title: Combination of host susceptibility and virulence of Mycobacterium tuberculosis determines dual role of nitric oxide in the protection and control of inflammation.
abstract: Tuberculosis (TB) remains a global health threat. Although it is generally accepted that TB results from intensive cross-talk between the host and the pathogen Mycobacterium tuberculosis, underlying mechanisms remain elusive. The first evidence of human polymorphisms related to susceptibilities to distinct M. tuberculosis lineages has been gathered. Confrontation of limited host resistance with heightened bacterial virulence forms a most hazardous combination. We investigated extreme combinations, confronting inducible nitric oxide synthase-deficient (iNOS(-/-)) and wild-type (WT) mice with 2 related M. tuberculosis strains that differ markedly in virulence, namely, the M. tuberculosis laboratory strains H37Rv and H37Ra. We provide evidence that deregulated chemokine signaling and excessive neutrophil necrosis contribute to disproportionate neutrophil influx and exacerbated TB in iNOS(-/-) mice infected with virulent M. tuberculosis (strain H37Rv), whereas resistant and susceptible mice controlled attenuated H37Ra equally well. Thus, a combination of host susceptibility and M. tuberculosis virulence determines the role of iNOS in the protection and control of inflammation.
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Beisiegel
authors.forename: Mischo
authors.initials: M
authors.lastname: Kursar
authors.forename: Markus
authors.initials: M
authors.lastname: Koch
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kuhlmann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zedler
authors.forename: Manuela
authors.initials: M
authors.lastname: Stäber
authors.forename: Robert
authors.initials: R
authors.lastname: Hurwitz
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D004198:Disease Susceptibility; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000276:immunology / Q000472:pathogenicity*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D014774:Virulence
chemical_list: D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II