Tuberculosis is a current major world-health problem, exacerbated by the causative pathogen, Mycobacterium tuberculosis (Mtb), becoming increasingly resistant to conventional antibiotic treatment. Mtb is able to counteract the bactericidal mechanisms of leukocytes to survive intracellularly and develop a niche permissive for proliferation and dissemination. Understanding of the pathogenesis of mycobacterial infections such as tuberculosis (TB) remains limited, especially for early infection and for reactivation of latent infection. Signaling via hypoxia inducible factor α (HIF-α) transcription factors has previously been implicated in leukocyte activation and host defence. We have previously shown that hypoxic signaling via stabilization of Hif-1α prolongs the functionality of leukocytes in the innate immune response to injury. We sought to manipulate Hif-α signaling in a well-established Mycobacterium marinum (Mm) zebrafish model of TB to investigate effects on the host's ability to combat mycobacterial infection. Stabilization of host Hif-1α, both pharmacologically and genetically, at early stages of Mm infection was able to reduce the bacterial burden of infected larvae. Increasing Hif-1α signaling enhanced levels of reactive nitrogen species (RNS) in neutrophils prior to infection and was able to reduce larval mycobacterial burden. Conversely, decreasing Hif-2α signaling enhanced RNS levels and reduced bacterial burden, demonstrating that Hif-1α and Hif-2α have opposing effects on host susceptibility to mycobacterial infection. The antimicrobial effect of Hif-1α stabilization, and Hif-2α reduction, were demonstrated to be dependent on inducible nitric oxide synthase (iNOS) signaling at early stages of infection. Our findings indicate that induction of leukocyte iNOS by stabilizing Hif-1α, or reducing Hif-2α, aids the host during early stages of Mm infection. Stabilization of Hif-1α therefore represents a potential target for therapeutic intervention against tuberculosis.

Introduction: Laboratory biosecurity is of continuously growing interest due to increasing concerns about deliberate misuse of biological materials and emerging biological risks. These risks continue to be magnified by globalization, the rapid pace of scientific development, and dual-use technologies. Worldwide laboratory capacities are expanding, which calls for concrete actions to improve laboratory biosafety and biosecurity practices to protect researchers and the community. Hence, laboratories require comprehensive biorisk management programs to minimize the risk of accidental and deliberate release of infectious biological materials. Objective: Malaysia has prioritized the concern of national biosecurity and aims to consolidate laboratory biosecurity performance to detect and prevent the deliberate release of biological agents. Methods: Two 3-day workshops were organized over the course of four months in which Malaysia collaborated with The Netherlands. This bilateral engagement aimed to integrate biosecurity practices in their national biorisk management programs, and resulted into a comprehensive biosecurity checklist for laboratory assessment and monitoring. Results: This biosecurity checklist is based on Malaysian and Dutch expert opinions and national and international guidelines and regulations. The biosecurity checklist is a survey-driven tool that consists of a set of concrete questions for each key biosecurity area, which are discussion points for assessment. Conclusion: We display a practical biosecurity checklist for laboratory assessment and monitoring. Although the presented checklist was the template for the specific Malaysia checklist, it could serve as a template for other countries.

One of the challenges of global biosecurity is to protect and control dangerous pathogens from unauthorized access and intentional release. A practical and feasible option to protect life science institutes against theft and sabotage, and secure their biological materials against misuse, is to establish a national electronic database with a comprehensive overview of the locations of all controlled dangerous pathogens in a country. This national database could be used as an instrument to secure and account for dangerous pathogens in a country, but it could also assist in establishing a biosecurity assessing and monitoring system for laboratories that work with these controlled biological agents. The Republic of Uganda is one of the first countries, prompted by the World Health Organization's (WHO's) Joint External Evaluation (JEE), to implement a national electronic database that assembles information collected from relevant Ugandan laboratories. This Ugandan Inventory of Dangerous Pathogens is different from an institute-specific pathogen inventory system, as it is intended to store the information collected from laboratories in the country working with dangerous pathogens in 1 centralized secure location. The Uganda National Council for Science and Technology (UNCST) has coordinated the implementation of the Ugandan national inventory. The inventory was recognized by the WHO JEE as contributing to Uganda's developed capacities regarding biosafety and biosecurity. This article describes the steps in implementing Uganda's National Inventory of Dangerous Pathogens. In addition, it presents a straightforward approach that can be adapted by other countries that aim to enhance their biosecurity capacities.

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Some viruses cause tumor regression and can be used to treat cancer patients; these viruses are called oncolytic viruses. To assess whether oncolytic viruses from animal origin excreted by patients pose a health risk for livestock, a quantitative risk assessment (QRA) was performed to estimate the risk for the Dutch pig industry after environmental release of Seneca Valley virus (SVV). The QRA assumed SVV excretion in stool by one cancer patient on Day 1 in the Netherlands, discharge of SVV with treated wastewater into the river Meuse, downstream intake of river water for drinking water production, and consumption of this drinking water by pigs. Dose-response curves for SVV infection and clinical disease in pigs were constructed from experimental data. In the worst scenario (four log 10 virus reduction by drinking water treatment and a farm with 10,000 pigs), the infection risk is less than 1% with 95% certainty. The risk of clinical disease is almost seven orders of magnitude lower. Risks may increase proportionally with the numbers of treated patients and days of virus excretion. These data indicate that application of wild-type oncolytic animal viruses may infect susceptible livestock. A QRA regarding the use of oncolytic animal virus is, therefore, highly recommended. For this, data on excretion by patients, and dose-response parameters for infection and clinical disease in livestock, should be studied.

International regulations stipulate that countries need to organize their biosafety and biosecurity systems to minimize the risk of accidental (biosafety) or malicious intentional (biosecurity) release of dangerous pathogens. International Health Regulations (IHR) benchmarks from the WHO state that even for a level of limited capacity countries need to 'Identify and document human and animal health facilities that store/maintain dangerous pathogens and toxins in the relevant sectors and health professionals responsible for them'. This study provides a stepwise, systematic approach and best practices for countries to initiate a national inventory of dangerous pathogens. With a national inventory of dangerous pathogens a country can identify and document information in a dedicated electronic database on institutes that store or maintain dangerous pathogens. The systematic approach for the implementation of a national inventory of dangerous pathogens consists of four stages; identification, preparation, implementation, and maintenance and evaluation. In the identification phase, commitment of the relevant national ministries is to be established, and a responsible government entity needs to be identified. In the preparatory phase, a list of pathogens to be incorporated in the inventory, as well as a list of institutes to include, is to be agreed upon. In the implementation phase, the institutes are contacted, and the collected data is stored safely and securely in a electronical database. Finally, in the maintenance and evaluation phase meaningful insights are derived and reported to the relevant government authorities. Also, preparations for updates and modifications are undertaken, such as modifications of pathogen lists or institute lists. The approach and database, which is available from the authors, have been tested for the implementation of a national inventory of dangerous pathogens in multiple East-African countries. A national inventory of dangerous pathogens helps countries in strengthening national biosafety and biosecurity as well as in their compliance to IHR.