Pathogen exchange at the human wildlife interface - a comprehensive molecular study on vector-borne disease in rural Sulawesi.

The rural poor, the wildlife they encounter and the potential exchange of pathogens between humans and wildlife is not known in much of the world, including Sulawesi, yet emerging infections of zoonotic origin that become epidemic and pandemic are feared. The collaborative molecular study proposed here focuses on emerging mosquito-borne infections with the fundamental goal to discover pathogen exchange where humans and wild Sulawesi macaques share habitat. The UK PI has a strong track record in this field as co-investigator and investigator in ground breaking molecular research that lead to the discovery and characterization of zoonotic malaria in the human population in Malaysian Borneo. Plasmodium knowlesi, a malaria parasite of macaque monkeys, had entered the human population and as a result of that work is now recognised as the 5th type of malaria in humans. The Indonesian PI is a clinically qualified medical entomologist with special interest in mosquito vectors of disease. He has extensive field research experience and is based in Hasanuddin University, Sulawesi. By joining their expertise and that of key co-investigators and collaborators, with particular expertise in patient recruitment in remote rural Borneo (CJD) and wildlife veterinary research (DKS) they plan to investigate, for the first time, pathogen transmission, particularly malaria transmission, within and between the unique Sulawesi macaque species and remote rural populations. Clinical, pathogen, mosquito, and wildlife data will be generated from study sites where rural populations share habitat with the Sulawesi macaques. The expected primary outcomes are: 1) to describe the clinical impact and molecular fingerprint of vector-borne pathogens transmitted within remote rural populations in Sulawesi; 2) to identify mosquito vector species and the pathogen genotypes they transmit between humans at each location; 3) to catalogue mosquito vectors that feed on, and vector-borne pathogens harboured by macaque troops, that overlap with humans at each location; 4)compare pathogen genetic fingerprints generated from mosquito vectors, macaque and human hosts to determine pathogen crossover events between hosts, particularly zoonotic crossover from macaque monkeys to humans and 5) develop location-specific tools and strategies for the Indonesian department of health and local communities to use to pre-empt emerging vector-borne zoonoses.

The information generated by this study will immediately inform measures to reduce vector-borne infections and improve health and wellbeing of the study populations, by definition the remote rural poor. The study protocol could be used as a template for similar study in the region. The approach is internationally competitive molecular research (genetics, genomics and bioinformatics) and the partnership will foster human resource and capacity strengthening in cutting-edge infectious disease research in Indonesia. Our ODA compliant study when viewed through the lens of the sustainable development goals (SDG's) will contribute to Goal 1 - Ending poverty that includes ensuring that the poor and vulnerable have access to basic services - including health. Goal 3 Health - that includes ending neglected tropical diseases and malaria. Goal 8 - decent job creation, in this case through building expertise in the bio-medical research sector in Sulawesi and Goal 17 Partnerships - achieving the SDG's through sustainable equal partnerships.

Vector-borne pathogen entry into the human population from macaque monkeys is on-going in Southeast Asia, currently the best-known example is zoonotic malaria. The UK PI was co-investigator on ground breaking research in Malaysian Borneo that uncovered the entry of Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, into the human population. Sulawesi has seven unique macaque species that most probably radiated from Borneo in the middle Pleistocene. The macaques of Borneo have up to five Plasmodium species and it is not known if any of those species traveled with the macaques to Sulawesi. Using field-appropriate sampling, downstream genetics, genomics and bioinformatics the applicants propose to investigate, for the first time, vector-borne pathogen transmission, particularly but not limited to malaria transmission, within and between the unique Sulawesi macaque species and remote rural populations. A comprehensive set of pathogen DNA fingerprints from mosquito vectors, macaque hosts and the human population will be produced to capture vector-borne pathogen transmission at each remote study site in Sulawesi. The expected outcomes are to: 1) describe the clinical impact and molecular fingerprint of vector-borne pathogens transmitted within remote rural populations in Sulawesi; 2) identify mosquito vector species and the pathogen genotypes they transmit between humans at each location; 3) catalogue mosquito vectors that feed on, and vector-borne pathogens harboured by, macaque troops that overlap with humans at each location; 4)compare pathogen genetic fingerprints generated from mosquito vectors, macaque and human hosts to determine pathogen crossover events between hosts, particularly zoonotic crossover from macaque monkeys to humans. The outputs will inform location-specific strategies to pre-empt emerging vector-borne zoonoses.

The joint research proposed is inspired by UKRI driving innovation and maximizing impact of research investment and also ODA compliance and the Newton fund model.

Fundamentally the genetic sweep approach proposed to determine pathogen exchange at the human wildlife interface includes next generation sequencing platforms, genetics and bioinformatics yet the remote rural poor in Sulawesi will benefit in several ways: The study will draw attention to the needs of remote communities, particularly health needs and also the degree of poverty, through interaction with the study team. More specifically the study will identify vector-borne disease exposure in each community in a way that will identify reservoirs of disease, shared host and mosquito vectors. This information will inform the rational design of strategies to prevent vector borne - disease and immediately offer a means to improve the health and well-being of the rural poor. A general health check will have the potential to identify additional needs and problems that will help local authorities and the communities to begin to develop solutions. At the very least the study will reduce the health impact of vector-borne disease, including malaria, and go some way to improve community empowerment, wellbeing and productivity and in the best possible case to begin to alleviate poverty.

Capacity strengthening and human resource development is an integral part of our research partnership. During a pump-priming exercise in Hasanuddin University the UKPI identified international standard molecular biology as an area in need of strengthening. Through physical space and sustainable human resource development Sulawesi will have the potential to become competitive in international standard bio-medical research collaborations. To this end sustainable training and mentoring in international standard research for early career scientists, from the UK and Indonesia, recruited onto the project will be offered. Particularly developing expertise field studies and molecular biology. With this expertise in place in Sulawesi there is the potential for economic development through increased investment in the bio-medical research sector opening career opportunities for biomedical scientists.

Sulawesi is a megadiverse island of interest to biologists, ecologists, primatologists, entomologists to name but a few. Strong research ties between the UK and Sulawesi will facilitate a wide range of equally partnered research activities with facilities for international standard equally partnered collaborative research. Equally partnered international research should not be underestimated in improving the quality and quantity of outputs. Relevant UK science communities would have opportunities to address research questions with Indonesian partners in uniquely biodiverse setting.

Therefore our proposed study will impact the remote rural poor in Sulawesi, the biomedical research sector in Indonesia, career scientists in Indonesia and the UK and local and international users of our research outputs.