Orientia tsutsugamushi: A neglected but fascinating obligate intracellular bacterial pathogen

Our understanding of the molecular systems that bacteria have developed over millennia of evolutionary tinkering remains limited compared with the incredible diversity of the bacterial kingdom. A detailed understanding of the tricks and tools developed by the bacterial world provides insights into fundamental processes in biology (e.g., transcriptional networks), provides researchers with inspiration and molecular reagents for synthetic biology (e.g., restriction enzymes and CRISPR/Cas systems), and arms us with an understanding of essential bacterial processes that can be undermined by antibiotic therapy. In the case of bacteria that coexist intimately with mammalian hosts, in particular within the intracellular niche, a detailed study of these organisms can yield insights into important processes in eukaryotic biology (e.g., actin polymerisation and autophagy) [1]. However, whilst a number of model organisms have been studied in enormous detail, there remain a wealth of pathogenic and nonpathogenic bacteria whose molecular secrets remain largely unknown. This is partly due to our focus on species that inflict a high burden of human and agricultural damage and partly due to the difficulty of dissecting the molecular mechanisms of nonmodel bacterial species, which often cannot be propagated easily under laboratory conditions or manipulated genetically. The Rickettsia-related bacterium Orientia tsutsugamushi is an example of an important human pathogen whose fundamental cell biology is poorly understood compared with other pathogens of equivalent prevalence and severity. Research is hampered by a lack of availability of tools for genetic manipulation, technical limitations associated with working with an obligate intracellular bacterium, and the cost and logistical challenges of working with a bacterium classified as a biosafety level 3 pathogen. However, there are multiple aspects of the biology of this organism that are unusual and intriguing and that can be used to address fundamental questions in host–pathogen and bacterial cell biology, and this serves to illustrate the value of taking up the challenge to study nonclassical model systems. In this review, I have highlighted some particularly fascinating aspects of the biology of this neglected intracellular pathogen.