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PubMed2004

Antibody regulation of Tcell immunity: implications for vaccine strategies against intracellular pathogens.

Intracellular microbial pathogens cause a plethora of diseases that pose a huge public health challenge. Efficacious prophylactic vaccines are needed to protect the population from this myriad of infectious diseases. Contemporary approaches to vaccine design are guided by the immunobiological paradigm that extracellular pathogens are controlled principally by humoral immunity, involving specific antibodies, whereas host protection against intracellular pathogens requires effectors of cell-mediated immunity. However, this distinct T-helper (Th) type 1 and 2 paradigm of host defense has encountered a major challenge due to the reality that most antigens or vaccines induce mixed immune responses comprising of both humoral and CMI effectors. Besides, the true functional independence of antibodies and T-cells under in vivo physiologic conditions is uncertain. Recent findings have revealed that antibodies exert a significant immunoregulatory effect on T-cell immunity. Thus, a robust and protective T-cell memory response against microbial pathogens such as Chlamydia and Mycobacteria require an effective primary humoral immune response characterized by specific antibody isotypes whose role is to modulate Th1 activation via Fc receptors (FcR) by facilitating a rapid uptake, processing and presentation of pathogen-derived antigens for an enhanced T-cell response. These findings have crystallized into a paradigm shift in host defense wherein different components of the apparently disparate mixed immune responses elicited against a microbial pathogen function concertedly to maximize the principal effector mechanism. This review focuses on the essential role of both arms of the immune system in controlling intracellular microbial pathogens, especially the regulatory role of FcR-mediated antibody function in optimizing the induction of a protective Th1 response. The immunobiological implications are discussed in the context of vaccine design, delivery and evaluation against intracellular microbial pathogens of bacteria, fungi and parasitic origin.

Animals↗

PubMed2006

DspA/E, a type III effector essential for Erwinia amylovora pathogenicity and growth in planta, induces cell death in host apple and nonhost tobacco plants.

Erwinia amylovora is responsible for fire blight, a necrotic disease of apples and pears. E. amylovora relies on a type III secretion system (TTSS) to induce disease on hosts and hypersensitive response (HR) on nonhost plants. The DspA/E protein is essential for E. amylovora pathogenicity and is secreted via the TTSS in vitro. DspA/E belongs to a type III effector family that is conserved in several phytopathogenic bacteria. In E. amylovora, DspA/E has been implicated in the generation of an oxidative stress during disease and the suppression of callose deposition. We investigated the fate of DspA/E in planta. DspA/E delivered artificially to apple or tobacco cells by agroinfection induced necrotic symptoms, indicating that DspA/E was probably injected via the TTSS. We confirmed that DspA/E acts as a major cell-death inducer during disease and HR, because the dspA/E mutant is severely impaired in its ability to induce electrolyte leakage in apple and tobacco leaves. Expression of the defense marker gene PR1 was delayed when dspA/E was transiently expressed in tobacco, suggesting that DspA/E-mediated necrosis may be associated with an alteration of defense responses.

Amino Acid Sequence↗

PubMed2004

Effector proteins encoded by Salmonella pathogenicity island 2 interfere with the microtubule cytoskeleton after translocation into host cells.

The facultative intracellular pathogen Salmonella enterica has evolved strategies to modify its fate inside host cells. One key virulence factor for the intracellular pathogenesis is the type III secretion system encoded by Salmonella Pathogenicity Island 2 (SPI2). We have previously described SPI2-encoded SseF and SseG as effector proteins that are translocated by intracellular Salmonella. Detailed analysis of the subcellular localization of SseF and SseG within the host cell indicated that these effector proteins are associated with endosomal membranes as well as with microtubules. Specific association with microtubules was observed after translocation by intracellular Salmonella as well as after expression by transfection vectors. In epithelial cells infected with Salmonella, both SseF and SseG are required for the aggregation of endosomal compartments along microtubules and to induce the formation of massive bundles of microtubules. These observations demonstrate that SPI2 effectors interfere with the microtubule cytoskeleton and suggest that microtubule-dependent host cell functions such as vesicle transport or organelle positioning are altered by intracellular Salmonella.

Bacterial Proteins↗

PubMed1996

A secreted protein tyrosine phosphatase with modular effector domains in the bacterial pathogen Salmonella typhimurium.

A number of bacterial pathogens have evolved sophisticated strategies to subvert host-cell signal-transduction pathways for their own benefit. These bacteria produce and export proteins capable of specific interactions with key mammalian cell regulatory molecules in order to derail the normal functions of the cells. In this study, we describe the identification of a modular effector protein secreted by the bacterial pathogen Salmonella typhimurium that is required for its full display of virulence. Sequence analysis revealed that a carboxy-terminal region of this protein, which we have termed SptP, is homologous to the catalytic domains of protein tyrosine phosphatases. Purified SptP protein efficiently dephosphorylated peptide substrates phosphorylated on tyrosine. An engineered mutant of SptP in which a critical Cys residue in the catalytic domain was changed to Ser was devoid of phosphatase activity, indicating a catalytic mechanism similar to that of other tyrosine phosphatases. In addition, an amino-terminal region of SptP exhibited sequence similarity to the ribosyltransferase exoenzyme S from Pseudomonas aeruginosa and the cytotoxin YopE from Yersinia spp. The modular nature of this effector protein may allow multiple interactions with host-cell signalling functions.

Amino Acid Sequence↗

PubMed2005

Type III effector proteins from the plant pathogen Xanthomonas and their role in the interaction with the host plant.

Pathogenicity of Xanthomonas campestris pathovar (pv.) vesicatoria and most other Gram-negative bacterial plant pathogens largely depends on a type III secretion (TTS) system which is encoded by hypersensitive response and pathogenicity (hrp) genes. These genes are induced in the plant and are essential for the bacterium to be virulent in susceptible hosts and for the induction of the hypersensitive response (HR) in resistant host and non-host plants. The TTS machinery secretes proteins into the extracellular milieu and effector proteins into the plant cell cytosol. In the plant, the effectors presumably interfere with cellular processes to the benefit of the pathogen or have an avirulence activity that betrays the bacterium to the plant surveillance system. Type III effectors were identified by their avirulence activity, co-regulation with the TTS system and homology to known effectors. A number of effector proteins are members of families, e.g., the AvrBs3 family in Xanthomonas. AvrBs3 localizes to the nucleus of the plant cell where it modulates plant gene expression. Another family that is also present in Xanthomonas is the YopJ/AvrRxv family. The latter proteins appear to act as SUMO cysteine proteases in the host. Here, we will present an overview about the regulation of the TTS system and its substrates and discuss the function of the AvrRxv and AvrBs3 family members in more detail.

Amino Acid Sequence↗

PubMed2005

Regulation of type III secretion hierarchy of translocators and effectors in attaching and effacing bacterial pathogens.

Human enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC), and the mouse pathogen Citrobacter rodentium (CR) belong to the family of attaching and effacing (A/E) bacterial pathogens. They possess the locus of enterocyte effacement (LEE) pathogenicity island, which encodes a type III secretion system. These pathogens secrete a number of proteins into culture media, including type III effector proteins and translocators that are required for the translocation of effectors into host cells. Preliminary evidence indicated that the LEE-encoded SepL and Rorf6/SepD may form a molecular switch that controls the secretion of translocators and effectors in CR. Here, we show that SepL and SepD indeed perform this function in A/E pathogens such as EHEC and EPEC. Their sepL and sepD mutants do not secrete translocators but exhibit enhanced secretion of effectors. We demonstrate that SepL and SepD interact with each other and that both SepL and SepD are localized to the bacterial membranes. Furthermore, we demonstrate that culture media influence the type III secretion profile of EHEC, EPEC, and CR and that low-calcium concentrations inhibit secretion of translocators but promote the secretion of effectors, similar to effects on type III secretion by mutations in sepL and sepD. However, the secretion profile of the sepD and sepL mutants is not affected by these culture conditions. Collectively, our results suggest that SepL and SepD not only are necessary for efficient translocator secretion in A/E pathogens but also control a switch from translocator to effector secretion by sensing certain environmental signals such as low calcium.

Bacterial Outer Membrane Proteins↗

PubMed2004

Human antibody-Fc receptor interactions illuminated by crystal structures.

Immunoglobulins couple the recognition of invading pathogens with the triggering of potent effector mechanisms for pathogen elimination. Different immunoglobulin classes trigger different effector mechanisms through interaction of immunoglobulin Fc regions with specific Fc receptors (FcRs) on immune cells. Here, we review the structural information that is emerging on three human immunoglobulin classes and their FcRs. New insights are provided, including an understanding of the antibody conformational adjustments that are required to bring effector cell and target cell membranes sufficiently close for efficient killing and signal transduction to occur. The results might also open up new possibilities for the design of therapeutic antibodies.

Antibodies↗

PubMed2003

Role of lipid-mediated signal transduction in bacterial internalization.

Receptor-mediated phagocytosis normally represents an important first line of immune defence. Invading microbes are internalized into phagosomes and are typically killed by exposure to a battery of microbicidal agents. To some intracellular pathogens, however, receptor-mediated phagocytosis represents an opportunity to access a protected niche within the host cell. Another type of intracellular pathogen, including Salmonella enterica serovar Typhimurium and Shigella flexneri, invade host cells in a more direct manner. These pathogens deliver effectors into the host cell via a type III secretion apparatus, initiating a ruffling response that leads to their uptake into intracellular vacuoles. Recent studies have demonstrated the importance of lipid signal transduction events in the uptake of pathogenic bacteria by both receptor-mediated phagocytosis and type III secretion-mediated invasion. In this review we highlight some of these discoveries, with a focus on phospholipid-dependent signalling events.

Animals↗

PubMed2002

A functional screen for the type III (Hrp) secretome of the plant pathogen Pseudomonas syringae.

Type III secreted "effector" proteins of bacterial pathogens play central roles in virulence, yet are notoriously difficult to identify. We used an in vivo genetic screen to identify 13 effectors secreted by the type III apparatus (called Hrp, for "hypersensitive response and pathogenicity") of the plant pathogen Pseudomonas syringae. Although sharing little overall homology, the amino-terminal regions of these effectors had strikingly similar amino acid compositions. This feature facilitated the bioinformatic prediction of 38 P. syringae effectors, including 15 previously unknown proteins. The secretion of two of these putative effectors was shown to be type III--dependent. Effectors showed high interstrain variation, supporting a role for some effectors in adaptation to different hosts.

Amino Acid Sequence↗

PubMed2005

The locus of enterocyte effacement-encoded effector proteins all promote enterohemorrhagic Escherichia coli pathogenicity in infant rabbits.

The genes encoding the enterohemorrhagic Escherichia coli (EHEC) type III secretion system (TTSS) and five effector proteins secreted by the TTSS are located on the locus of enterocyte effacement (LEE) pathogenicity island. Deletion of tir, which encodes one of these effector proteins, results in a profound reduction (approximately 10,000-fold) in EHEC colonization of the infant rabbit intestine, but the in vivo phenotypes of other LEE genes are unknown. Here, we constructed in-frame deletions in escN, the putative ATPase component of the TTSS, and the genes encoding the four other LEE-encoded effector proteins, EspH, Map, EspF, and EspG, to investigate the contributions of the TTSS and the translocated effector proteins to EHEC pathogenicity in infant rabbits. We found that the TTSS is required for EHEC colonization and attaching and effacing (A/E) lesion formation in the rabbit intestine. Deletion of escN reduced EHEC recovery from the rabbit intestine by approximately 10,000-fold. Although EspH, Map, EspF, and EspG were not required for A/E lesion formation in the rabbit intestine or in HeLa cells, these effector proteins promote EHEC colonization. Colonization by the espH and espF mutants was reduced throughout the intestine. In contrast, colonization by the map and espG mutants was reduced only in the small intestine, indicating that Map and EspG have organ-specific effects. EspF appears to down-regulate the host response to EHEC, since we observed increased accumulation of polymorphonuclear leukocytes in the colonic mucosa of rabbits infected with the EHEC espF mutant. Thus, all the known LEE-encoded effector proteins influence EHEC pathogenicity.

Animals↗

PubMedDate not supplied

HB-107, a nonbacteriostatic fragment of the antimicrobial peptide cecropin B, accelerates murine wound repair.

Antimicrobial peptides are essential to innate host defense as effectors of pathogen clearance and can modify host cell behaviors to promote wound repair. While these two functions appear interrelated, it is unclear whether the ability to aid in wound repair requires inherent antimicrobial function. We hypothesized that the influence of antimicrobial peptides on wound repair is not dependent on antimicrobial function. To explore this, we analyzed the microbial killing activity of peptide fragments and correlated this with the ability to influence wound repair in mice. HB-107, a peptide lacking antimicrobial activity and originally derived from the antimicrobial cecropin B, showed up to 64 percent improvement in wound repair compared to scrambled peptide and vehicle controls, an effect comparable to treatment with recombinant human platelet-derived growth factor-BB (formulated as Regranex). Wounds treated with HB-107 showed keratinocyte hyperplasia and increased leukocyte infiltration. Furthermore, HB-107 stimulated interleukin-8 secretion from cultured endothelial cells, an effect that may explain the increase in leukocyte migration. These findings confirm that antimicrobial peptides can function as effectors of cutaneous wound repair. Moreover, this study furthers our understanding of antimicrobial peptides by showing that their wound repair properties can be independent of antimicrobial function.

Animals↗

PubMed2004

Modulation of Rho GTPases by type III secretion system translocated effectors of Yersinia.

Pathogenic species of the bacterial genus Yersinia subdue the immune system to proliferate and spread within the host organism. For this purpose yersiniae employ a type III secretion apparatus which governs injection of six effector proteins ( Y ersinia outer proteins; Yops) into host cells. Yops control various regulatory and signalling proteins in a unique and highly specific manner. YopE, YopT, and YpkA/YopO modulate the activity of Rho GTP-binding proteins, whereas YopH dephosphorylates phospho-tyrosine residues in focal adhesion proteins. Furthermore, YopP/YopJ and YopM affect cell survival/apoptosis and cell proliferation, respectively. In this review the focus will be on the biochemistry and cellular effects of YopT, YopE, YopO/YpkA, and YopH.

Bacterial Proteins↗

PubMed2025

Exploring effector protein dynamics and natural fungicidal potential in rice blast pathogen Magnaporthe oryzae.

Rice blast, caused by Magnaporthe oryzae, is one of the most destructive fungal diseases in rice, resulting in major economic losses worldwide. Genetic and genomic studies have identified key genes and proteins, such as AvrPik variants and MAX proteins, that are crucial for the pathogen's virulence. These effector proteins interact with specific alleles of the Pik gene family on rice chromosome 11, modulating the host's immune response. In this study, we investigated 35 plant-derived metabolites known for their antifungal properties as potential fungicides against M. oryzae. Using molecular docking, we identified Hecogenin and Cucurbitacin E as strong binders to MAX40 and APIKL2A proteins, which are essential for the fungus's immune evasion and pathogenicity. Molecular dynamics simulations further confirmed that these compounds form stable, strong interactions with the target proteins, validating their potential as therapeutic agents. Additionally, the compounds were evaluated based on Lipinski's rule of five and toxicity predictions, indicating their suitability for agricultural use. These results suggest that Hecogenin and Cucurbitacin E could serve as promising lead candidates in the development of novel fungicides for rice blast, offering new strategies for crop protection and sustainable agricultural practices.

Oryza↗

PubMedDate not supplied

Mucosal immune network in the gut for the control of infectious diseases.

The common mucosal immune system (CMIS) consists of an integrated cross-communication pathway of lymphoid tissues made up of inductive and effector sites for host protection against pathogenic microorganisms. Major effector molecules of the CMIS include IgA antibodies and cytokines, chemokines and their corresponding receptors. Secretory IgA (S-IgA), the major immunoglobulin, is induced by gut-associated lymphoreticular tissue (GALT)-derived B cells with the help of Th1- and Th2-type CD4(+) T lymphocytes. Cytotoxic T lymphocytes (CTLs) in the mucosal epithelium, a subpopulation of intraepithelial lymphocytes (IELs), also help maintain the mucosal barrier. The CMIS is unique in that it can provide both positive and negative signals for the induction and regulation of immune responses in both the mucosal and systemic compartments after oral or nasal antigen exposure. Prevention of infection through mucosal surfaces can be achieved by the CMIS through connections between inductive (e.g. GALT) and effector tissues. When vaccine antigens are enterically administered together with mucosal adjuvants [e.g. cholera toxin (CT), heat-labile toxin produced by Escherichia coli (LT) and IL-12], antigen-specific Th1/Th2 and IgA B cell responses are induced simultaneously in the mucosal effector compartment. Since these antigen-specific immune responses are not generated by oral vaccine without mucosal adjuvant, safe and effective adjuvants for the induction of antigen-specific S-IgA and CTL responses are essential for the development of mucosal vaccines for protection against infectious diseases. Finally, recent findings suggest the presence of a CMIS-independent IgA induction pathway, which also must be considered in the development of mucosal vaccines.

Animals↗

PubMed1999

YopH dephosphorylates Cas and Fyn-binding protein in macrophages.

The tyrosine phosphatase YopH is an essential virulence effector of pathogenic Yersinia spp. YopH, which is translocated from extracellularly located bacteria into interacting target cells, blocks phagocytosis by professional phagocytes. We show here that immunoprecipitation of YopH from lysates of J774 cells infected with Y. pseudotuberculosis expressing an inactive form of YopH resulted in co-precipitation of certain phosphotyrosine proteins. The association between the inactive YopH and phosphotyrosine proteins in the 120 kDa range was rapid and could be detected after 2 min of infection. The proteins were identified as the docking proteins Cas and Fyn-binding protein (FYB). Upon infection of J774 cells with Y. pseudotuberculosis lacking YopH expression both of these proteins became tyrosine phosphorylated. Moreover, this infection caused recruitment of Cas to peripheral focal complexes, and FYB was relocalized to areas surrounding these structures. Both Cas and FYB became dephosphorylated upon infection with Y. pseudotuberculosis expressing active YopH, and this was associated with disruption of focal complexes. With regard to the previous identification of Cas and focal complexes as targets of YopH in HeLa cells, the present study supports an important role for these targets in a general mechanism of bacterial uptake.

Bacterial Outer Membrane Proteins↗

PubMed2006

Exogenous IL-12 suppresses experimental autoimmune encephalomyelitis (EAE) by tuning IL-10 and IL-5 levels in an IFN-gamma-dependent way.

Endogenous IL-12 is considered to be required for the generation and function of pathogenic Th1 effector cells in experimental autoimmune encephalomyelitis (EAE). We show here that IL-12 administration together with the immunization suppressed actively induced CREAE in SJL/J and in Biozzi/ABH mice and even subsequent spontaneous relapse incidence and severity in Biozzi ABH mice. IL-12 given during remission of primary disease inhibited re-induced relapses in SJL/J, but not spontaneous relapses in Biozzi mice. The protective effect of IL-12 is time- and dose-dependent. Protection is accompanied by subsequent increased production of IL-10 and IL-5 by lymph node and spleen cells and an inhibition of cell proliferation. Mice depleted of IFN-gamma by administration of neutralizing antibodies were poorly protected by exogenous IL-12, indicating that the inhibitory effect of IL-12 is partially IFN-gamma dependent.

Animals↗

PubMed2001

The MHC class II transactivator: prey and hunter in infectious diseases.

The MHC class II transcriptional activator (CIITA) is the major regulator of expression of MHC class II genes. Thus, CIITA plays a fundamental role in the regulation of the immune response. Here, we discuss our findings on the dual role of CIITA during infections, as the target (prey) for certain pathogens but the host effector (hunter) against other pathogens, including HIV-1. This dual role is placed in an evolutionary context as a rather peculiar example of a strategy used by pathogens to evade host defenses and a counteraction of the host to minimize the survival and spread of the pathogen.

Animals↗

PubMed2006

Plant NBS-LRR proteins in pathogen sensing and host defense.

Plant proteins belonging to the nucleotide-binding site-leucine-rich repeat (NBS-LRR) family are used for pathogen detection. Like the mammalian Nod-LRR protein 'sensors' that detect intracellular conserved pathogen-associated molecular patterns, plant NBS-LRR proteins detect pathogen-associated proteins, most often the effector molecules of pathogens responsible for virulence. Many virulence proteins are detected indirectly by plant NBS-LRR proteins from modifications the virulence proteins inflict on host target proteins. However, some NBS-LRR proteins directly bind pathogen proteins. Association with either a modified host protein or a pathogen protein leads to conformational changes in the amino-terminal and LRR domains of plant NBS-LRR proteins. Such conformational alterations are thought to promote the exchange of ADP for ATP by the NBS domain, which activates 'downstream' signaling, by an unknown mechanism, leading to pathogen resistance.

Amino Acid Sequence↗