Comparative Phylogenomics and Evolution of the Brucellae Reveal a Path to Virulence

Brucella species include important zoonotic pathogens that have a substantial impact on both agriculture and human health throughout the world. Brucellae are thought of as “stealth pathogens” that escape recognition by the host innate immune response, modulate the acquired immune response, and evade intracellular destruction. We analyzed the genome sequences of members of the family Brucellaceae to assess its evolutionary history from likely free-living soil-based progenitors into highly successful intracellular pathogens. Phylogenetic analysis split the genus into two groups: recently identified and early-dividing “atypical” strains and a highly conserved “classical” core clade containing the major pathogenic species. Lateral gene transfer events brought unique genomic regions into Brucella that differentiated them from Ochrobactrum and allowed the stepwise acquisition of virulence factors that include a type IV secretion system, a perosamine-based O antigen, and systems for sequestering metal ions that are absent in progenitors. Subsequent radiation within the core Brucella resulted in lineages that appear to have evolved within their preferred mammalian hosts, restricting their virulence to become stealth pathogens capable of causing long-term chronic infections.     

Using food for different purposes: female responses to prey in the predator Coccinella septempunctata L. (Coleoptera: Coccinellidae)

Abstract.  1. Although predatory insects often feed on diverse prey, their reproductive activity may be linked most strongly to a more restricted range of prey. The propensity of adult females of the ladybird beetle, Coccinella septempunctata L., to attack two natural prey species, pea aphids [ Acyrthosiphon pisum (Harris)] and alfalfa weevil larvae [ Hypera postica (Gyllenhal)], was compared, and the degree to which ladybird egg production depends on consumption of aphids vs. weevils was assessed.
2. Coccinella septempunctata females more readily attacked aphids than weevil larvae. This was true regardless of whether females had fed previously on aphids or on weevil larvae.
3. When females were provided with few to many aphids daily, or few aphids plus an excess number of weevil larvae, their rates of egg production depended primarily on the number of aphids consumed.
4. Addition of weevil larvae to diets of limited numbers of aphids increased egg production, but only modestly. Thus, consumption of weevil larvae may have served mostly for self-maintenance, thereby enabling females to use for egg production more of the nutrients and energy obtained from limited consumption of aphids.
5. The females' linkage of egg production primarily to aphid rather than weevil consumption may be adaptive, as their offspring are much less able as larvae to survive and mature on a diet of weevils rather than aphids.     

Depletion of B cells in murine lupus: efficacy and resistance

In mice, genetic deletion of B cells strongly suppresses systemic autoimmunity, providing a rationale for depleting B cells to treat autoimmunity. In fact, B cell depletion with rituximab is approved for rheumatoid arthritis patients, and clinical trials are underway for systemic lupus erythematosus. Yet, basic questions concerning mechanism, pathologic effect, and extent of B cell depletion cannot be easily studied in humans. To better understand how B cell depletion affects autoimmunity, we have generated a transgenic mouse expressing human CD20 on B cells in an autoimmune-prone MRL/MpJ-Fas(lpr) (MRL/lpr) background. Using high doses of a murine anti-human CD20 mAb, we were able to achieve significant depletion of B cells, which in turn markedly ameliorated clinical and histologic disease as well as antinuclear Ab and serum autoantibody levels. However, we also found that B cells were quite refractory to depletion in autoimmune-prone strains compared with non-autoimmune-prone strains. This was true with multiple anti-CD20 Abs, including a new anti-mouse CD20 Ab, and in several different autoimmune-prone strains. Thus, whereas successful B cell depletion is a promising therapy for lupus, at least some patients might be resistant to the therapy as a byproduct of the autoimmune condition itself.     

Regulatory rewiring confers serotype‐specific hyper‐virulence in the human pathogen group A Streptococcus

Phenotypic heterogeneity is commonly observed between isolates of a given pathogen. Epidemiological analyses have identified that some serotypes of the group A Streptococcus (GAS) are non‐randomly associated with particular disease manifestations. Here, we present evidence that a contributing factor to the association of serotype M3 GAS isolates with severe invasive infections is the presence of a null mutant allele for the orphan kinase RocA. Through use of RNAseq analysis, we identified that the natural rocA mutation present within M3 isolates leads to the enhanced expression of more than a dozen immunomodulatory virulence factors, enhancing phenotypes such as hemolysis and NAD⁺ hydrolysis. Consequently, an M3 GAS isolate survived human phagocytic killing at a level 13‐fold higher than a rocA complemented derivative, and was significantly more virulent in a murine bacteremia model of infection. Finally, we identified that RocA functions through the CovR/S two‐component system as levels of phosphorylated CovR increase in the presence of functional RocA, and RocA has no regulatory activity following covR or covS mutation. Our data are consistent with RocA interfacing with the CovR/S two‐component system, and that the absence of this activity in M3 GAS potentiates the severity of invasive infections caused by isolates of this serotype.     

Synthesis of anomeric 1,5-anhydrosugars as conformationally locked selective α-mannosidase inhibitors

Anomeric 1,5-anhydrosugar 2 was synthesized from d-glucose derived N-Cbz protected aminodiol 8. The key step involves, acid catalyzed hydrolysis of 1,2-acetonide group in 8 to get hemiacetal that concomitantly undergoes formation of the pyranose ring by attack of C-3 hydroxyethyl group on anomeric C-1, leading to the formation of dioxabicyclo[3.2.1]octane skeleton which on hydrogenolyis gave 2. The glycosidase inhibitory activities of hydroxy- and amino-substituted anomeric 1,5-anhydrosugars 1 and 2, respectively, showed selective inhibition of α-mannosidase. These results were substantiated by molecular docking studies using WHAT IF software and AUTODOCK 4.0 program.