Modern Lineages of Mycobacterium tuberculosis Exhibit Lineage-Specific Patterns of Growth and Cytokine Induction in Human Monocyte-Derived Macrophages

Abstract

BackgroundStrains of Mycobacterium tuberculosis vary in virulence. Strains that have caused outbreaks in the United States and United Kingdom have been shown to subvert the innate immune response as a potential immune evasion mechanism. There is, however, little information available as to whether these patterns of immune subversion are features of individual strains or characteristic of broad clonal lineages of M. tuberculosis.MethodsStrains from two major modern lineages (lineage 2 [East-Asian] and lineage 4 [Euro-American]) circulating in the Western Cape in South Africa as well as a comparator modern lineage (lineage 3 [CAS/Delhi]) were identified. We assessed two virulence associated characteristics: mycobacterial growth (in liquid broth and monocyte derived macrophages) and early pro-inflammatory cytokine induction.ResultsIn liquid culture, Lineage 4 strains grew more rapidly and reached higher plateau levels than other strains (lineage 4 vs. lineage 2 p = 0.0024; lineage 4 vs. lineage 3 p = 0.0005). Lineage 3 strains were characterized by low and early plateau levels, while lineage 2 strains showed an intermediate growth phenotype. In monocyte-derived macrophages, lineage 2 strains grew faster than lineage 3 strains (p<0.01) with lineage 4 strains having an intermediate phenotype. Lineage 2 strains induced the lowest levels of pro-inflammatory TNF and IL-12p40 as compared to other lineages (lineage 2: median TNF 362 pg/ml, IL-12p40 91 pg/ml; lineage 3: median TNF 1818 pg/ml, IL-12p40 123 pg/ml; lineage 4: median TNF 1207 pg/ml, IL-12p40 205 pg/ml;). In contrast, lineage 4 strains induced high levels of IL-12p40 and intermediate level of TNF. Lineage 3 strains induced high levels of TNF and intermediate levels of IL-12p40.ConclusionsStrains of M. tuberculosis from the three major modern strain lineages possess distinct patterns of growth and cytokine induction. Rapid growth and immune subversion may be key characteristics to the success of these strains in different human populations.

Strain-specific estimation of epidemic success provides insights into the transmission dynamics of tuberculosis

“…in their US patient population and those found in our French cohort: 87.0 vs. 80.0%, 86.2 vs. 75.3%, 77.4 vs. 64.9% and 65.7 and 50.0% for the East Asian/Beijing, Euro-American, Indo-Oceanic and East African-Indian lineages, respectively (R 2  = 0.99, P  = 0.006). Taken collectively, these results bring additional support to the hypothesis of MTBC lineage-specific adaptations impacting on disease14446474849, including the ability to generate active pulmonary TB as a major driving force of MTBC population dynamics4450.…”

Magnitude and sources of bias in the detection of mixed strain M. tuberculosis infection

“…We considered n ¼ 186 patients, n mix ¼ 35 of whom are detected with mixed infection, as in Warren et al (2004). The values for the growth rates are in line with the estimations in Sarkar et al (2012). The raw estimate from the data would indicate a mixed infection prevalence of approximately n mix =n ¼ 19%, corresponding to ρ ¼ 0:19, however we observe that, even in the most optimistic scenario (green dashed line) the posterior ρ is higher that is 0.19 with probability 0.9 and has mean over 0.23.…”

Transcriptome changes upon in vitro challenge with Mycobacterium bovis in monocyte-derived macrophages from bovine tuberculosis-infected and healthy cows

“…However, the second scenario was possible, because cytokines secreted by lymphocytes could have changed the gene expression profile of macrophages. Furthermore, different strains of M. bovis possess different growth patterns and cytokine induction abilities on macrophages (Sarkar et al, 2012;Tanveer et al, 2009), which might also contributed to the differences we have observed.…”