It is estimated that approximately one billion people are at risk of infection with obligate intracellular bacteria, but little is known about the underlying mechanisms that govern their life cycles. The difficulty in studying Chlamydia spp., Coxiella spp., Rickettsia spp., Anaplasma spp., Ehrlichia spp. and Orientia spp. is, in part, due to their genetic intractability. Recently, genetic tools have been developed; however, optimizing the genomic manipulation of obligate intracellular bacteria remains challenging. In this Review, we describe the progress in, as well as the constraints that hinder, the systematic development of a genetic toolbox for obligate intracellular bacteria. We highlight how the use of genetically manipulated pathogens has facilitated a better understanding of microbial pathogenesis and immunity, and how the engineering of obligate intracellular bacteria could enable the discovery of novel signalling circuits in host-pathogen interactions.
Bibliographical noteFunding Information:
The authors apologize to those colleagues whose work could not be cited owing to the broad scope of the Review and space limitations. Work in the authors’ laboratories was supported by the US National Institutes of Health (Institutional Training Grant T32AI007540 to E.E.M.; R01 AI072683, R56 AI123346 and R21 AI122014 to J.A.C.; R01 AI100759 to R.H.V.; U19 AI084044 to P.M.B.; R01 AI070908 to R.R.G.; R01 AI020384 and R21 AI103272 to D.O.W.; R01 AI042792 to U.G.M. and K.A.B.; R01 AI072606 and R21 AI111086 to J.J.M.; R01 AI106859 and R21 AI115449 to J.W.M.; and R01 AI093653 and R01AI116523 to J.H.F.P.), the US Department of Agriculture (USDA-ARS 2090-32000-038-00D to S.M.N.), the Center of Excellence for Vector-Borne Diseases at Kansas State University (to R.R.G.) and the University of Maryland School of Medicine (to J.H.F.P.). The content of this Review is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institute of Allergy and Infectious Diseases or the US National Institutes of Health.
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