Although the mechanisms underlying the cytotoxic effect of NK cells on tumor cells and intracellular bacteria have been studied extensively, it remains unclear how these cells kill extracellular bacterial pathogens. In this study, we examine how human NK cells kill Mycobacterium kansasii and M.tb. The underlying mechanism is contact dependent and requires two cytolytic proteins: perforin and granulysin. Mycobacteria induce enhanced expression of the cytolytic proteins via activation of the NKG2D/NCR cell-surface receptors and intracellular signaling pathways involving ERK, JNK, and p38 MAPKs. These results suggest that NK cells use similar cellular mechanisms to kill both bacterial pathogens and target host cells. This report reveals a novel role for NK cells, perforin, and granulysin in killing mycobacteria and highlights a potential alternative defense mechanism that the immune system can use against mycobacterial infection.

Complicated underlying conditions and infections may increase mortality in patients with antibiotic-related SCARs. The selection of structurally different alternative drugs is important to avoid recurrence.

Mycobacterium kansasii has emerged as an important nontuberculous mycobacterium pathogen, whose incidence and prevalence have been increasing in the last decade. M. kansasii can cause pulmonary tuberculosis clinically and radiographically indistinguishable from that caused by Mycobacterium tuberculosis infection. Unlike the widely-studied M. tuberculosis, little is known about the innate immune response against M. kansasii infection. Although inflammasome activation plays an important role in host defense against bacterial infection, its role against atypical mycobacteria remains poorly understood. In this report, the role of inflammasome activity in THP-1 macrophages against M. kansasii infection was studied. Results indicated that viable, but not heat-killed, M. kansasii induced caspase-1-dependent IL-1β secretion in macrophages. The underlying mechanism was found to be through activation of an inflammasome containing the NLR (Nod-like receptor) family member NLRP3 and the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). Further, potassium efflux, lysosomal acidification, ROS production and cathepsin B release played a role in M. kansasii-induced inflammasome activation. Finally, the secreted IL-1β derived from caspase-1 activation was shown to restrict intracellular M. kansasii. These findings demonstrate a biological role for the NLRP3 inflammasome in host defense against M. kansasii.

BACKGROUND During follow‐up for patients with cervical carcinoma, elevation of serum squamous cell carcinoma antigen (SCC‐Ag) levels in the absence of detectable recurrent lesions presents a diagnostic and therapeutic challenge. In the current prospective study, the authors evaluated the use of fluorine‐18‐labeled fluoro‐2‐deoxy‐D‐glucose (FDG) positron emission tomography (PET) to detect disease recurrence in this setting. METHODS Women with cervical carcinoma who experienced complete responses to primary treatment or salvage therapy and who had no evidence of recurrent disease as detected by conventional methods but had serum SCC‐Ag levels ≥ 2.0 ng/mL on 2 consecutive occasions were eligible for the study. PET was performed within 2 weeks after the completion of conventional studies for the assessment of recurrence. RESULTS Twenty‐seven consecutive patients were registered for the current study. PET findings were positive for 19 patients: 14 who had a distant lesion or lesions, 2 who had a local lesion or lesions, and 3 who had both local and distant lesions. Of these 19 patients, 17 were confirmed to have recurrent disease; the remaining two were found to be free of disease but had severe anthracosis in the PET‐positive mediastinal lymph nodes. Seven of the eight patients with negative PET findings were not found to have recurrent disease on follow‐up. Overall, PET detected FDG‐avid lesions in 17 (94%; P < 0.001) of the 18 patients with recurrent disease. Seven of these 18 patients received therapy with curative intent; complete control was achieved in 6, four of whom currently are alive and free of disease. The addition of PET in the current setting curbed the use of futile curative therapy and significantly increased overall survival for patients in the current cohort compared with a historical group of 30 consecutive patients who had elevated SCC‐Ag levels as a first sign of recurrence. CONCLUSIONS PET expedited the detection of recurrent cervical carcinoma in patients with unexplained elevation of SCC‐Ag levels. Such expedited detection may have positive effects on patient survival. Cancer 2004. © 2004 American Cancer Society.