Abstract
Tuberculosis (TB) remains a serious public health problem despite the great scientific advances in the recent decades. We have previously shown that aggressive forms of TB caused by hypervirulent strains of Mycobacterium tuberculosis and Mycobacterium bovis are attenuated in mice lacking the P2X7 receptor, an ion channel activated by extracellular ATP. Therefore, P2X7 receptor is a potential target for therapeutic intervention. In vitro, hypervirulent mycobacteria cause macrophage death by a P2X7-dependent mechanism that facilitates bacillus dissemination. However, as P2X7 receptor is expressed in both bone marrow (BM)-derived cells and lung structural cells, several cellular mechanisms can operate in vivo. To investigate whether the presence of P2X7 receptor in BM-derived cells contributes to TB severity, we generated chimeric mice by adoptive transfer of hematopoietic cells from C57BL/6 or P2X7−/− mice into CD45.1 irradiated mice. After infection with hypervirulent mycobacteria (MP287/03 strain of M. bovis), P2X7−/−>CD45.1 mice recapitulated the TB resistance observed in P2X7−/− mice. These chimeric mice showed lower lung bacterial load and attenuated pneumonia compared to C57BL/6>CD45.1 mice. Lung necrosis and bacterial dissemination to the spleen and liver were also reduced in P2X7−/−>CD45.1 mice compared to C57BL/6>CD45.1 mice. Furthermore, an immature-like myeloid cell population showing a Ly6Gint phenotype was observed in the lungs of infected C57BL/6 and C57BL/6>CD45.1 mice, whereas P2X7−/− and P2X7−/−>CD45.1 mice showed a typical neutrophil (Ly6Ghi) population. This study clearly demonstrates that P2X7 receptor in BM-derived cells plays a critical role in the progression of severe TB.
Highlights
A quarter of the global population harbors bacteria of the Mycobacterium tuberculosis complex, resulting in an estimated 10.4 million new cases of active tuberculosis (TB) in 2015 [1, 2]
To determine whether P2X7 receptor in bone marrow (BM)-derived cells is responsible for the deleterious role of this receptor in severe TB, hematopoietic cells from C57BL/6 and P2X7−/− mice were transferred into irradiated CD45.1 mice (Figure 1A)
As a hallmark of severe TB is the presence of massive neutrophil infiltrates in the lungs [26,27,28], we investigated whether the absence of P2X7 receptor in BM-derived cells influences the pulmonary myeloid cell populations in MP287/03-infected chimeric mice
Summary
A quarter of the global population harbors bacteria of the Mycobacterium tuberculosis complex, resulting in an estimated 10.4 million new cases of active tuberculosis (TB) in 2015 [1, 2]. Infection typically occurs when an individual inhales aerosolized droplets containing the mycobacteria [3]. The equilibrium between host defense and the mycobacteria leads to latent infection. Active TB can develop through progression of recently acquired infection (primary disease) or reactivation of latent infection. Around 10% of active TB cases are due to progressive primary TB, which is an aggressive form of the illness that affect mostly immunodeficient patients and children under 5 years [5]. By promoting a progressive decline in cell-mediated immunity, co-infection with human immunodeficiency virus (HIV) greatly enhances TB incidence and severity. HIV co-infection was reported in 1.2 million (11%) of the people who developed TB in 2014 [1]. TB is the leading cause of death among individuals with acquired immunodeficiency syndrome [9, 10]
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