Abstract
It is uncertain whether differences in Mycobacterium tuberculosis (Mtb) virulence defined in vitro influence clinical tuberculosis pathogenesis, transmission, and mortality. We primarily used a macrophage lysis model to characterize the virulence of Mtb isolates collected from 153 Vietnamese adults with pulmonary tuberculosis. The virulence phenotypes were then investigated for their relationship with sputum bacterial load, bacterial lineages, bacterial growth, and cytokine responses in macrophages. Over 6 days of infection, 34 isolates (22.2%) showed low virulence (< 5% macrophages lysed), 46 isolates (30.1%) showed high virulence (≥90% lysis of macrophages), and 73 isolates (47.7%) were of intermediate virulence (5–90% macrophages lysed). Highly virulent isolates were associated with an increased bacterial load in patients' sputum before anti-tuberculosis therapy (P = 0.02). Isolate-dependent virulence phenotype was consistent in both THP-1 and human monocyte-derived macrophages. High virulence isolates survived better and replicated in macrophages one hundred fold faster than those with low virulence. Macrophages infected with high virulence isolates produced lower concentrations of TNF-α and IL-6 (P = 0.002 and 0.0005, respectively), but higher concentration of IL-1β (P = 5.1 × 10−5) compared to those infected with low virulence isolates. High virulence was strongly associated with East Asian/Beijing lineage [P = 0.002, Odd ratio (OR) = 4.32, 95% confident intervals (CI) 1.68–11.13]. The association between virulence phenotypes, bacterial growth, and proinflammatory cytokines in macrophages suggest the suppression of certain proinflammatory cytokines (TNF-α and IL-6) but not IL-1β allows better intracellular survival of highly virulent Mtb. This could result in rapid macrophage lysis and higher bacterial load in sputum of patients infected with high virulence isolates, which may contribute to the pathogenesis and success of the Beijing lineage.
Highlights
Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death globally, causing active tuberculosis (TB) in 10.4 million and killing 1.3 million people annually (World Health Organization, 2017)
We investigated the association between the virulence phenotypes and bacterial load in sputum samples from TB patients, bacterial lineages, Mtb growth, and host cytokine responses in macrophages
We examined the interaction of macrophages and Mtb every day for 10 days after infection
Summary
Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death globally, causing active tuberculosis (TB) in 10.4 million and killing 1.3 million people annually (World Health Organization, 2017). Mtb is an intracellular pathogen that requires human disease to replicate and spread. The variation has been primarily attributed to host factors (Berrington and Hawn, 2007; Thuong et al, 2016), but there is evidence suggesting that differential Mtb virulence could be important (Malik and Godfrey-Faussett, 2005). A better understanding of how virulence varies between Mtb strains and genetic determinants of virulence would inform efforts to develop new treatments. This knowledge would help in appraisal of potential virulencerelated antigens, which may contribute to the design of novel antitubercular vaccines
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
