Smith Kristen L Jurcic, Saini Divey, Bardarov Svetoslav, Larsen Michelle, Frothingham Richard, Gandhi Neel R, Jacobs William R, Sturm A Willem, Lee Sunhee
Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, United States of America.
South Nassau Communities Hospital, Oceanside, New York, United States of America.
PLoS One. 2014 Apr 14;9(4):e94953. doi: 10.1371/journal.pone.0094953. eCollection 2014.
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.
细菌耐药性通常与适应性代价相关。已报道了多药耐药（MDR）和广泛耐药（XDR）结核病的大规模暴发，这些暴发主要影响艾滋病毒感染者。我们从南非夸祖鲁-纳塔尔省（KZN）的一次疫情中获得了4株密切相关的结核分枝杆菌菌株（基因型F15/LAM4/KZN），包括药敏、MDR和XDR临床分离株。我们在气溶胶型结核分枝杆菌感染的小鼠模型中比较了这些菌株在四种表型方面的毒力：（1）肺和脾中的体内竞争性生长；（2）肺和脾中的体内非竞争性生长；（3）小鼠存活时间；（4）肺部病理学。当敏感、MDR和XDR KZN菌株的混合物雾化吸入时（竞争性模型），感染后60天时肺中的菌落形成单位（CFU）相似，脾中的CFU顺序如下：敏感株>MDR株>XDR株。当单个菌株雾化吸入时（非竞争性模型），观察到肺和脾中CFU有适度差异，顺序相同。与敏感菌株相比，C57BL/6、C3H/FeJ和SCID小鼠感染MDR菌株后存活时间更长。感染XDR菌株的SCID小鼠比感染MDR或敏感菌株的小鼠存活时间更长。与敏感或MDR结核病感染相比，XDR结核病感染后肺部病理学表现减轻。总之，通过所有四种毒力表型测量，在这组KZN菌株中，耐药程度增加与小鼠毒力降低相关。MDR和XDR结核病暴发中艾滋病毒感染患者占主导地位，可能是由于这些菌株在人类中的毒力降低。
