Susceptibility of Mycobacterium tuberculosis-infected host cells to phospho-MLKL driven necroptosis is dependent on cell type and presence of TNFα.

An important feature of Mycobacterium tuberculosis pathogenesis is the ability to control cell death in infected host cells, including inhibition of apoptosis and stimulation of necrosis. Recently an alternative form of programmed cell death, necroptosis, has been described where necrotic cell death is induced by apoptotic stimuli under conditions where apoptotic execution is inhibited. We show for the first time that M. tuberculosis and TNFα synergise to induce necroptosis in murine fibroblasts via RIPK1-dependent mechanisms and characterized by phosphorylation of Ser345 of the MLKL necroptosis death effector. However, in murine macrophages M. tuberculosis and TNFα induce non-necroptotic cell death that is RIPK1-dependent but independent of MLKL phosphorylation. Instead, M. tuberculosis-infected macrophages undergo RIPK3-dependent cell death which occurs both in the presence and absence of TNFα and involves the production of mitochondrial ROS. Immunocytochemical staining for MLKL phosphorylation further demonstrated the occurrence of necroptosis in vivo in murine M. tuberculosis granulomas. Phosphorylated-MLKL immunoreactivity was observed associated with the cytoplasm and nucleus of fusiform cells in M. tuberculosis lesions but not in proximal macrophages. Thus whereas pMLKL-driven necroptosis does not appear to be a feature of M. tuberculosis-infected macrophage cell death, it may contribute to TNFα-induced cytotoxicity of the lung stroma and therefore contribute to necrotic cavitation and bacterial dissemination.

Tuberculosis trends in Saudis and non-Saudis in the Kingdom of Saudi Arabia--a 10 year retrospective study (2000-2009).

BACKGROUND: Tuberculosis (TB) remains a public health problem in the Kingdom of Saudi Arabia (KSA), which has a very large labour force from high TB endemic countries. Understanding the epidemiological and clinical features of the TB problem, and the TB burden in the immigrant workforce, is necessary for improved planning and implementation of TB services and prevention measures. METHODS: A 10 year retrospective study of all TB cases reported in KSA covering the period 1st January 2000 to 31st December 2009. Data was obtained from TB reporting forms returned to the Ministry of Health. Data were then organised, tabulated and analysed for annual incidence rates by province, nationality, country of origin and gender. RESULTS: There was an annual increase in the number of TB cases registered from 3,284 in 2000 to 3,964 in 2009. Non-Saudis had nearly twice the TB incidence rate compared to Saudis (P = <0.05). All but four provinces (Najran, Riyadh, Makkah, Tabuk) showed decreasing TB incidence rates. The highest rates were seen in the 65+ age group. In the 15-24 year age group the incidence rate increased from 15.7/100,000 in 2000 to 20.9/100,00 in 2009 (P = <0.05). The incidence of TB in Saudi males was higher than Saudi females. Conversely, for non-Saudis the TB incidence rates were significantly higher in females compared to males. CONCLUSIONS: Despite significant investments in TB control over 15 years, TB remains an important public health problem in the KSA affecting all age groups, and Saudis and non-Saudis alike. Identification of the major risk factors associated with the persistently high TB rates in workers migrating to KSA is required. Further studies are warranted to delineate whether such patients re-activate latent Mycobacterium tuberculosis (M.tb) infection or acquire new M.tb infection after arrival in KSA. Appropriate interventions are required to reduce TB incidence rates as have been implemented by other countries.