Reduced virulence of an extensively drug-resistant outbreak strain of Mycobacterium tuberculosis in a murine model.

Kristen L Jurcic Smith,Sunhee Lee,Neel R Gandhi,Svetoslav Bardarov,Michelle Larsen,A Willem Sturm,Divey Saini,William R Jacobs Jr,Richard Frothingham

doi:10.1371/journal.pone.0094953

Kristen L Jurcic Smith, Sunhee Lee + Show 7 more

Open Access

PDF Available

https://doi.org/10.1371/journal.pone.0094953

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

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.

Highlights

Multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR TB) represent a serious threat to global health [1,2,3]
In order to evaluate whether KZN strains differ in their ability to evade innate immune responses, we assessed the induction or inhibition of apoptosis and necrosis in alveolar epithelial cells (A549) infected with KZN strains and reference M. tuberculosis strains
We detected varying degrees of necrosis induced by clinical isolates that are not part of the F15/LAM4/ KZN family of M. tuberculosis (Figure S1), which confirms our finding that an innate ability to induce a significant level of necrosis by the KZN strains is not a general phenotype of all clinical isoates

Summary

Introduction

Multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR TB) represent a serious threat to global health [1,2,3]. MDR TB is defined by resistance to both isoniazid and rifampin. XDR TB is defined by resistance to isoniazid, rifampin, any quinolone, and at least one of three injectable drugs (amikacin, kanamycin, or capreomycin) [1]. There were an estimated 500,000 new cases of MDR TB globally in 2011, and XDR-TB has been reported by 84 countries worldwide [4]. TB cases with increasing degrees of drug resistance are associated with higher mortality, such that less than half of all XDR TB cases are curable, with one-year mortality rates as high as 85% [5,6,7]. Cases with resistance exceeding the definition of XDR TB have received considerable attention, as treatment options are minimal, if even possible [8,9,10]

Methods

Results

Conclusion