SummaryThe Drosophila tumor suppressor gene lethal (1) discs large (dlg) encodes a protein necessary for normal cell growth in epithelial and brain tissue. It shares high sequence identity to the mammalian synaptic proteins PSD-95 and SAP-70, whose functions are unknown. To determine the localization and role of dlg at synapses, we investigated its distribution and the effects of dlg mutations on Drosophila neuromuscular junctions. We show that dlg immunoreactivity is expressed at one type of glutamatergic synapse and is associated with both presynaptic and postsynaptic membranes. Mutations in dlg alter the expression of dlg and cause striking changes in the structure of the subsynaptic reticulum, a postsynaptic specialization at these synapses. These results indicate that dlg is required for normal synaptic structure and offer insights regarding the role of dlg homologs at vertebrate synapses.

BackgroundWe investigated the impact of antimicrobials in cervicovaginal lavage (CVL) from HIV(+) and HIV(−) women on target cell infection with HIV. Since female reproductive tract (FRT) secretions contain a spectrum of antimicrobials, we hypothesized that CVL from healthy HIV(+) and (−) women inhibit HIV infection.Methodology/Principal FindingsCVL from 32 HIV(+) healthy women with high CD4 counts and 15 healthy HIV(−) women were collected by gently washing the cervicovaginal area with 10 ml of sterile normal saline. Following centrifugation, anti-HIV activity in CVL was determined by incubating CVL with HIV prior to addition to TZM-bl cells. Antimicrobials and anti-gp160 HIV IgG antibodies were measured by ELISA. When CXCR4 and CCR5 tropic HIV-1 were incubated with CVL from HIV(+) women prior to addition to TZM-bl cells, anti-HIV activity in CVL ranged from none to 100% inhibition depending on the viral strains used. CVL from HIV(−) controls showed comparable anti-HIV activity. Analysis of CH077.c (clone of an R5-tropic, mucosally-transmitted founder virus) viral inhibition by CVL was comparable to laboratory strains. Measurement of CVL for antimicrobials HBD2, trappin-2/elafin, SLPI and MIP3α indicated that each was present in CVL from HIV(+) and HIV(−) women. HBD2 and MIP3α correlated with anti-HIV activity as did anti-gp160 HIV IgG antibodies in CVL from HIV(+) women.Conclusions/SignificanceThese findings indicate that CVL from healthy HIV(+) and HIV(−) women contain innate and adaptive defense mechanisms that inhibit HIV infection. Our data suggest that innate endogenous antimicrobials and HIV-specific IgG in the FRT can act in concert to contribute toward the anti-HIV activity of the CVL and may play a role in inhibition of HIV transmission to women.

Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease.

Staphylococcus aureus bacteremia (SAB) is a lethal and increasingly common infection in hospitalized patients. We assessed the impact of infectious diseases consultation (IDC) on clinical management and hospital mortality of SAB in 240 hospitalized patients in a retrospective cohort study. Patients who received IDC were older than those who did not (57.9 vs. 51.7 yr; p = 0.05), and were more likely to have a health care-associated infection (63% vs. 45%; p < 0.01). In patients who received IDC, there was a higher prevalence of severe complications of SAB such as central nervous system involvement (5% vs. 0%, p = 0.01), endocarditis (20% vs. 2%; p < 0.01), or osteomyelitis (15.6% vs. 3.4%; p < 0.01). Patients who received IDC had closer blood culture follow-up and better antibiotic selection, and were more likely to have pus or prosthetic material removed. Hospital mortality from SAB was lower in patients who received IDC than in those who did not (13.9% vs. 23.7%; p = 0.05). In multivariate survival analysis, IDC was associated with substantially lower hazard of hospital mortality during SAB (hazard 0.46; p = 0.03). This mortality benefit accrued predominantly in patients with methicillin-resistant SAB (hazard 0.3; p < 0.01), and in patients who did not require ICU admission (hazard 0.15; p = 0.01). In conclusion, IDC is associated with reduced mortality in patients with staphylococcal bacteremia.