title: Reduced virulence of an extensively drug-resistant outbreak strain of Mycobacterium tuberculosis in a murine model.
abstract: Bacterial drug resistance is often associated with a fitness cost. Large outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have been described that predominately affect persons with HIV infection. We obtained four closely-related Mycobacterium tuberculosis strains (genotype F15/LAM4/KZN) from an outbreak in KwaZulu-Natal (KZN), South Africa, including drug-sensitive, MDR, and XDR clinical isolates. We compared the virulence of these strains in a murine model of aerosol M. tuberculosis infection for four phenotypes: (1) competitive in vivo growth in lung and spleen, (2) non-competitive in vivo growth in lung and spleen, (3) murine survival time, and (4) lung pathology. When mixtures of sensitive, MDR, and XDR KZN strains were aerosolized (competitive model), lung CFUs were similar at 60 days after infection, and spleen CFUs were ordered as follows: sensitive > MDR > XDR. When individual strains were aerosolized (non-competitive model), modest differences in lung and spleen CFUs were observed with the same ordering. C57BL/6, C3H/FeJ, and SCID mice all survived longer after infection with MDR as compared to sensitive strains. SCID mice infected with an XDR strain survived longer than those infected with MDR or sensitive strains. Lung pathology was reduced after XDR TB infection compared to sensitive or MDR TB infection. In summary, increasing degrees of drug resistance were associated with decreasing murine virulence in this collection of KZN strains as measured by all four virulence phenotypes. The predominance of HIV-infected patients in MDR and XDR TB outbreaks may be explained by decreased virulence of these strains in humans.
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Kristen L Jurcic
authors.initials: KL
authors.lastname: Smith
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Divey
authors.initials: D
authors.lastname: Saini
authors.affiliation: South Nassau Communities Hospital, Oceanside, New York, United States of America.
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Bardarov
authors.affiliation: Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Larsen
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Frothingham
authors.affiliation: Emory University, Rollins School of Public Health, Atlanta, Georgia, United States of America.
authors.forename: Neel R
authors.initials: NR
authors.lastname: Gandhi
authors.affiliation: Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, United States of America.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: A Willem
authors.initials: AW
authors.lastname: Sturm
authors.affiliation: Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Lee
mesh_terms: D000336:Aerosols; D000818:Animals; D017209:Apoptosis; D058491:Bacterial Load; D004195:Disease Models, Animal; D004196:Disease Outbreaks; D007113:Immunity, Innate; D007121:Immunocompetence; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000472:pathogenicity*; D009336:Necrosis; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D016019:Survival Analysis; D018088:Tuberculosis, Multidrug-Resistant / Q000453:epidemiology* / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D014774:Virulence
chemical_list: D000336:Aerosols
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