This in addition to the lack of apoptosis

This in addition to the lack of apoptosis selleck kinase inhibitor assessed by caspase 3 levels sug gests that L. jensenii is capable of colonizing and self sustaining the human vaginal epithelia without cellular toxicity. In this model L. jensenii produced full length biologically active mCV N within the epithelial context. mCV N did not compromise cell viability or elicit an immuno inflammatory response when tested in both rabbits and macaques. This study confirmed the ability of bioengineered L. jensenii strains to reproducibly colonize the cervicovaginal epithelial model and to maintain anti HIV expression of functional peptides in vitro without the induction of a significant change in inflammation associated proteins. The ability for endogenous lactobacilli to colonize and es tablish dominance in the vaginal microenvironment has been previously investigated.

Lactobacillus isolates were Inhibitors,Modulators,Libraries successfully introduced intravaginally as a probiotic against BV and urinary tract infections in women. In a study conducted by Hemmerling et al. L. crispatus colonized BV infected women 61 78% of the time. We found all L. jensenii strains including the mCV N expressing L. jensenii capable of reproducibly and stably colonizing the human cervicovaginal epithelial Inhibitors,Modulators,Libraries cells over a 72 h period without significant perturbations to innate immune barrier parameters while abundantly expressing mCV N detectable by both Western blot and the functional Inhibitors,Modulators,Libraries gp120 assay. The stable colonization mCV N expressing L.

jensenii 1153 1666 strain and the stability and anti HIV activity of the mCV N protein have been confirmed in a mouse model Inhibitors,Modulators,Libraries over a period of six days and in the Rhesus macaque for six weeks post inoculation, where it reduced SHIV infection by 63% in Inhibitors,Modulators,Libraries a repeated challenge model, without altering mar kers associated with mucosal barrier function. Taken together these in vivo findings provide validation of our in vitro model. The bioengineered mCV N, similarly to the natural protein, is stable at a broad pH range from 4 8. 2. This wide pH stability spectrum encompasses both the acidic pH generated by lactic acid producing bacteria and the slightly more alkaline pH introduced to the vaginal environment with seminal fluid. The natural and modified CV N molecules are also resistant to thermal and chem ical denaturation, which would allow it to be produced and stored in a variety of environmental conditions. These attributes render mCV N to be a promising microbicide candidate. In this proof of concept in vitro model, the bioengi neered L. jensenii did not differ from the wild type pa rental strain in term of epithelial colonization capacity and did not induce a pro inflammatory profile in the human epithelial cell context.

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