ESX-1-induced apoptosis is involved in cell-to-cell spread ofMycobacterium tuberculosis

Abstract

SummaryApoptosis modulation is a procedure amply utilized by intracellular pathogens to favour the outcome of the infection. Nevertheless, the role of apoptosis during infection with Mycobacterium tuberculosis, the causative agent of human tuberculosis, is subject of an intense debate and still remains unclear. In this work, we describe that apoptosis induction in host cells is clearly restricted to virulent M. tuberculosis strains, and is associated with the capacity of the mycobacteria to secrete the 6 kDa early secreted antigenic target ESAT-6 both under in vitro and in vivo conditions. Remarkably, only apoptosis-inducing strains are able to propagate infection into new cells, suggesting that apoptosis is used by M. tuberculosis as a colonization mechanism. Finally, we demonstrate that in vitro modulation of apoptosis affects mycobacterial cell-to-cell spread capacity, establishing an unambiguous relationship between apoptosis and propagation of M. tuberculosis. Our data further indicate that BCG and MTBVAC vaccines are inefficient in inducing apoptosis and colonizing new cells, correlating with the strong attenuation profile of these strains previously observed in vitro and in vivo.

Immunity and Immunopathology in the Tuberculous Granuloma

“…A second signal emanating from dead or dying macrophages appears to draw these macrophages to them, and their encased bacteria are then phagocytosed to create new infected cells. Indeed, RD1-competent mycobacteria also induce more apoptotic death of infected macrophages in the granuloma (Volkman et al 2004;Davis and Ramakrishnan 2009), consistent with studies showing that the RD1-encoded virulence determinant ESAT-6 can induce multiple programs associated with cell death in vitro Derrick and Morris 2007;van der Wel et al 2007;Choi et al 2010;Mishra et al 2010;Aguilo et al 2013). It would be predicted that the coordinated acceleration of new macrophage recruitment and infected macrophage apoptosis would be required to maximize bacterial expansion in the granuloma.…”

Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

“…Compelling evidence from the zebrafish model shows that the ESX-1 secretion system, via secretion of EsxA (ESAT-6), is involved in the up-regulation of MMP9 on epithelial cells surrounding the granuloma, leading to recruitment of uninfected macrophages (Volkman et al 2010), and that this, together with apoptosis induction of infected macrophages, helps in the dissemination of the bacteria (Davis and Ramakrishnan 2009). The beneficial effect of host cell apoptosis in the spread of bacteria and its dependence on the ESX-1 system were supported by evidence from Mtb in mouse lung infections showing a correlation between strains that induce increased lung cell apoptosis and bacterial growth (Aguilo et al 2013). Consistently, the proapoptotic nuoG Mtb mutant was present in a larger number of diverse lung myeloid cells, albeit with fewer bacteria per cell, compared with wild-type Mtb during the early phase of aerosol mouse infection (Blomgran et al 2012).…”

Mycobacterial Pathogenomics and Evolution

“…It seems clear, though, that ESX-1-dependent pore formation and lysis of the vacuolar membrane allows pathogenic mycobacteria and/or bacterial components to gain access to the cytosolic compartment of the host cell at different stages of infection, which accounts for major differences observed between virulent M. tuberculosis and attenuated BCG, the latter lacking ESX-1 functions due to the RD1 deletion. Indeed, M. tuberculosis and BCG differ in a wide variety of features such as cell-tocell spread (115,150), apoptosis (151), autophagy induction, and/or impairment (152,153), and access of mycobacterial proteins to the class I-processing machinery contained in the proteasome, with impact on NLRP3 inflammasome activation (154)(155)(156), type I interferon responses (157), and induction of CD8 T-cell responses (158).…”