title: Exploitation of Mycobacterium tuberculosis reporter strains to probe the impact of vaccination at sites of infection.
abstract: Mycobacterium tuberculosis (Mtb) remains a major public health problem, with an effective vaccine continuing to prove elusive. Progress in vaccination strategies has been hampered by a lack of appreciation of the bacterium's response to dynamic changes in the host immune environment. Here, we utilize reporter Mtb strains that respond to specific host immune stresses such as hypoxia and nitric oxide (hspX'::GFP), and phagosomal maturation (rv2390c'::GFP), to investigate vaccine-induced alterations in the environmental niche during experimental murine infections. While vaccination undoubtedly decreased bacterial burden, we found that it also appeared to accelerate Mtb's adoption of a phenotype better equipped to survive in its host. We subsequently utilized a novel replication reporter strain of Mtb to demonstrate that, in addition to these alterations in host stress response, there is a decreased percentage of actively replicating Mtb in vaccinated hosts. This observation was supported by the differential sensitivity of recovered bacteria to the front-line drug isoniazid. Our study documents the natural history of the impact that vaccination has on Mtb's physiology and replication and highlights the value of reporter Mtb strains for probing heterogeneous Mtb populations in the context of a complex, whole animal model.
authors.affiliation: Cornell University, College of Veterinary Medicine, Department of Microbiology and Immunology, Ithaca, New York, United States of America.
authors.forename: Neelima
authors.initials: N
authors.lastname: Sukumar
authors.affiliation: Cornell University, College of Veterinary Medicine, Department of Microbiology and Immunology, Ithaca, New York, United States of America.
authors.forename: Shumin
authors.initials: S
authors.lastname: Tan
authors.affiliation: Tufts University School of Medicine, Department of Molecular Biology and Microbiology, Boston, Massachusetts, United States of America.
authors.forename: Bree B
authors.initials: BB
authors.lastname: Aldridge
authors.affiliation: Cornell University, College of Veterinary Medicine, Department of Microbiology and Immunology, Ithaca, New York, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Russell
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods*; D017930:Genes, Reporter; D054884:Host-Pathogen Interactions / Q000187:drug effects; D000860:Hypoxia / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D007538:Isoniazid / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000276:immunology / Q000627:therapeutic use*; D014611:Vaccination
chemical_list: D000995:Antitubercular Agents; D032581:Tuberculosis Vaccines; D009569:Nitric Oxide; D007538:Isoniazid