Group B Streptococcus: global incidence and vaccine development

An ongoing public health challenge is to develop vaccines that are effective against infectious diseases that have global relevance. Vaccines against serotypes of group B Streptococcus (GBS) that are prevalent in the United States and Europe are not optimally efficacious against serotypes common to other parts of the world. New technologies and innovative approaches are being used to identify GBS antigens that overcome serotype-specificity and that could form the basis of a globally effective vaccine against this opportunistic pathogen. This Review highlights efforts towards this goal and describes a template that can be followed to develop vaccines against other bacterial pathogens.     

Environmental and spatial drivers of beta diversity components of chironomid metacommunities in contrasting freshwater systems

Marine sponges are exposed to predation as well as to a wide array of potentially harmful microorganisms, and therefore they often possess chemical activity against putative predators and/or pathogens. Some crude extracts from sponges are effective in avoiding microbial colonization or potential infections, and in protecting them against predation. Here, the antibacterial activity of 18 sponge species of Antarctic shallow-waters was tested against four Antarctic and four human pathogenic bacteria. Moreover, all sponge extracts were tested for feeding repellence against the seastar Odontaster validus, one of the main predators living in those habitats. All the sponges showed antibacterial activity against at least one bacterial isolate, although not all of them were active against pathogenic bacteria. The antibacterial effect against sympatric bacteria was stronger than to pathogenic bacteria. In contrast, feeding deterrence was low, with similar activities in both hydrophilic and lipophilic extracts. Only four sponges (Myxilla lyssostyla, Phorbas areolatus, Polymastia invaginata and Iophon sp.), presented repellent chemical defenses. Therefore, we conclude that chemical defenses are widespread in Antarctic shallow-water sponges, and in fact, these sponges are better protected against bacteria than against the seastar predator. We conclude that Antarctic sponges represent a valuable source of biological active compounds with pharmacological and potential ecological relevance.     

Differential effectiveness of salicylate-dependent and jasmonate/ethylene-dependent induced resistance in Arabidopsis

Salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) are each involved in the regulation of basal resistance against different pathogens. These three signals play important roles in induced resistance as well. SA is a key regulator of pathogen-induced systemic acquired resistance (SAR), whereas JA and ET are required for rhizobacteria-mediated induced systemic resistance (ISR). Both types of induced resistance are effective against a broad spectrum of pathogens. In this study, we compared the spectrum of effectiveness of SAR and ISR using an oomycete, a fungal, a bacterial, and a viral pathogen. In noninduced Arabidopsis plants, these pathogens are primarily resisted through either SA-dependent basal resistance (Peronospora parasitica and Turnip crinkle virus [TCV]), JA/ET-dependent basal resistance responses (Alternaria brassicicola), or a combination of SA-, JA-, and ET-dependent defenses (Xanthomonas campestris pv. armoraciae). Activation of ISR resulted in a significant level of protection against A. brassicicola, whereas SAR was ineffective against this pathogen. Conversely, activation of SAR resulted in a high level of protection against P. parasitica and TCV, whereas ISR conferred only weak and no protection against P. parasitica and TCV, respectively. Induction of SAR and ISR was equally effective against X. campestris pv. armoraciae. These results indicate that SAR is effective against pathogens that in noninduced plants are resisted through SA-dependent defenses, whereas ISR is effective against pathogens that in noninduced plants are resisted through JA/ET-dependent defenses. This suggests that SAR and ISR constitute a reinforcement of extant SA- or JA/ET-dependent basal defense responses, respectively.     

Utilization of Fc receptors as a mucosal vaccine strategy against an intracellular bacterium, Francisella tularensis

Numerous studies have demonstrated that targeting Ag to Fc receptors (FcR) on APCs can enhance humoral and cellular immunity. However, studies are lacking that examine both the use of FcR-targeting in generating immune protection against infectious agents and the use of FcRs in the induction of mucosal immunity. Francisella tularensis is a category A intracellular mucosal pathogen. Thus, intense efforts are underway to develop a vaccine against this organism. We hypothesized that protection against mucosal infection with F. tularensis would be significantly enhanced by targeting inactivated F. tularensis live vaccine strain (iFt) to FcRs at mucosal sites, via intranasal immunization with mAb-iFt complexes. These studies demonstrate for the first time that: 1) FcR-targeted immunogen enhances immunogen-specific IgA production and protection against subsequent infection in an IgA-dependent manner, 2) FcgammaR and neonatal FcR are crucial to this protection, and 3) inactivated F. tularensis, when targeted to FcRs, enhances protection against the highly virulent SchuS4 strain of F. tularensis, a category A biothreat agent. In summary, these studies show for the first time the use of FcRs as a highly effective vaccination strategy against a highly virulent mucosal intracellular pathogen.     

A facile synthesis, antibacterial, and antitubercular studies of some piperidin-4-one and tetrahydropyridine derivatives

The raise in clinical significance of multidrug-resistant bacterial pathogens has directed us to synthesize 2,6-diarylpiperidin-4-one and Delta(3)-tetrahydropyridin-4-ol based benzimidazole and O-arylsulfonyl derivatives. X-ray crystal structure of tetrahydropyridinol (23) confirmed a change in conformation and orientation of substituents upon amide formation. Antibacterial activities evaluated against a wide number of bacterial pathogens (both sensitive and multidrug-resistant) revealed that 19, 27 against Staphylococcus aureus, 27 against Enterococcus faecalis, and 19, 21, 23, and 27 against Enterococcus faecium are significantly good at lowest MIC(90) (16 microg/mL). Inhibitory power noticed by 23 against Vancomycin-Linezolid-resistant E. faecalis and 27 against Vancomycin-resistant E. faecium are onefold better than the standard Linezolid and Trovafloxacin drugs, respectively. Moreover, antitubercular activity for the selected compounds against Mycobacterium tuberculosis H37Rv revealed that compounds 23, 24, and 27 expressed onefold improved potency compared to the standard Rifampicin drug.     

Antimicrobial activities of some Bacillus spp. strains isolated from the soil

In this study a total of 29 Bacillus species isolated from the soil was analyzed using the agar diffusion method in terms of their general inhibition effects to some test bacteria. It has been found that isolates are effective against gram-positive and gram-negative bacteria whereas their extensive inhibition effect is particularly against gram-positive bacteria. On the other hand, B. cereus M15 strain has an inhibitory effect against both gram-positive and gram-negative bacteria. Furthermore some isolates are more effective against test bacteria when compared to some antibiotics.     

The exact values of the probability of fixation of underdominant chromosomal rearrangements.

A numerical analysis of the probability of fixation of a chromosomal mutation with partial sterility of the heterozygote in a single population is performed. Three different genetic models are considered: the first model entails constant selection against the heterozygote and is the model almost universally used in previous works; in the other two models selection against the heterozygote depends on its frequency. The exact values of the fixation probability are found by iterating transition matrices with genotype specification. Differences in results among models are small. The exact values found in the first model are compared to estimates obtained from approximations. Solutions based on diffusion models give good approximations when selection against the heterozygote is low, especially if the population is very small. For the higher values of the selection coefficient against the heterozygote, the estimates are rather imprecise, especially when the populations are not very small.     

Do parasitoid preferences for different host species match virulence?

Abstract.  Leptopilina boulardi is a parasitoid wasp specialist of Drosophila larvae of the melanogaster subgroup. In Mediterranean areas, natural populations are highly virulent against their main host Drosophila melanogaster . In Congo, populations are less virulent against D. melanogaster but are able to develop successfully inside the tropical African species Drosophila yakuba . Host preferences are compared between two laboratory isofemale lines of L. boulardi , obtained from populations of Congo and Tunisia, respectively, and differing in virulence levels against D. melanogaster and D. yakuba . Host selection is studied by offering female parasitoids a choice between larvae of the two host species. In agreement with optimal foraging models, the line highly virulent against D. melanogaster shows a clear preference for this host species. The other line, less virulent against D. melanogaster but more virulent against D. yakuba , prefers to oviposit on D. yakuba . Such preferences can be observed after a period of host-patch exploitation only, suggesting that experience plays an important role in the host-selection process. These results evidence the existence of intraspecific variability in preference between two host species in L. boulardi , a major requisite in theoretical models of parasite specialization by the host. They also sustain the hypothesis that intraspecific variation in parasitoid preferences between host species might mirror intraspecific variation in virulence.     

Enhancing Blockade of Plasmodium falciparum Erythrocyte Invasion: Assessing Combinations of Antibodies against PfRH5 and Other Merozoite Antigens

No vaccine has yet proven effective against the blood-stages of Plasmodium falciparum, which cause the symptoms and severe manifestations of malaria. We recently found that PfRH5, a P. falciparum-specific protein expressed in merozoites, is efficiently targeted by broadly-neutralizing, vaccine-induced antibodies. Here we show that antibodies against PfRH5 efficiently inhibit the in vitro growth of short-term-adapted parasite isolates from Cambodia, and that the EC₅₀ values of antigen-specific antibodies against PfRH5 are lower than those against PfAMA1. Since antibody responses elicited by multiple antigens are speculated to improve the efficacy of blood-stage vaccines, we conducted detailed assessments of parasite growth inhibition by antibodies against PfRH5 in combination with antibodies against seven other merozoite antigens. We found that antibodies against PfRH5 act synergistically with antibodies against certain other merozoite antigens, most notably with antibodies against other erythrocyte-binding antigens such as PfRH4, to inhibit the growth of a homologous P. falciparum clone. A combination of antibodies against PfRH4 and basigin, the erythrocyte receptor for PfRH5, also potently inhibited parasite growth. This methodology provides the first quantitative evidence that polyclonal vaccine-induced antibodies can act synergistically against P. falciparum antigens and should help to guide the rational development of future multi-antigen vaccines.     

Human immunodeficiency virus neutralizing antibodies recognize several conserved domains on the envelope glycoproteins.

Serum neutralizing antibodies against the human immunodeficiency virus were frequently detected in infected individuals, and low or absent serum neutralizing titers correlated with poor prognosis. Multiple diverse human immunodeficiency virus isolates were found to exhibit similar susceptibility to neutralization by a panel of human seropositive sera, suggesting that neutralizing antibodies are largely directed against conserved viral domains. Furthermore, utilizing antisera raised against a library of synthetic env peptides, four regions which are important in the neutralization process have been identified within both human immunodeficiency virus envelope glycoproteins (gp41 and gp120). Three of these are in conserved domains and should be considered for inclusion in a candidate vaccine.     

Elevated MnSOD is not required for exercise-induced cardioprotection against myocardial stunning

Endurance exercise provides cardioprotection against ischemia-reperfusion-induced myocardial stunning and infarction. A recent study demonstrates that an exercise-induced increase in myocardial manganese superoxide dismutase (MnSOD) activity is essential to protect the heart against infarction. It is unknown if an elevation in cardiac MnSOD is also a prerequisite to achieve exercise-induced protection against myocardial stunning. Therefore, this study determined if an exercise-induced increase in myocardial MnSOD activity is a requirement to achieve protection against myocardial stunning. Adult male rats remained sedentary or performed successive bouts of endurance exercise. Hearts were exposed to 25 min of global ischemia followed by reperfusion in an isolated working heart preparation. Postischemic recovery of cardiac external work during reperfusion was significantly higher (84 +/- 3 vs. 67 +/- 4%) in exercised animals compared with sedentary controls. Furthermore, prevention of exercise-induced expression of myocardial MnSOD via antisense oligonucleotides did not retard this exercise-induced protection against myocardial stunning. These data demonstrate that exercise-induced increases in cardiac MnSOD activity are not essential to achieve exercise-mediated protection against myocardial stunning. Therefore, we conclude that different mediators are responsible for exercise-induced cardioprotection against myocardial stunning and infarction.     

Effective induction of high-titer antibodies by viral vector vaccines

Protein-in-adjuvant vaccines have shown limited success against difficult diseases such as blood-stage malaria. Here we show that a recombinant adenovirus-poxvirus prime-boost immunization regime (known to induce strong T cell immunogenicity) can also induce very strong antigen-specific antibody responses, and we identify a simple complement-based adjuvant to further enhance immunogenicity. Antibodies induced against a blood-stage malaria antigen by this viral vector platform are highly effective against Plasmodium yoelii parasites in mice and against Plasmodium falciparum in vitro.     

Myrosinase: gene family evolution and herbivore defense in Brassicaceae

Glucosinolates are a category of secondary products present primarily in species of the order Capparales. When tissue is damaged, for example by herbivory, glucosinolates are degraded in a reaction catalyzed by thioglucosidases, denoted myrosinases, also present in these species. Thereby, toxic compounds such as nitriles, isothiocyanates, epithionitriles and thiocyanates are released. The glucosinolate-myrosinase system is generally believed to be part of the plant's defense against insects, and possibly also against pathogens. In this review, the evolution of the system and its impact on the interaction between plants and insects are discussed. Further, data suggesting additional functions in the defense against pathogens and in sulfur metabolism are reviewed.     

Immunological comparison of the b and c1 cytochromes from bovine heart mitochondria and the photosynthetic bacterium Rhodopseudomonas sphaeroides R-26

Antibodies against cytochromes b and c1 of bovine heart mitochondria and the photosynthetic bacterium, Rhodopseudomonas sphaeroides R-26, were raised in rabbits. The purified antibodies showed high titers against their respective antigens in enzyme-linked immunosorbent assays. Less than 15% cross-reactivity between the mitochondrial and bacterial cytochromes was detected. Although antibodies against mitochondrial cytochrome b did not inhibit the mitochondrial cytochrome b-c1 complex, a 70% inhibition was obtained when these antibodies were incubated with delipidated mitochondrial cytochrome b-c1 complex prior to reconstitution with phospholipids indicating that the catalytic site(s) of mitochondrial cytochrome b are masked by phospholipids. On the other hand, antibodies against bacterial cytochrome b showed significant inhibition of the intact bacterial cytochrome b-c1 complex, indicating that some of the catalytic site epitopes of bacterial cytochrome b are exposed to the hydrophilic environment. Similar to antibodies against mitochondrial cytochrome b, antibodies against bacterial cytochrome b inhibited 50% activity of the mitochondrial cytochrome b-c1 complex only when they were incubated with the delipidated mitochondrial cytochrome b-c1 complex prior to reconstitution with phospholipids, indicating that the common epitopes between the cytochromes b are masked by phospholipids. Antibodies against mitochondrial and bacterial cytochromes c1 completely inhibited their respective cytochrome b-c1 complexes but no cross-immunoinhibition was observed. However, when antibodies against bacterial cytochrome c1 were incubated with the delipidated mitochondrial cytochrome b-c1 complex before reconstitution with phospholipids, a 65% inhibition was observed, indicating that the common epitopes between the cytochromes c1 were also somewhat masked by phospholipids. Antibodies against mitochondrial cytochrome c1 inhibited 70% of the succinate oxidase activity in the intact mitochondria preparation, but no inhibition was observed in submitochondrial particles, indicating that some mitochondrial cytochrome c1 epitopes are exposed to the cytoplasmic side.     

Autoantibodies against red blood cell antigens are common in a malaria endemic area

Plasmodium falciparum malaria can cause severe anemia. Even after treatment, hematocrit can decrease. The role of autoantibodies against erythrocytes is not clearly elucidated and how common they are, or what they are directed against, is still largely unknown.We have investigated antibodies against erythrocytes in healthy adult men living in a highly malaria endemic area in Uganda. We found antibodies in more than half of the individuals, which is significantly more than in a non-endemic area (Sweden). Some of the Ugandan samples had a broad reactivity where it was not possible to determine the exact target of the autoantibodies, but we also found specific antibodies directed against erythrocyte surface antigens known to be of importance for merozoite invasion such as glycophorin A (anti-En^a, anti-M) and glycophorin B (anti-U, anti-S). In addition, several autoantibodies had partial specificities against glycophorin C and the blood group systems Rh, Diego (located on Band 3), Duffy (located on ACKR1), and Cromer (located on CD55), all of which have been described to be important for malaria and therefore of interest for understanding how autoantibodies could potentially stop parasites from entering the erythrocyte.In conclusion, specific autoantibodies against erythrocytes are common in a malaria endemic area.     

Synthesis, biochemical evaluation of a range of potent 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17alpha-Hydroxylase/17,20-Lyase (P45017alpha)

We report the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of azole-based compounds as inhibitors of the two components of the cytochrome P-450 enzyme 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), i.e. 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results suggest that the compounds synthesised are potent inhibitors, with 7-phenyl heptyl imidazole (11) (IC(50)=320 nM against 17alpha-OHase and IC(50)=100 nM against lyase); 1-[7-(4-fluorophenyl) heptyl] imidazole (14) (IC(50)=170 nM against 17alpha-OHase and IC(50)=57 nM against lyase); 1-[5-(4-bromophenyl) pentyl] imidazole (19) (IC(50)=500 nM against 17alpha-OHase and IC(50)=58 nM against lyase) being the most potent inhibitors within the current study, in comparison to ketoconazole (KTZ) (IC(50)=3.76 microM against 17alpha-OHase and IC(50)=1.66 microM against lyase). Furthermore, consideration of the inhibitory activity against the two components shows that all of the compounds tested are less potent towards the 17alpha-OHase in comparison to the lyase component, a desirable property in the development of novel inhibitors of P450(17alpha). From the modelling of these compounds onto the novel substrate heme complex (SHC) for the overall enzyme complex, the length of the compound, along with its ability to undergo interaction with the active site corresponding to the C(3) area of the steroidal backbone, are suggested to play a key role in determining the overall inhibitory activity.     

Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17alpha-hydroxylase/17,20-lyase (P450(17alpha))

The cytochrome P-450 enzyme, 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), is a potential target in hormone-dependent cancers. Here, we report the synthesis and biochemical evaluation of a range of benzyl imidazole-based compounds which have been targeted against the two components of this enzyme, that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results from the biochemical testing suggest that the compounds synthesised are good inhibitors, with N-4-iodobenzyl imidazole (5) (IC50=10.06 microM against 17alpha-OHase and IC50=1.58 microM against lyase) showing equipotent activity against lyase compared to the standard compound, ketoconazole (KTZ) (IC50=3.76+/-0.01 microM against 17alpha-OHase and IC50=1.66+/-0.15 microM against lyase). Furthermore, the compounds tested are less potent towards the 17alpha-OHase component, a desirable property in the development of novel inhibitors of P450(17alpha).     

Specific and Selective Bacteriophages in the Fight against Multidrug-resistant Acinetobacter baumannii

Acinetobacter baumannii causes serious infections especially in immunocompromised and/or hospitalized patients. Several A. baumannii strains are multidrug resistant and infect wounds, bones, and the respiratory tract. Current studies are focused on finding new effective agents against A. baumannii. Phage therapy is a promising means to fight this bacterium and many studies on procuring and applying new phages against A. baumannii are currently being conducted. As shown in animal models, phages against multidrug-resistant A. baumannii may control bacterial infections caused by this pathogen and may be a real hope to solve this dangerous health problem.     

Immunocharacterization of the mucin-type proteins from the intracellular stage of Trypanosoma cruzi

The surface of Trypanosoma cruzi is covered by different groups of mucins that are differentially expressed during the parasite life cycle. We have previously identified the major mucins from the bloodstream trypomastigote stage. Here, we present additional evidence that together with our previous observations allows for the identification of a second mucin group also expressed in the mammal-dwelling stages, but predominant in the intracellular amastigote. These mucins are encoded by many genes, are mostly composed of tandem repeats and are highly conserved except for an exposed hypervariable (HV) N-terminal peptide. Antibodies against HV-peptides are restricted to approximately 50% of the chronically infected human population, are monospecific (i.e. directed towards a single HV), and display low-avidity. In contrast, immunization with a single HV-peptide triggers high-avidity, cross-reacting humoral responses against multiple HV sequences, but not against other T. cruzi surface antigens. The diversity present in the HV regions and the characteristics of the antibody response against them suggest a role of these molecules in eluding and/or modulating the mammalian host immune system.     

Antioxidant activity of carotenoids

Carotenoids are pigments which play a major role in the protection of plants against photooxidative processes. They are efficient antioxidants scavenging singlet molecular oxygen and peroxyl radicals. In the human organism, carotenoids are part of the antioxidant defense system. They interact synergistically with other antioxidants; mixtures of carotenoids are more effective than single compounds. According to their structure most carotenoids exhibit absorption maxima at around 450 nm. Filtering of blue light has been proposed as a mechanism protecting the macula lutea against photooxidative damage. There is increasing evidence from human studies that carotenoids protect the skin against photooxidative damage.