Prevalence and Predictors of Colposcopic-Histopathologically Confirmed Cervical Intraepithelial Neoplasia in HIV-Infected Women in India

Background

Prevalence estimates of cervical intraepithelial neoplasia (CIN) among HIV-infected women in India have been based on cervical cytology, which may have underestimated true disease burden. We sought to better establish prevalence estimates and evaluate risk factors of CIN among HIV-infected women in Pune, India using colposcopy and histopathology as diagnostic tools.

Methodology

Previously unscreened, non-pregnant HIV-infected women underwent cervical cancer screening evaluation including standardized diagnostic colposcopy by a gynecologist. Histopathologic confirmation was conducted among consenting women with clinical suspicion of CIN. The prevalence of CIN was evaluated by a composite diagnosis based on colposcopy and histopathology results. Multivariable ordinal logistic regression analysis was conducted to determine independent predictors of increasing severity of CIN.

Results

The median age of the n = 303 enrolled HIV-infected women was 30 years (interquartile range, 27–34). A majority of the participants were widowed or separated (187/303, 61.7%), more than one-third (114/302, 37.7%) were not educated beyond primary school, and nearly two-thirds (196/301, 64.7%) had a family per capita income of <1,000 Indian Rupees (∼US$22) per month. Cervical high-risk HPV-DNA was detected in 41.7% (124/297) of participants. The composite colposcopic-histopathologic diagnoses revealed no evidence of CIN in 220 out of 303 (72.6%) women, CIN1 in 33/303 (10.9%), CIN2 in 31/303 (10.2%), CIN3 in 18/303 (5.9%) and 1 (0.3%) woman was diagnosed with ICC. Thus, over a quarter of the participants [83/303: 27.7% (95% CI: 22.7–33.1)] had ≥CIN1 lesions and a sixth [50/303: 16.5% (95% CI: 12.2–21.9)] had evidence of advanced (≥CIN2) neoplastic disease. The independent predictors of increasing severity of CIN as revealed by a proportional odds model using multivariable ordinal logistic regression included (i) currently receiving antiretroviral therapy [adjusted odds ratios (aOR): 2.24 (1.17, 4.26), p = 0.01] and (ii) presence of cervical high-risk HPV-DNA [aOR: 1.93 (1.13, 3.28), p = 0.02].

Conclusions

HIV-infected women in Pune, India have a substantial burden of cervical precancerous lesions, which may progress to invasive cervical cancer unless appropriately detected and treated. Increased attention should focus on recognizing and addressing this entirely preventable cancer among HIV-infected women, especially in the context of increasing longevity due to antiretroviral therapy.     

Colonic Immune Stimulation by Targeted Oral Vaccine

Background

Currently, sufficient data exist to support the use of lactobacilli as candidates for the development of new oral targeted vaccines. To this end, we have previously shown that Lactobacillus gasseri expressing the protective antigen (PA) component of anthrax toxin genetically fused to a dendritic cell (DC)-binding peptide (DCpep) induced efficacious humoral and T cell-mediated immune responses against Bacillus anthracis Sterne challenge.

Methodology/Principal Finding

In the present study, we investigated the effects of a dose dependent treatment of mice with L. gasseri expressing the PA-DCpep fusion protein on intestinal and systemic immune responses and confirmed its safety. Treatment of mice with different doses of L. gasseri expressing PA-DCpep stimulated colonic immune responses, resulting in the activation of innate immune cells, including dendritic cells, which induced robust Th1, Th17, CD4⁺Foxp3⁺ and CD8⁺Foxp3⁺ T cell immune responses. Notably, high doses of L. gasseri expressing PA-DCpep (10¹² CFU) were not toxic to the mice. Treatment of mice with L. gasseri expressing PA-DCpep triggered phenotypic maturation and the release of proinflammatory cytokines by dendritic cells and macrophages. Moreover, treatment of mice with L. gasseri expressing PA-DCpep enhanced antibody immune responses, including IgA, IgG₁, IgG_2b, IgG_2c and IgG₃. L. gasseri expressing PA-DCpep also increased the gene expression of numerous pattern recognition receptors, including Toll-like receptors, C-type lectin receptors and NOD-like receptors.

Conclusion/Significance

These findings suggest that L. gasseri expressing PA-DCpep has substantial immunopotentiating properties, as it can induce humoral and T cell-mediated immune responses upon oral administration and may be used as a safe oral vaccine against anthrax challenge.     

Characterization of halophilic bacteria from environmental samples from the brackish water of Pulicat Lake, India

Culture dependent phenotypic characterization and 16S rDNA based phylogenetic analyses were applied to study the aerobic halophilic bacterial population present in the Pulicat brackish-water Lake of India. Five different media were employed for isolation of bacteria. A total of 198 morphotypes were recovered, purified and screened for salt tolerance in nutrient agar medium amended with 5–25% NaCl. Based on 16S rDNA restriction fragment length polymorphism analysis with three restriction endonucleases, 51 isolates tolerant to 5% or more NaCl were grouped into 29 clusters. Phylogenetic analysis using 16S rRNA gene sequences revealed that 29 strains could further be allocated into two clades: 19 to Firmicutes and 10 to γ-Proteobacteria. Firmicutes included low G+C Gram-positive bacteria related to family Bacillaceae, which included five genera Bacillus, Virgibacillus, Rummelibacillus, Alkalibacillus and Halobacillus. Another genera included in Firmicutes was Salimicrobium halophilum. In the γ-Proteobacteria group, all the isolates belonged to one genus Halomonas, represented by six different species Halomonas salina, H. shengliensis, H. salifodinae, H. pacifica, H. aquamarina and H. halophila. Most of the isolates exhibited cellulase, xylanase, amylase and protease activities.     

SIGNR3‐dependent immune regulation by Lactobacillus acidophilus surface layer protein A in colitis

Intestinal immune regulatory signals govern gut homeostasis. Breakdown of such regulatory mechanisms may result in inflammatory bowel disease (IBD). Lactobacillus acidophilus contains unique surface layer proteins (Slps), including SlpA, SlpB, SlpX, and lipoteichoic acid (LTA), which interact with pattern recognition receptors to mobilize immune responses. Here, to elucidate the role of SlpA in protective immune regulation, the NCK2187 strain, which solely expresses SlpA, was generated. NCK2187 and its purified SlpA bind to the C-type lectin SIGNR3 to exert regulatory signals that result in mitigation of colitis, maintenance of healthy gastrointestinal microbiota, and protected gut mucosal barrier function. However, such protection was not observed in Signr3^−/− mice, suggesting that the SlpA/SIGNR3 interaction plays a key regulatory role in colitis. Our work presents critical insights into SlpA/SIGNR3-induced responses that are integral to the potential development of novel biological therapies for autoinflammatory diseases, including IBD.     

Pattern separation: a common function for new neurons in hippocampus and olfactory bulb

While adult-born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information. See the related Perspective from Aimone, Deng, and Gage, "Resolving New Memories: A Critical Look at the Dentate Gyrus, Adult Neurogenesis, and Pattern Separation," in this issue of Neuron.     

ROCK I-mediated activation of NF-kappaB by RhoB

RhoB is a short-lived protein whose expression is increased by a variety of extra-cellular stimuli including UV irradiation, epidermal growth factor (EGF) and transforming growth factor beta (TGF-beta). Whereas most Rho proteins are modified by the covalent attachment of a geranylgeranyl group, RhoB is unique in that it can exist in either a geranylgeranylated (RhoB-GG) or a farnesylated (RhoB-F) form. Although each form is proposed to have different cellular functions, the signaling events that underlie these differences are poorly understood. Here we show that RhoB can activate NF-kappaB signaling in multiple cell types. Whereas RhoB-F is a potent activator of NF-kappaB, much weaker activation is observed for RhoB-GG, RhoA, and RhoC. NF-kappaB activation by RhoB is not associated with increased nuclear translocation of RelA/p65, but rather, by modification of the RelA/p65 transactivation domain. Activation of NF-kappaB by RhoB is dependent upon ROCK I but not PRK I. Thus, ROCK I cooperates with RhoB to activate NF-kappaB, and suppression of ROCK I activity by genetic or pharmacological inhibitors blocks NF-kappaB activation. Suppression of RhoB activity by dominant-inhibitory mutants, or siRNA, blocks NF-kappaB activation by Bcr, and TSG101, but not by TNFalpha or oncogenic Ras. Collectively, these observations suggest the existence of an endosome-associated pathway for NF-kappaB activation that is preferentially regulated by the farnesylated form of RhoB.     

Piriformospora indica, a Cultivable Plant-Growth-Promoting Root Endophyte

Piriformospora indica (Hymenomycetes, Basidiomycota) is a newly described cultivable endophyte that colonizes roots. Inoculation with the fungus and application of fungal culture filtrate promotes plant growth and biomass production. Due to its ease of culture, this fungus provides a model organism for the study of beneficial plant-microbe interactions and a new tool for improving plant production systems.