At early stages of infection, these isolates induced significantly lower TNF-α production than the other isolates, and maintained this level until the end of infection, thus indicating failure to correctly induce the cytokine-dependent Th1-type protective immune response. Other authors

have also observed a wide range of intracellular replication rates among Beijing isolates and an inverse association between intracellular replication levels and TNF-α production [30, 39]. Furthermore, low-virulence strains are associated with a more vigorous immune response with high levels of type 1 cytokines (TNF-α, IFN-γ, IL-12) [10, 13, 40]. These data suggest that the infective advantage of Beijing strains

should not be considered as an intrinsic NVP-BSK805 feature of the lineage, but as a characteristic of certain representatives. These findings are highly relevant, as the outcome of the infection is related to FG-4592 in vivo the ability of MTB to regulate the induction of cytokines that are essential for the development of an efficient immune response [41]. As shown by our study and others, the virulent Beijing representatives induced high production of proinflammatory cytokines, which is quickly controlled, thus decreasing their levels and giving rise to a more effective infection. Phenol glycolipid (PGL), has recently been proposed as a virulence factor in Beijing strains [12]. This molecule can inhibit the release of key inflammatory effector molecules in vitro and has been considered responsible for the hypervirulent phenotype of Beijing strains, ZD1839 molecular weight both in murine and rabbit infection models [12, 42]. The different sub-groups of the Beijing lineage have recently been shown to contain different percentages of PGL-producing strains [18]; therefore, other factors could determine the hypervirulence of certain Beijing strains. As most of the isolates in our study belonged to

sub-group 3, it was not possible to explore in depth the relationships between infectivity and PGL production. However, isolates Small molecule library chemical structure belonging to sub-group 3 displayed different intracellular growth rates. The only representative belonging to sub-group 4 (with the highest percentage of PGL-producing strains) showed the highest intracellular replication levels. Therefore, according to Reed et al [18], it would be very interesting to evaluate PGL production in these isolates to determine whether their hypervirulent phenotype (high intracellular replication rates, low production of TNF-α) could correlate with the synthesis of this complex glycolipid. Some studies have analyzed the relationship between intracellular growth and transmissibility [40, 43], and concluded that the extensive spread of an MTB strain correlated with its high capacity to replicate, which is considered a marker of virulence.