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Grand Challenges is a family of initiatives fostering innovation to solve key global health and development problems. Each initiative is an experiment in the use of challenges to focus innovation on making an impact. Individual challenges address some of the same problems, but from differing perspectives.

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S. Typhi and Protozoa in Contaminated Water in Zimbabwe

Robert KingsleyQuadram Institute BioscienceNorwich, United Kingdom
Grand Challenges Explorations
Salmonella Typhi
1 Nov 2019

Robert Kingsley of the Quadram Institute Bioscience in the United Kingdom will locate the typhoid fever-causing bacteria S. Typhi in water reservoirs in Harare, Zimbabwe, and identify any associated protozoa species present in the water that may be supporting disease spread. Typhoid fever is endemic in Zimbabwe, with several major outbreaks reported in the last decade. The bacteria persist in unclean aquatic environments, possibly supported by protozoa, and are transmitted to humans through ingestion of contaminated drinking water. They will detect S. Typhi in sewage effluent and low-quality drinking water in hotspots of typhoid transmission by enrichment culture and PCR, and use whole genome sequencing to establish the phylogenetic relationship between these bacteria and clinical typhoid isolates in the same city. They will also amplify 18S rDNA from the sewage and drinking water samples to characterize the microbial community in water and define the protozoa population. These data will help identify potential synergistic interactions between S. Typhi and other microbes to inform prevention strategies.

S. Typhi in Water and Role of Microbial Partners

France DaigleUniversité de MontréalMontreal, Quebec, Canada
Grand Challenges Explorations
Salmonella Typhi
1 Nov 2019

France Daigle of the University of Montreal in Canada will identify the microorganisms that enable the survival of the typhoid fever-causing bacterium, Salmonella enterica serovar Typhi, at low levels in water, and thereby enhances disease spread. Typhoid fever spreads through contaminated food and water, and results in over 125,000 deaths annually worldwide. S. Typhi are so-called auxotrophic bacteria because they rely on an external source of the essential amino acids that they need to grow. Microbial interactions may provide nutrients and also increase bacterial fitness and support persistence by protecting them from the environment, thereby increasing the rate of disease transmission. They will assemble a microbial community in water consisting of three components: one protozoan (from a group known to promote bacterial survival); a defined consortium of bacteria representative of the human fecal microbiota; and fluorescently-tagged S. Typhi. They will evaluate the ability of S. Typhi to grow in these microcosms, and how they grow, such as in biofilms or inside the protozoa. They will also determine whether these persistent S. Typhi are better able to infect and survive in human cells. Finally, water samples from an endemic region in East Africa will be analyzed for the presence of S. Typhi and identified beneficial microbial partners using quantitative PCR.

S. Typhi Mechanisms of Temperature- and Microbiota-Dependent Environmental Persistence

Denise MonackStanford UniversityStanford, California, United States
Grand Challenges Explorations
Salmonella Typhi
1 Nov 2019

Denise Monack of Stanford University in the U.S. will use a genetic approach to identify the molecular mechanisms that enable the typhoid fever-causing bacterium S. Typhi to survive in aquatic environments and to rapidly adapt to transmission to humans. Annually, S. Typhi causes over 20 million infections and 200,000 deaths, mostly among populations that lack access to clean drinking water. Understanding how S. Typhi persists in water and then quickly adapts to its human host is critical for controlling transmission. Bacteria use various mechanisms to adapt to environmental changes, including so-called RNA thermometers (RNATs), which form secondary structures in mRNAs that can rapidly activate gene expression when temperatures change. They will use their established genetic screening approach to identify new RNATs in S. Typhi and validate their ability to promote bacterial persistence within aquatic microbial communities by generating mutants. They will also follow up on past work in which a bioinformatics approach identified new RNATs that may regulate the expression of the chitinase enzyme, which is used by the cholera-causing bacterium to bind to plankton and create a protective environmental niche. They will evaluate whether chitin is also important for S. Typhi persistence and transmission.

S. Typhi Survival and Gene Acquisition in Biofilm Communities

Windy TannerUniversity of UtahSalt Lake City, Utah, United States
Grand Challenges Explorations
Salmonella Typhi
1 Nov 2019

Windy Tanner and Jim VanDerslice of the University of Utah in the U.S., together with colleagues from Mehran University of Engineering and Technology in Pakistan, will analyze water samples to determine the conditions that promote the survival of the typhoid fever causing bacterium Salmonella Typhi, and they will use metagenomic deconvolution to identify any gene exchange from other microbial species that may produce drug-resistant strains. S. Typhi is responsible for over 100,000 deaths each year, mostly in the developing world where fecal contamination of food and drinking water is common. The emergence of drug-resistant strains has limited the available treatment options. Biofilms are environmental niches with complex microbial communities and are ubiquitous in the environments where S. Typhi is commonly found. They will sample water and biofilms from a variety of these environments along the fecal-drinking water transmission route in the Sindh province of Pakistan and test for the presence of S. Typhi using qPCR and culture methods. They will also evaluate whether specific organisms stabilize and protect S. Typhi in these biofilms and could cause resistance gene exchange.

A Live Recombinant Attenuated Salmonella Anti-Pneumococcal Vaccine for Newborns

Roy CurtissArizona State UniversityTempe, Arizona, United States
Grand Challenges in Global Health
Single-Dose Vaccines
1 Jul 2005

The current vaccine against bacterial pneumonia (pneumococcus) requires a regimen of four injections given at specific intervals. In developing countries, this not only complicates the vaccination process for health workers and children, but it also is a serious obstacle for families who must travel long distances to the nearest health clinic. Dr. Curtiss and his colleagues are working to develop new vaccines against bacterial pneumonia that require only a single dose, can be delivered orally, and are safe for newborns, infants, and people who are malnourished or whose immune systems are compromised.

A Low-Cost, Highly Scalable Continuous Culture System for Rapid Optimization and Precise Tuning of Gut Microbial Formulations

Ahmad KhalilBoston UniversityBoston, Massachusetts, United States
Grand Challenges Explorations
Microbial Biotherapeutics
1 May 2019

Ahmad Khalil of Boston University in the U.S. will develop a low-cost bioreactor platform to simultaneously optimize growth conditions of multiple bacterial species for large scale production of biotherapeutics. The human gut microbiome plays an essential role in health and development and living microbial biotherapeutics could be an effective treatment in the case of damage by illness or malnutrition. Commercial production is limited by the capacity of bioreactors, which are costly and challenging to scale and relatively inflexible. Using their eVOLVER continuous culture system, which is modular, inexpensive, and highly scalable, they will adapt the set-up and optimize protocols to allow for the management of unique growth conditions for individual species in parallel, and dynamic mixing of cultures from individual pools to precisely tune multi-species formulations. They will conduct full-scale tests to evaluate their approach for optimizing production of human gut microbiota.

A Malaria Mosquito Gut On-a-Chip

Pietro AlanoIstituto Superiore di SanitàRome, Italy
Grand Challenges Explorations
EmergingTechnologies
1 Nov 2019

Pietro Alano of the Instituto Superiore de Sanità in Italy will develop a biochip that mimics the midgut of the Anopheles mosquito and can be used to more easily and quickly test candidate anti-malarial compounds for blocking transmission of the causative Plasmodium parasite. Malaria is a potentially fatal infection caused by parasites transmitted between humans through the bites of infected mosquitoes. When a mosquito bites an infected person, immature Plasmodium gametocytes enter the mosquito and transform into an invasive ookinete stage in its midgut. They then traverse the gut wall to the external gut lumen, where they enter their parasite stage. To eliminate malaria, compounds are needed that block the transmission of Plasmodium. However, current methods to evaluate the candidate transmission-blocking drugs or vaccines that are under development are slow and involve feeding malaria-infected blood to mosquitoes, which is potentially dangerous. As an alternative, they will create a biochip to reproduce the mosquito midgut environment that can support the development of parasites, and develop a bioluminescent antibody-based technique to count successfully traversing ookinetes. They will test the performance of the biochip using known anti-transmission drugs.

A Mouse Model to Evaluate Live Attenuated Vaccine Candidates

Richard FlavellYale UniversityNew Haven, Connecticut, United States
Grand Challenges in Global Health
Vaccine Model Systems
1 Jul 2005

To develop new vaccines against some of the world's biggest killers, including HIV, malaria, and tuberculosis, scientists must be able to evaluate promising candidates. Some of the most promising potential vaccines, are made from weakened live versions of the infectious agent. As a result, they cannot be studied in human trials unless researchers can be confident that the weakened vaccines will be safe. Dr. Flavell and his colleagues are working to genetically engineer laboratory mice whose immune systems are similar enough to humans to permit testing of vaccines against diseases that disproportionately affect people in the developing world. Flavell (Grand Challenges in Global Health: 2005-2015 retrospective)

A Point-of-Care Diagnostic System for the Developing World

Paul YagerUniversity of WashingtonSeattle, Washington, United States
Grand Challenges in Global Health
Point-of-Care Diagnostics
1 Jul 2005

In the developing world, lack of convenient and accurate tools that can detect and diagnose diseases and other health problems means that many health risks remain undetected or receive inappropriate treatment. Dr. Yager's team, in collaboration with research groups from private industry as well as the nonprofit sector, is working to develop a low­-cost, easy-­to-­use device that will rapidly test blood for a range of health problems prevalent in developing countries, such as bacterial infections, nutritional status, and HIV­-related illnesses.

A Protective Genetically Attenuated P. Falciparum Sporozoite Vaccine

Stefan KappeSeattle Biomedical Research InstituteSeattle, Washington, United States
Grand Challenges in Global Health
Antigen Design
1 Jul 2005

Attenuated vaccines, composed of weakened organisms incapable of causing disease, provide prolonged exposure to antigens and have proven effective against several viral or bacterial diseases. Dr. Kappe's team is attempting to extend this concept to a malaria vaccine. In the case of malaria, disease develops when the malaria sporozoite – the form of the parasite that is transmitted from mosquitoes to humans – enters the bloodstream and moves to the liver. There, it grows and divides into thousands of parasites that invade and destroy red blood cells, causing disease. Dr. Kappe's team is working toward development of a malaria vaccine using a malaria sporozoite that has been weakened by gene deletion to stimulate immune response. Kappe (Grand Challenges in Global Health: 2005-2015 retrospective)

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