Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane C-type Lectin Receptors

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes

Visioning the Future: Scenarios Modeling of the Florida Coastal Everglades

In this paper, we provide screening-level analysis of plausible Everglades ecosystem response by 2060 to sea level rise (0.50 m) interacting with macroclimate change (1.5 °C warming, 7% increase in evapotranspiration, and rainfall that either increases or decreases by 10%). We used these climate scenarios as input to the Ecological Landscape Model to simulate changes to seven interactive hydro-ecological metrics. Mangrove forest and other marine influences migrated up to 15 km inland in both scenarios, delineated by the saltwater front. Freshwater habitat area decreased by 25–30% under our two climate change scenarios and was largely replaced by mangroves and, in the increased rainfall scenario, open water as well. Significant mangroves drowned along northern Florida Bay in both climate change scenarios due to sea level rise. Increased rainfall of 10% provided significant benefits to the spatial and temporal salinity regime within the marine-influenced zone, providing a more gradual and natural adjustment for at-risk flora and fauna. However, increased rainfall also increased the risk of open water, due to water depths that inhibited mangrove establishment and reduced peat accumulation rates. We infer that ecological effects related to sea level rise may occur in the extreme front-edge of saltwater intrusion, that topography will control the incursion of this zone as sea level rises, and that differences in freshwater availability will have ecologically significant effects on ecosystem resilience through the temporal and spatial pattern of salinity changes

Shifting Ground: Landscape-Scale Modeling of Biogeochemical Processes under Climate Change in the Florida Everglades

Scenarios modeling can be a useful tool to plan for climate change. In this study, we help Everglades restoration planning to bolster climate change resiliency by simulating plausible ecosystem responses to three climate change scenarios: a Baseline scenario of 2010 climate, and two scenarios that both included 1.5 °C warming and 7% increase in evapotranspiration, and differed only by rainfall: either increase or decrease by 10%. In conjunction with output from a water-use management model, we used these scenarios to drive the Everglades Landscape Model to simulate changes in a suite of parameters that include both hydrologic drivers and changes to soil pattern and process. In this paper we focus on the freshwater wetlands; sea level rise is specifically addressed in prior work. The decreased rainfall scenario produced marked changes across the system in comparison to the Baseline scenario. Most notably, muck fire risk was elevated for 49% of the period of simulation in one of the three indicator regions. Surface water flow velocity slowed drastically across most of the system, which may impair soil processes related to maintaining landscape patterning. Due to lower flow volumes, this scenario produced decreases in parameters related to flow-loading, such as phosphorus accumulation in the soil, and methylmercury production risk. The increased rainfall scenario was hydrologically similar to the Baseline scenario due to existing water management rules. A key change was phosphorus accumulation in the soil, an effect of flow-loading due to higher inflow from water control structures in this scenario

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin- kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P = 0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P = 0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients