SSTP1, a Host Defense Peptide, Exploits the Immunomodulatory IL6 Pathway to Induce Apoptosis in Cancer Cells.

While the immunomodulatory pathways initiated in immune cells contribute to therapeutic response, their activation in cancer cells play a role in cancer progression. Also, many of the aberrantly expressed immunomodulators on cancer cells are considered as therapeutic targets. Here, we introduce host defense peptide (HDP), a known immuomodulator, as a therapeutic agent to target them. The cationic host defense peptides (HDPs), an integral part of the innate immune system, possess membranolytic activity, which imparts antimicrobial and antitumor efficacy to it. They act as immunomodulators by activating the immune cells. Though their antimicrobial function has been recently reassigned to immunoregulation, their antitumor activity is still attributed to its membranolytic activity. This membrane pore formation ability, which is proportional to the concentration of the peptide, also leads to side effects like hemolysis, limiting their therapeutic application. So, despite the identification of a variety of anticancer HDPs, their clinical utility is limited. Though HDPs are shown to exert the immunomodulatory activity through specific membrane targets on immune cells, their targets on cancer cells are unknown. We show that SSTP1, a novel HDP identified by shotgun cloning, binds to the active IL6/IL6Rα/gp130 complex on cancer cells, rearranging the active site residues. In contrast to the IL6 blockers inhibiting JAK/STAT activity, SSTP1 shifts the proliferative IL6/JAK/STAT signaling to the apoptotic IL6/JNK/AP1 pathway. In IL6Rα-overexpressing cancer cells, SSTP1 induces apoptosis at low concentration through JNK pathway, without causing significant membrane disruption. We highlight the importance of immunomodulatory pathways in cancer apoptosis, apart from its established role in immune cell regulation and cancer cell proliferation. Our study suggests that identification of the membrane targets for the promising anticancer HDPs might lead to the identification of new drugs for targeted therapy.

Comprehensive genomics depict accessory genes encoding pathogenicity and biofilm determinants in Enterococcus faecalis.

Aim:Enterococcus faecalis is a leading nosocomial pathogen in biofilm-associated polymicrobial infections. The study aims to understand pathogenicity and biofilm determinants of the pathogen by genome analysis. Methodology: Genome sequencing of a strong biofilm forming clinical isolate Enterococcus faecalis SK460 devoid of Fsr quorum-signaling system, was performed and comparative genomics was carried out among a set of pathogenic biofilm formers and nonpathogenic weak biofilm formers. Results: Analysis revealed a pool of virulence and adhesion related factors associated with pathogenicity. Absence of CRISPR-Cas system facilitated acquisition of pheromone responsive plasmid, pathogenicity island and phages. Comprehensive analysis identified a subset of accessory genes encoding polysaccharide lyase, sugar phosphotransferase system, phage proteins and transcriptional regulators exclusively in pathogenic biofilm formers. Conclusion: The study identified a set of genes specific to pathogenic biofilm formers and these can act as targets which in turn help to develop future treatment endeavors against enterococcal infections.

Genetic structure and demographic history of Indirana semipalmata, an endemic frog species of the Western Ghats, India.

The evolutionary potential of a species mainly depends on the level of genetic variation in their populations. Maintenance of gene variation enables populations to adapt more quickly to environmental changes. The geographical gaps also influence the distribution and evolutionary history of many mountain frogs in the world. Hence, a sound knowledge in population genetic structure of a species will help understand its population dynamics and develop conservation strategies. In the context of facing threats to the amphibian fauna of Western Ghats due to habitat loss, we used both mitochondrial and nuclear DNA markers to investigate the genetic structure of an endemic frog species of the Western Ghats (Indirana semipalmata) with restricted distribution. The present study showed the importance of mountain gaps in shaping the species' structuring in the Western Ghats. Though a high genetic diversity was observed for the species when considering a single unit in the southern Western Ghats, the restricted gene flow on/between either side of the Shencottah gap with genetic clustering of the sampled populations may warrant a unique management plan for the species. The habitat fragmentation of the Western Ghats through anthropogenic activities may result in severe setbacks to the survival of the species in the future.

Epidemiological and pathogenic characteristics of Haitian variant V. cholerae circulating in India over a decade (2000-2018).

Vibrio cholerae, causative agent of the water-borne disease cholera still threatens a large proportion of world's population. The major biotypes of the pathogen are classical and El Tor. There have been recent reports of variant V. cholerae strains circulating around the world. In the present study, the epidemiological status of V. cholerae strains circulating in the country over a decade was assessed. Also, a comprehensive analysis of the difference in pathogenicity between the different biotypes of V. cholerae strains was evaluated both in-vitro and in-vivo. The amount of CT produced by different biotypes of V. cholerae strains were analyzed by GM1 ELISA and the probable reasons for the difference in toxin production was discussed. MLST analysis grouped the isolates into a single Sequence Type (ST 69) whereas PFGE analysis clustered the isolates into ten different pulsotypes revealing molecular diversity. The circulating strains were identified to produce cholera toxin and CT mRNA intermediate to the classical and prototype El Tor strains. Also, the circulating strains were identified to possess four ToxR binding sequences. In-vivo pathogenicity analysis by rabbit ileal loop fluid accumulation assay revealed the Haitian variant strains to be more hyperemic than the prototype strains.