind edema factor EF and lethal factor LF.

LT is a zinc-dependent metalloprotease that inhibits activation of neutrophils and macrophages, expression of inflammatory cytokines and cell motility by disrupting mitogen activated protein kinase kinases MAPKKs -regulated pathways. ET is a calcium and calmodulin-dependent adenylate cyclase that increases intracellular cAMP concentration, leading to the suppression of the expression of inflammatory cytokines and cell chemotaxis through protein kinase A PKA -dependent pathways.

The concerted action of LT and ET blocks the function of phagocytic cells. As discussed above in the context of the ACT from B. Anthrax has for long been described as a toxin-mediated disease, mainly because LT and ET can be lethal for experimental animals and anti-toxin immunization is effective in protecting against infection Kaur et al. However, it has recently been proposed that extreme bacteraemia and severe sepsis rather than the anthrax toxins per se are the cause of anthrax-induced lethality Coggeshall et al.

Indeed, the fact that anthrax toxins act on multiple tissues simultaneously, due to the ubiquitous expression of the anthrax toxin receptors, complicate untangling their effects on the host and delayed the identification of the key tissue targets responsible for its lethal effects. Recently, using cell-type specific CMG2-null mice and the correspondent cell-type specific CMG2-expressing mice, Liu and colleagues have shown that LT-induced mortality requires targeting of cardiomyocytes and vascular smooth muscle cells, whereas ET-induced lethality relies mainly on targeting hepatocytes Liu et al.

Using myeloid-specific CMG2-null mice, in which both macrophages and neutrophils are insensitive to LT and ET due to their inability to bind and internalize the toxins, the same authors have also clarified the role of macrophages and other myeloid cells in anthrax toxins induced lethality and in B. Myeloid-specific CMG2-null mice are fully sensitive to both LT and ET, indicating that lethality does not depend on the targeting of macrophages, neutrophils, and other myeloid cells Liu et al.

However, they are completely resistant to infection by B. Available data indicate that LT and ET act in concert to inhibit macrophage activation as well as the activation and recruitment of other immune cells, such as neutrophils, early in infection Baldari et al. This favors bacterial escape and multiplication, and contributes to the severe bacteraemia observed in terminal disease. Macrophage activation requires signaling through MAPK cascades, including JNK and p38 pathways, which are central for induction of inflammatory molecules, including cytokines and chemoattractants, as well as Cox-2 and iNOS.

Several reports show that LT inhibits the secretion of pro-inflammatory cytokines by macrophages as well as by DCs in vitro and in vivo Pellizzari et al. ET has been shown to suppress secretion of inflammatory mediators by DCs Tournier et al. In addition to suppress pro-inflammatory cytokine secretion by macrophages, LT is also able to trigger programmed cell death in these cells in vitro. Furthermore, although treatment of three different human monocytic cell lines HL, THP-1, and U did not result in cell death, upon differentiation into macrophage-like phenotypes, the cells become susceptible to a cell death program that has features of apoptosis but apparently does not requires the activity of effector caspases Kassam et al.

Lethal toxin has also been shown to induce a rapid and lytic form of caspasedependent cell death, called pyroptosis, in macrophages from specific rat and mice strains. The susceptibility of macrophages to pyroptosis has been linked to polymorphisms of the Nlrp1b gene in mice Boyden and Dietrich, and of the orthologous Nlrp1 gene in rat Newman et al.

The ability of LT to induce macrophage pyroptosis was initially interpreted as a virulence mechanism of B. It was speculated that the destruction of macrophages by LT compromised their role in restricting B. More recently, it has been shown that LT is able to directly cleave mouse Nlrp1b and rat Nlrp1 close to their N-terminus Hellmich et al. Therefore, the current view is that LT-mediated activation of Nlrp1 that leads to inflammasome activation and macrophage pyroptosis is not a virulence mechanism used by B.

Neutrophils play a major role in controlling B. In vitro studies suggest that by reducing F-actin formation, LT and ET cooperate to inhibit neutrophil chemotaxis, chemokinesis, and ability to polarize During et al. Additionally, LT has been shown to suppress cytokine production by neutrophils in vitro Barson et al.

In the case of ET, it has been shown that the inhibition of superoxide production results from an impairment of the activation of the neutrophil NADPH oxidase, an effect that likely results from the activity of ET as an adenylate cyclase Crawford et al. It is now unquestionable that anthrax toxins are crucial in anthrax pathogenesis, but their precise roles during human anthrax infections remain to be further clarified.

Following the discovery of the anthrax toxins more than half a century ago, a myriad of studies were developed aiming at defining their role in anthrax disease and lethality.

However, most of the infection studies were performed in animal models that may not completely reflect the events occurring during human infections. Concerning the data documenting the immunomodulatory effects of the anthrax toxins, most were obtained in vitro , often in experimental set-ups that involve the use of purified toxins and do not allow examining intoxication in the context of infection.

Therefore, the available data need to be validated in the context of relevant animal models of infections before being extrapolated to the human disease scenario. Photobacterium damselae piscicida is a Gram-negative extracellular bacterium that causes a systemic and deadly infection with a rapid course and very high mortalities in both wild and cultured marine fish Romalde, ; Barnes et al.

Phdp infections are characterized by the occurrence of generalized bacteraemia and extensive cytopathology with abundant tissue necrosis do Vale et al. Infected fish often present whitish tubercle-like lesions of about 0.

The lesions consist of accumulations of bacteria and apoptotic and necrotic cell debris Kubota et al. Photobacterium damselae piscicida -associated pathology is triggered by AIP56 apoptosis inducing protein of 56 kDa , a plasmid-encoded toxin secreted by virulent Phdp strains do Vale et al.

The toxin is systemically disseminated in infected animals and induces selective apoptotic destruction of macrophages and neutrophils do Vale et al.

The simultaneous destruction of these cell types by AIP56 has two dramatic consequences for the host. On one hand, the drastic reduction of the number of phagocytes impairs the phagocytic defense, favoring pathogen dissemination do Vale et al. On the other hand, it compromises the host capacity to clear apoptosing cells, leading to the lysis of the phagocytes by post-apoptotic secondary necrosis with consequent release of their highly cytotoxic tissue-damaging contents do Vale et al.

AIP56 is the founding and the only characterized member of a continuously growing family of bacterial proteins identified in different organisms, mainly marine Vibrio species and Arsenophonus nasoniae.

AIP56 has likely originated from a fusion of two components: its A domain is related to NleC, a type III secreted effector present in several enteric pathogenic bacteria Yen et al. AIP56 blocks innate immunity by inducing massive apoptosis of host macrophages and neutrophils. Upon encountering susceptible cells, apoptosis-inducing protein of 56 kDa AIP56 binds to a still unidentified cell-surface receptor and undergoes clathrin-mediated endocytosis. Once in early endosomes, the toxin either follows the recycling pathway back to the extracellular medium or suffers low pH-induced translocation across the endosomal membrane into the cytosol to display its toxic activity.

During infection, AIP56 disseminates systemically and its activity leads to depletion of macrophages and neutrophils by post-apoptotic secondary necrosis, thereby blocking the phagocytic defense of the host and contributing to the occurrence of tissue damage. Although mammals are not susceptible to Phdp infection, likely due to temperature and osmolality restrictions, AIP56 is able to intoxicate mouse bone marrow derived macrophages mBMDM; Pereira et al.

Upon encountering susceptible cells, AIP56 binds to a still unidentified cell-surface receptor and is internalized through clathrin-mediated endocytosis Pereira et al. Once in early endosomes, the toxin either follows the recycling pathway back to the extracellular medium or undergoes low pH-induced translocation across the endosomal membrane into the cytosol to display its toxic activity Pereira et al.

During intoxication, the proteolytic activity of AIP56 results in a complete depletion of p65 and leads to the apoptotic death of cells Silva et al. AIP56 plays a pivotal role in the establishment of Phdp infection and in the development of the infection-associated pathology. In the initial phase of Phdp infection, when local multiplication of Phdp becomes detectable in infected tissues, extensive infiltration of macrophages and neutrophils occurs do Vale et al.

As the infection progresses, the pathogen extensively multiplies and disseminates systemically, which leads to a septicemic situation paralleled by the occurrence of AIP56 in the systemic circulation do Vale et al. The presence of circulating toxin correlates with the appearance of high numbers of apoptotic macrophages and neutrophils in the peripheral blood, in the spleen, liver, and head—kidney vasculature, as well as in the splenic and head-kidney parenchyma and gut lamina propria do Vale et al.

This systemic apoptotic destruction of macrophages and neutrophils triggered by AIP56 explains the extensive phagocyte depletion observed in advanced Phdp infections do Vale et al. The ability of the toxin to neutralize the main players responsible for the phagocytic defense of the host is a very effective pathogenicity strategy that contributes to the severity of Phdp infections by promoting survival of the pathogen and its unrestricted extracellular multiplication.

Concomitantly, the AIPinduced apoptosis of both professional phagocytes leads to tissue damage with deleterious consequences for the host. In fact, the destruction of macrophages, the cells with the crucial role of eliminating apoptotic cells Parnaik et al. This has particularly serious consequences in the case of neutrophils, due to their richness in highly cytotoxic molecules, which damage many cell types and produce tissue injury, thus contributing to the genesis of the Phdp-associated cytopathology.

Staphylococcus aureus is a Gram-positive bacterium that often colonizes the human nares and the skin. Besides being a commensal, S. To set up a successful infection, S. Such infiltrated immune cells would usually eliminate the bacteria. However, to counter their action, S. Several recent and comprehensive reviews highlight how S. Here we will focus on its secreted molecules mainly targeting neutrophils, modulating their function, or inducing cell killing.

In general, upon pathogen recognition, pro-inflammatory signals released by resident macrophages promote the adhesion of circulating neutrophils and further extravasation across capillary endothelium to the site of infection.

This process relies on interactions between the endothelial surface receptors e. To inhibit neutrophil recruitment to the infected tissues, S. The staphylococcal SSL5 binds PSGL1 in a glycan dependent manner at the surface of neutrophils, blocking its interaction with P-selectin expressed by endothelial cells and abrogating the early steps of neutrophil attachment Bestebroer et al.

In addition, SSL5 was shown to inactivate matrix metalloproteinase from human neutrophils, accounting for the limited capacity of neutrophils to transmigrate into infected tissues Itoh et al.

Strategies evolved by Staphylococcus aureus to counteract innate immune response. A Secreted bacterial factors that inhibit neutrophils extravasation, chemotaxis and activation. Neutrophil rolling is modulated by staphylococcal superantigen-like 5 SSL5 that binds P-selectin glycoprotein ligand-1 PSGL-1 , blocking its interaction with P-selectin.

The adhesion of neutrophils to the endothelium and consequent transmigration is inhibited by extracellular adherence protein Eap , which binds to intercellular adhesion molecule 1 ICAM In addition to inhibiting PSGL-1, SSL5 inhibits neutrophil responses to chemokines and to anaphylatoxins, by binding to different chemokine receptors. Several staphylococcal molecules impair neutrophil chemotaxis and important co-signaling events during migration and phagocytosis: chemotaxis-inhibitor protein of S.

The cytolytic peptides phenol-soluble modulins PSMs have an amphipathic alpha-helical region that likely contributes to their lytic activity, presumably by membrane insertion and pore formation. B Secreted bacterial factors that inhibit opsonization and phagocytosis by neutrophils. The secreted metalloprotease aureolysin inhibits phagocytosis and killing of bacteria by neutrophils by cleaving C3.

The extracellular fibrinogen binding protein EFB and the extracellular complement-binding protein ECB also inhibit complement activation by inactivating C5 convertase and staphylococcal SSL7 targets C5. Staphylococcal binder of immunoglobulin SBI affect both the function of complement and immunoglobulin binding, blocking the classical complement activation pathway, and associates with C3 inhibiting the alternative pathway. Staphylokinase SAK forms enzymatically active complexes with C3b blocking complement activation.

Staphylococcus aureus also secretes a number of antagonists of neutrophil receptors interfering with chemokine signaling and limiting neutrophil recruitment Figure 4A. In particular, SSL5 directly binds the N-terminus of G-protein coupled chemokine receptors GPCRs inhibiting calcium mobilization and actin polymerization, thus impairing neutrophil responses to a huge diversity of chemokines e.

In addition, SSL5 was shown to bind to platelet glycoproteins, inducing platelet activation and aggregation, which could be important for colonization and immune evasion by S. Phenol-soluble modulins are produced by all S. At nanomolar concentrations, PSMs bind to and activate FPRs, with the strongest activation occurring through FPR2, stimulating several FPRs effector functions such as chemotaxis and pro-inflammatory cytokine production e. However, human isolates of S.

Inhibition of FPRs-mediated pro-inflammatory signaling occurs via the secretion of the chemotaxis-inhibitor protein of S. The repertoire of secreted molecules by S. Stathopain A inhibits CXCR2-mediated calcium mobilization, migration, intracellular signaling and activation of neutrophils Laarman et al. Staphylococcus aureus display intrinsic physical features e.

In addition, S. Several of these secreted molecules target C3 or C3 convertases, both central molecules in the complement activation cascade. Aureolysin is a metalloproteinase that cleaves C3, generating a modified C3b fragment that is further degraded instead of being covalently linked to the bacterial surface where it would promote the generation of the chemoattractant molecule C5a Laarman et al.

In addition, this proteinase degrades human antimicrobial peptides highly potent against S. Thus, aureolysin activity promotes infection by blocking the complement cascade impairing bacterial C3b opsonization, phagocytosis, and neutrophil-mediated killing Sieprawska-Lupa et al. Staphylococcal component inhibitor SCIN specifically binds to human C3 convertase and blocks its activity thereby preventing the production of C3a, C3b, and C5a, thus interfering with complement activation and with neutrophil-mediated killing of S.

Other S. Besides their role in blocking neutrophil extravasation and chemotaxis described above , some SSLs also hinder complement activation and phagocytosis. SSL7 binds IgA and complement C5, inhibiting the production of C5a and further phagocytosis and bacterial clearance during in vivo infection Bestebroer et al. In addition to phagocytosis and intracellular killing, neutrophils evolved an alternative defense mechanism to trap extracellular pathogens and prevent their dissemination.

This strategy relies on the release of nuclear content together with antimicrobial cytosolic and granular proteins to form neutrophil extracellular traps NETs , which are scaffolds that act as physical barriers to pathogen progression protecting host tissues from damage Papayannopoulos and Zychlinsky, NET degradation by Nuc leads to the production of monophosphate nucleotides that are further converted into deoxyadenosine through the activity of adenosine synthase AdsA , another S.

Interestingly, the accumulation of deoxyadenosine generated by AdsA activity promotes the autocleavage of pro-caspase-3, triggering caspaseinduced apoptosis of infiltrating macrophages Thammavongsa et al. Together, staphylococcal Nuc and AdsA act in a concerted mode to promote bacterial survival in S. In line with its ability to evade almost every step of the innate immune response, S. As mentioned above, PSMs are S. They trigger inflammatory responses by interacting with FPR2 and display, at higher concentrations, FPR2-independent cytolytic activity likely through membrane insertion and pore formation Kretschmer et al.

In vitro , expression levels of PSMs correlate with levels of cytotoxicity Rasigade et al. In addition to PSMs whose cytolytic activity is receptor-independent, S.

In vivo infection studies have shown that Hla is required for several S. Although these results suggest that the outcome of Hla-mediated effects may dependent on the infected tissue, the role of Hla on tissue-specific innate immunity requires further analysis. Leukocidins are composed by two distinct and independently secreted subunits that form heteromultimeric pores in the membrane of host myeloid cells Otto, In vitro assays with purified proteins, as well as ex-vivo infections with S.

LukED, produced by a large majority of clinical isolates of S. Importantly, LukED was shown to play a critical role in S. Despite the several attempts to evaluate the exact contribution of each of these toxins to S.

In this context, the data obtained from commonly used animal infection models e. Mycobacterium ulcerans is the causative agent of Buruli ulcer, a chronic ulcerative skin disease that usually starts as painless nodules on the limbs that then develop into large ulcers. Buruli ulcer occurs most frequently in children living in tropical environments, near wetlands.

The disease is more common in poor and rural areas of Africa but is also found in South America, Asia and Australia. Genetically very close to M. Mycolactone displays cytotoxic and immunosuppressive activities and is considered the major pathogenicity factor in Buruli ulcer, being essential for M. In animal models, injection of mycolactone alone is sufficient to cause ulcers similar to those found in infected hosts George et al.

Concerning the mechanism of cellular intoxication, it has been proposed that, due to its hydrophobic nature, mycolactone passively diffuses through the plasma membrane Snyder and Small, ; Figure 5.

At micromolar concentrations, mycolactone is highly cytotoxic to a variety of mammalian cells, with variable susceptibility levels depending on the cell type Hall and Simmonds, The mycolactone cytotoxicity has been linked to its apoptogenic activity. Apoptosis was observed in several cell types incubated in vitro with mycolactone George et al. More importantly, massive apoptosis has been observed in Buruli ulcer lesions Walsh et al. The mycolactone-induced cell death mechanisms appear to be complex and are not completely understood.

Early studies on mycolactone reported the occurrence of early actin cytoskeleton rearrangements, cell rounding, and detachment following incubation with the toxin George et al. More recently, studies with HeLa and Jurkat T cells have shown that mycolactone induces increased actin polymerisation in intoxicated cells, as a consequence of its binding to the GTPase domain of the actin-cytoskeleton regulator Wiskott-Aldrich syndrome protein WASP Guenin-Mace et al. In epithelial cells, this causes loss of cell adhesion and E-cadherin-dependent tight junctions, ultimately leading to the death of detached cells by anoikis Guenin-Mace et al.

Recent studies performed in vitro with murine fibroblasts confirmed the cytoskeleton as a main target of mycolactone, by showing that mycolactone causes changes in microtubules and affects several regulators and structural components of microtubules and microfilaments Gama et al. These deleterious effects inflicted by mycolactone upon the cytoskeleton likely contribute to the formation of the lesions characteristic of Burulli ulcer.

Additionally, given the central role of the cytoskeleton in controlling key cellular functions, such as endocytosis, intracellular trafficking, cell adhesion and migration, it is reasonable to speculate that, by highjacking cytoskeleton functions, mycolatone perturbs the functions of phagocytic cells. Indeed, it is likely that the decreased phagocytic activity of macrophages exposed to mycolactone Adusumilli et al. Further investigations are required to determine whether cytoskeleton is manipulated by mycolactone in macrophages and neutrophils and what are the consequences of this manipulation in vivo.

Mycolactone inhibits the secretion of most cytokines, chemokines and other inflammatory mediators by macrophages. In eukaryotic cells, secretory proteins cross the ER membrane before being transported in vesicles to the Golgi complex and then to the plasma membrane. Mycolactone enters cells by passive diffusion through the plasma membrane and inhibits the production of inflammatory mediators by macrophages by blocking the translocation of nascent proteins into the ER.

The proteins wrongly accumulated in the cytosol are then degraded by the proteasome. In addition to its known cytotoxic effects toward distinct cell types, at non-cytotoxic concentrations, mycolactone interferes with important functions of immune cells, including monocytes, macrophages, and DCs Arango Duque and Descoteaux, ; Hall and Simmonds, It is well recognized that macrophages play crucial roles in mycobacterial infections, including in Buruli ulcer.

Although Buruli ulcer histopathology is characterized by extensive areas of necrosis with abundant extracellular bacteria, studies on infected humans, and experimental M. Usually, phagocytosis of a microorganism triggers signaling events that rapidly culminate in a controlled inflammatory response involving the secretion of several cytokines and chemokines that recruit other inflammatory cells to the site of infection. However, available evidence suggests that this early response is heavily perturbed by mycolactone.

Indeed, cells exposed to mycolactone-producing strains of M. It has been proposed that this suppression is associated with a mycolactone-induced blockade of co-translational protein translocation into the ER and subsequent degradation of the aberrantly located proteins in the cytosol Hall et al.

Failure to produce cytokines and chemokines may contribute to the absence of inflammatory infiltrate at the central necrotic areas of the lesion containing high numbers of extracellular bacilli, in addition to the lysis of recruited inflammatory cells induced by the build-up of mycolactone.

The inflammatory infiltrates occupy a band at the periphery of the lesion that represents a front that is continuously advancing into healthy tissues in progressive M. The clearance of infectious agents greatly depends on the host innate immune responses that take place at early stages of infection and in which macrophages and neutrophils are the central players.

To counteract the host defense mechanisms, bacterial pathogens secrete a bench of different toxins that neutralize, at different levels, the host innate immune response and in particular, annihilate the function of macrophages and neutrophils. Furthermore, a single pathogen may secrete several toxins that act differently to produce the same outcome e.

These apparently redundant strategies of bacterial attack ensure the multistep impairment of the early host immune responses mounted against the pathogen and guarantee the control of host—pathogen interaction providing a window of time and opportunity for bacterial growth and establishment within the host. In the past, many studies aiming to uncover the molecular functions of bacterial toxins on host cells were performed in vitro in several cultured cell lines, and more recently in primary cells, using a wide range of concentrations of purified toxins.

In addition, studies on animal models mainly in rodents using either purified toxins, wild type bacteria and toxin-deficient mutants, provided a number of important observations regarding the toxin-mediated pathologies. Together, these studies generated an incredible amount of data that paradoxically poorly contributed to the understanding of the role of toxins in human infections. Whereas in the perspective of using toxins as molecular tools to address cell biology topics there is great value in testing toxin effects in many in vitro cell systems, several issues render extremely difficult the interpretation of data from in vitro studies in the context of infection.

In particular, the concentration of purified toxin used is often much higher than that produced by bacteria during infection and it is highly variable among different studies, and the cell lines tested are often non-relevant for the pathophysiology of the infection. Regarding studies performed in animal models, two major concerns have been pointed out: 1 many toxins display species-specificity and thus routinely used models, specially rodents, are non-relevant for the study of many toxin-mediated human pathologies compromising the extrapolation of data and 2 direct inoculation of purified toxins in the animals only provide limited information that do not necessarily recapitulate the effect of a given toxin in the context of human bacterial infection.

Thus, the data generated so far needs to be cautiously analyzed whenever we aim to better understand the role of toxins in the in vivo infectious process.

The accurate role of toxins in human infections needs to be analyzed in the context of bacterial infections in different animal species. In this perspective, future efforts should concentrate in the development and use of appropriate animal models, possibly non-human primates, in which available in vitro and in vivo data can be confirmed and possibly extrapolated to the human pathologies. AdV and SS wrote the manuscript.

DC contributed with figures design. The manuscript content was discussed and decided by all the authors. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We apologize to authors whose relevant work could not be cited owing to space limitations. Abrami, L. Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway. Cell Biol. Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process.

Adusumilli, S. Mycobacterium ulcerans toxic macrolide, mycolactone modulates the host immune response and cellular location of M. Agrawal, A. Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin. Nature , — Ahmad, J. Cell Microbiol. Alileche, A. Anthrax lethal toxin-mediated killing of human and murine dendritic cells impairs the adaptive immune response.

PLoS Pathog 1:e Alonzo, F. III, Benson, M. Staphylococcus aureus leucocidin ED contributes to systemic infection by targeting neutrophils and promoting bacterial growth in vivo. III, Kozhaya, L. Nature , 51— Andreasen, C. Pertussis toxin inhibits early chemokine production to delay neutrophil recruitment in response to Bordetella pertussis respiratory tract infection in mice.

Role of neutrophils in response to Bordetella pertussis infection in mice. Pertussis toxin stimulates IL production in response to Bordetella pertussis infection in mice. Appelberg, R. Neutrophils and intracellular pathogens: beyond phagocytosis and killing.

Trends Microbiol. Arango Duque, G. Macrophage cytokines: involvement in immunity and infectious diseases. Baker, H. Crystal structures of the staphylococcal toxin SSL5 in complex with sialyl Lewis X reveal a conserved binding site that shares common features with viral and bacterial sialic acid binding proteins.

Baldari, C. Anthrax toxins: a paradigm of bacterial immune suppression. Trends Immunol. Barnes, A. Update on bacterial vaccines: Photobacterium damselae subsp. Basel , 75— Google Scholar. Barson, H. Anthrax lethal toxin suppresses chemokine production in human neutrophil NB-4 cells. Barth, H. Baruch, K. EMBO J. Bassinet, L. Role of adhesins and toxins in invasion of human tracheal epithelial cells by Bordetella pertussis.

Becker, R. Tissue-specific patterning of host innate immune responses by Staphylococcus aureus alpha-toxin. Innate Immun. Berends, E. Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. Bergman, N.

Murine macrophage transcriptional responses to Bacillus anthracis infection and intoxication. Berube, B. Staphylococcus aureus alpha-toxin: nearly a century of intrigue.

Toxins Basel 5, — Bestebroer, J. Functional basis for complement evasion by staphylococcal superantigen-like 7. Blood , — PubMed Abstract Google Scholar. Staphylococcal SSL5 inhibits leukocyte activation by chemokines and anaphylatoxins. The ability to manipulate the process of phagocytosis is a mechanism often utilized by bacteria to ensure they effectively invade a host.

Phagocytosis is a process utilized by phagocytes white blood cells as a defense mechanism to protect from foreign bodies.

The phagocytes engulf invaders and present them to additional factors within the immune system that result in their destruction. However, a successful and destructive pathogen often exhibits the ability to evade phagocytosis. The mechanism s utilized by pathogens to avoid phagocytosis include avoiding both contact and engulfment. This is accomplished by the ability of the bacteria to exhibit produce molecules that interfere with the phagocytes ability to internalize the bacteria.

Molecules that interfere with this process include certain types of proteins and sugars that block engulfment. Protected from Phagocytosis : Staphylococcus aureus exhibit physical properties, specifically a capsule, that protect the bacteria from phagocytosis. Once the pathogen has successfully evaded engulfment and destruction by the immune system, it is detrimental because the bacteria then multiply.

Often times, bacteria will directly attach themselves to host cells and utilize nutrients from the host cell for their own cellular processes. Upon the use of host nutrients for its own cellular processes, the bacteria may also produce toxins or enzymes that will infiltrate and destroy the host cell. The production of these destructive products results in the direct damage of the host cell. The waste products of the microbes will also damage to the cell. Examples of bacteria that will damage tissue by producing toxins, include, Corynebacterium diphtheriae and Streptococcus pyogenes.

Specifically, Corynebacterium diphtheriae causes diphtheria, which isa disease of the upper respiratory tract. It produces a toxin, diphtheria toxin, which alters host protein function. The toxin can then result in damage to additional tissues including the heart, liver, and nerves. Fibrin clots will form at sites of injury, in this case, at the site of foreign invasion.

The enzymes, capable of digesting fibrin, will open an area within the epithelial cells and promote invasion of the bacteria into the tissues. Type III and IV secretion systems are utilized by pathogenic bacteria to transfer molecules from the bacterial cell to the host cell. In regards to pathogenecity, secretion in microorganisms such as bacterial species involves the movement of effector molecules from the interior of a pathogenic organism to the exterior.

The secretion of specific molecules allows for adaptation to occur, thereby promoting survival. Effector molecules secreted include proteins, enzymes or toxins.

The mechanisms by which pathogenic bacteria secrete proteins involve complex and specialized secretion systems. Specifically, Type III and Type IV secretion systems are utilized by gram-negative pathogenic bacteria to transport proteins that function as pathogenic components. Type III secretion systems are characterized by the ability to inject a protein directly from the bacterial cell to the eukaryotic cell.

It is often compared to the bacterial flagellar basal body which functions as a motor unit and extracellular appendage that is comprised of numerous proteins.

The pathogenic bacteria which exhibit this capability contain a critical structural component, considered a protein appendage, that allows the injection of the protein into the host cell. The process of injecting or transferring the secretory protein from the bacterial cell to the host eukaryotic cell requires a membrane-associated ATPase.

For example, in Salmonella, most commonly associated with Enteritis salmonellosis , or food poisoning, the bacteria injects a toxin, AvrA, that inhibits activation of the innate immune system of the host. The mechanism by which AvrA is injected involves exact and proper assembly of proteins which promote invasion of the host cell.

Misalignment or improper organization of proteins involved in the type III secretion system prevent injection of secretory substances from the pathogen into the host cell. Another pathogen, Shigella , which utilizes type III secretion systems is able to successfully carry out its infection by evading the immune system.

The movement between neighboring cells and evading the immune system, enhances its ability to inject its secretory protein into the host cell. Type IV Secretion System : Type IV secretion systems are characterized by the ability to transfer material using machinery similar to the bacterial conjugation machinery.

Type IV secretion systems are characterized by the ability to transfer secretory molecules via a mechanism similar to the bacterial conjugation machinery. The type IV secretion systems can either secrete or receive molecules. The bacterial conjugation machinery allows transfer of genetic material to occur via direct cell-to-cell contact or by a bridge-like apparatus between the two cells. The type IV secretion system utilizes a process similar to this. However, the exact mechanism s this process utilizes is unknown but there is a general understanding.

This specific secretion system can transport both DNA and proteins. An example of a pathogenic bacteria that utilizes the type IV secretion system is Helicobacter pylori. The secretory molecule injected into the epithelial cells is an inflammation-inducing agent derived from their own cellular wall. The secretory molecule, peptidoglycan, is recognized by the host system as a foreign substance and activates expression of cytokines which promotes an inflammatory response. This inflammatory response of the stomach is a key characteristic of individuals with ulcers.

Peptidoglycan is not the only secretory molecule transferred to the stomach epithelial cells but additional proteins, such as CagA, which function in disruption of host cell cellular activities can be transferred as well.

Both plasmids and lysogeny are used by bacteria and viruses to ensure transfer of genes and nucleic acids for viral reproduction. Plasmids are often characterized by their circular appearance and double-strands; they also vary in size and number. The plasmids are present within the cells as extra chromosomal genomes and are a common tool used in molecular biology to integrate new DNA into a host.

In addition, plasmid DNA provides a mechanism by which horizontal gene transfer can occur, contributing to antibiotic resistance. Horizontal gene transfer is a major mechanism promoting bacterial antibiotic resistance, as the plasmid DNA can transfer genes from one species of bacteria to another.

The plasmid DNA which is transferred often has developed genes that encode for resistance against antibiotics. The ability to transfer this resistance from one species to another is increasingly becoming an issue in clinics for treatment of bacterial infections.

The process of horizontal gene transfer can occur via three mechanisms: transformation, transduction and conjugation. Plasmid DNA transfer is associated with conjugation as the host-to-host transfer requires direct mechanical transfer.

The advantages of plasmid DNA transfer allow for survival advantages. Horizontal Gene Transfer : There are three mechanisms by which horizontal gene transfer can occur. Specifically, the exchange of plasmid DNA falls under transformation. Lysogeny is utilized by viruses to ensure the maintenance of viral nucleic acids within the genome of the bacterium host.