AbstractThe Top End of the Northern Territory (NT) is a unique place. Located on the northern Australian coastline, it has a tropical savanna climate and is closer to Asia than to major Australian cities. Spanning >500,000 km2, it is sparsely populated but culturally very diverse; approximately a third of the population are Australian First Nations peoples, and ~20% were born overseas. Due to the physical environment and climate, and the extent of social and health inequity, the rates of many infectious diseases are well above the national average.
At the commencement of this PhD, next generation sequencing technologies were increasingly being implemented for public health surveillance of infectious diseases; the COVID-19 pandemic has accelerated this globally. The applications of this technology are protean, from detection of novel pathogens, to tracing the source of cases with no obvious transmission link, to surveillance for emerging strains with increased transmissibility or immune evasion, and to detection of determinants of virulence or antimicrobial resistance. The questions that can be addressed and potential implications depend on the ecology, epidemiology, and public health response for each pathogen.
In this thesis, I use genomic sequencing to investigate the epidemiology of three bacterial pathogens that cause community-acquired infection in the NT Top End— Community-onset Acinetobacter baumannii infection occurs predominantly in tropical and subtropical climates, with most cases occurring during the wet season and manifesting as severe bacteraemic pneumonia. I combined patient epidemiology with genomic sequencing of A. baumannii isolates from the Top End. Pasteur sequence type (ST)10 accounted for approximately half of Top End community-onset A. baumannii cases, with some local non-multidrug-resistant ST10 isolates closely related to multidrug-resistant isolates from geographically distant locations in Southeast Asia and North America. The ST10 most recent common ancestor (MRCA) was estimated to have occurred in 1738 (95% highest posterior density, HPD 1626–1826), with evidence of multiple introduction events between Asia and northern Australia between then and the present day. The MRCA for an ST10 clade including genomes from the Top End, Vietnam, and the United States was estimated to be 1957 (95% HPD 1936–1972), the approximate time that both Australia and the United States were participating in the Vietnam war. A. baumannii can colonise humans, animals, and a wide variety of foods, and can survive on inert surfaces, likely accounting for this long-range dissemination. There was no association between putative virulence genes and patient outcomes in this study, and the reasons that A. baumannii causes such severe disease require further investigation.
Burkholderia pseudomallei, the causative agent of melioidosis, is endemic in tropical regions including the NT Top End where it is a common cause of sepsis. Due to lack of human-human transmission and its ecologic niche in soil and water, Australian B. pseudomallei strains are phylogenetically distinct from Asian strains. The Darwin Prospective Melioidosis Study (DPMS) has documented the clinical, epidemiological and genomic characteristics of all culture-confirmed melioidosis cases since October 1989. I investigated the emergence and expansion in urban Darwin since 2005 of an Asian B. pseudomallei strain, ST562, combining patient epidemiology from the DPMS with genomic sequencing of B. pseudomallei isolates. From 2005–2019, an increasing proportion of melioidosis cases were due to ST562. Cases initially occurred in suburbs surrounding a creek before spreading across urban Darwin and to an island community to the north. Two clusters of cases with epidemiological links were identified, with genomic analysis identifying further associated cases. Temporal genomic analysis suggested a single introduction event of ST562 into the Darwin region in approximately 1988. ST562 isolates from Hainan province, China, and Pingtung county, Taiwan, were genetically related but distinct from Australian ST562 isolates. The origin and transmission mode of ST562 into Australia remain uncertain.
The NT has the highest tuberculosis (TB) rate of all Australian jurisdictions. I combined TB public health surveillance data with genomic sequencing of Mycobacterium tuberculosis isolates in the NT Top End to investigate trends in TB incidence and transmission over three decades from 1989–2020. Of 741 culture-confirmed cases, 48% were born overseas, 44% were Australian First Nations peoples, and 7% were Australian-born and non-Indigenous. The annual incidence in First Nations peoples dropped by average 5% per year, but remained well above the national average. First Nations cases were more likely to die from TB than overseas-born cases, and mortality in First Nations cases occurred at a younger age. Of 250 cases belonging to genomic clusters, 86% were First Nations peoples and 76% were from a remote region. The time between cases and past epidemiologically- and genomically-linked contacts ranged from 4.5 months to 24 years, suggesting that both reactivation from latency and recent transmission are contributing to incident TB. The findings support prioritisation of timely case detection, contact tracing augmented by genomic sequencing, and latent TB treatment to break transmission chains in Top End remote hotspot regions.
There are distinct research priorities for these and other pathogens, however an overarching priority is the implementation of prospective sequencing for surveillance for and to guide the public health response to infectious diseases. During my PhD, SARS-CoV-2 emerged and local SARS-CoV-2 sequencing commenced at the NT public health laboratory. Further work is needed to embed this technology in public health infrastructure with appropriate staffing, laboratory equipment, computing resources, and quality assurance. Evaluation of the public health impact is vital, and community consultation and development of the NT First Nations public health workforce are crucial for ensuring the technology is used in a way that meets community expectations and has maximum benefit.
|Date of Award||2022|
|Supervisor||Bart Currie (Supervisor), Anna Ralph (Supervisor), Nicholas Anstey (Supervisor), Joshua Davis (Supervisor) & Derek Sarovich (Supervisor)|