Toward New Therapeutics for Skin and Soft Tissue Infections: Propargyl-Linked Antifolates Are Potent Inhibitors of MRSA and Streptococcus pyogenes

Hospital- and community-acquired, complicated skin and soft tissue infections, often attributed to Staphylococcus aureus and Streptococcus pyogenes, present a significant health burden that is associated with increased health care costs and mortality. As these two species are difficult to discern on diagnosis and are associated with differential profiles of drug resistance, the development of an efficacious antibacterial agent that targets both organisms is a high priority. Herein we describe a structure-based drug development effort that has produced highly potent inhibitors of dihydrofolate reductase from both species. Optimized propargyl-linked antifolates containing a key pyridyl substituent display antibacterial activity against both methicillin-resistant S. aureus and S. pyogenes at MIC values below 0.1 µg/mL and minimal cytotoxicity against mammalian cells. Further evaluation against a panel of clinical isolates shows good efficacy against a range of important phenotypes such as hospital- and community-acquired strains as well as strains resistant to vancomycin

Exogenous HIV-1 Nef Upsets the IFN-γ-Induced Impairment of Human Intestinal Epithelial Integrity

The mucosal tissues play a central role in the transmission of HIV-1 infection as well as in the pathogenesis of AIDS. Despite several clinical studies reported intestinal dysfunction during HIV infection, the mechanisms underlying HIV-induced impairments of mucosal epithelial barrier are still unclear. It has been postulated that HIV-1 alters enterocytic function and HIV-1 proteins have been detected in several cell types of the intestinal mucosa. In the present study, we analyzed the effect of the accessory HIV-1 Nef protein on human epithelial cell line.We used unstimulated or IFN-γ-stimulated Caco-2 cells, as a model for homeostatic and inflamed gastrointestinal tracts, respectively. We investigated the effect of exogenous recombinant Nef on monolayer integrity analyzing its uptake, transepithelial electrical resistance, permeability to FITC-dextran and the expression of tight junction proteins. Moreover, we measured the induction of proinflammatory mediators. Exogenous Nef was taken up by Caco-2 cells, increased intestinal epithelial permeability and upset the IFN-γ-induced reduction of transepithelial resistance, interfering with tight junction protein expression. Moreover, Nef inhibited IFN-γ-induced apoptosis and up-regulated TNF-α, IL-6 and MIP-3α production by Caco-2 cells while down-regulated IL-10 production. The simultaneous exposure of Caco-2 cells to Nef and IFN-γ did not affect cytokine secretion respect to untreated cells. Finally, we found that Nef counteracted the IFN-γ induced arachidonic acid cascade.Our findings suggest that exogenous Nef, perturbing the IFN-γ-induced impairment of intestinal epithelial cells, could prolong cell survival, thus allowing for accumulation of viral particles. Our results may improve the understanding of AIDS pathogenesis, supporting the discovery of new therapeutic interventions

Mechanisms of HIV-associated lymphocyte apoptosis: 2010

The inevitable decline of CD4T cells in untreated infection with the Human immunodeficiency virus (HIV) is due in large part to apoptosis, one type of programmed cell death. There is accumulating evidence that the accelerated apoptosis of CD4T cells in HIV infection is multifactorial, with direct viral cytotoxicity, signaling events triggered by viral proteins and aberrant immune activation adding to normal immune defense mechanisms to contribute to this phenomenon. Current antiviral treatment strategies generally lead to reduced apoptosis, but this approach may come at the cost of preserving latent viral reservoirs. It is the purpose of this review to provide an update on the current understanding of the role and mechanisms of accelerated apoptosis of T cells in the immunopathogenesis of HIV infection, and to highlight potential ways in which this seemingly deleterious process could be harnessed to not just control, but treat HIV infection

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

Strengthening anthrax outbreak response and preparedness: simulation and stakeholder education in Namisindwa district, Uganda

Background: Anthrax is a zoonotic disease caused by Bacillus anthracis that poses a significant threat to both human health and livestock. Effective preparedness and response to anthrax outbreak at the district level is essential to mitigate the devastating impact of the disease to humans and animals. The current diseaae surveillance in animals and humans uses two different infrastructure systems with online platform supported by established diagnostic facilities. The differences in surveillance systems affect timely outbreak response especially for zoonotic diseases like anthrax. We therefore aimed to assess the feasibility of implementing a simulation exercise for a potential anthrax outbreak in a local government setting and to raise the suspicion index of different district stakeholders for a potential anthrax outbreak in Namisindwa District, Uganda. Methods: We conducted a field-based simulation exercise and a health education intervention using quantitative data collection methods. The study participants mainly members of the District Taskforce (DTF) were purposively selected given their role(s) in disease surveillance and response at the sub-national level. We combined 26 variables (all dichotomized) assessing knowledge on anthrax and knowledge on appropriate outbreak response measures into an additive composite index. We then dichotomized overall score based on the 80% blooms cutoff i.e. we considered those scoring at least 80% to have high knowledge, otherwise low. We then assessed the factors associated with knowledge using binary logistic regression with time as a proxy for the intervention effect. Odds ratios (ORs) and 95% Confidence intervals (95%CI) have been reported. Results: The overall district readiness score was 35.0% (24/69) and was deficient in the following domains: coordination and resource mobilization (5/16), surveillance (5/11), laboratory capacity (3/10), case management (4/7), risk communications (4/12), and control measures (4/13). The overall community readiness score was 7 out of 32 (22.0%). We noted poor scores of readiness in all domains except for case management (2/2). The knowledge training did not have an effect on the overall readiness score, but improved specific domains such as control measures. Instead tertiary education was the only independent predictor of higher knowledge on anthrax and how to respond to it (OR = 1.57, 95% CI = 1.07–2.31). Training did not have a significant association with overall knowledge improvement but had an effect on several individual knowledge aspects. Conclusion: We found that the district’s preparedness to respond to a potential anthrax outbreak was inadequate, especially in coordination and mobilisation, surveillance, case management, risk communication and control measures. The health education training intervention showed increased knowledge levels compared to the pre-test and post-test an indicator that the health education sessions could increase the index of suspicion. The low preparedness underscores the urgency to strengthen anthrax preparedness in the district and could have implications for other districts. We deduce that trainings of a similar nature conducted regularly and extensively would have better effects. This study’s insights are valuable for improving anthrax readiness and safeguarding public and animal health in similar settings

Enhanced utilization of biotechnology research and development innovations in Eastern and Central Africa for agroecological intensification

The Association for Strengthening Agricultural Research in Eastern and Central Africa (ASARECA) through its Agrobiodiversity and Biotechnology Programme is enhancing the utilization of biotechnology research and development innovations in Eastern and Central Africa (ECA). We present successes in the application of biotechnology to enhance the productivity of cassava, sweet potato, banana, maize and sorghum in ECA. These products—drought tolerant maize, sorghum resistant to striga, as well as the technology for producing and distributing disease free planting materials of cassava, sweet potato and banana to farmers—are central for the agro-ecological intensification of farming systems in the central African highlands