Flagellin-modulated inflammasome pathways characterize the human alveolar macrophage response to Burkholderia pseudomallei, a lung-tropic pathogen.

Melioidosis is an emerging tropical infection caused by inhalation, inoculation, or ingestion of the flagellated, facultatively intracellular pathogen Burkholderia pseudomallei. The melioidosis case fatality rate is often high, and pneumonia, the most common presentation, doubles the risk of death. The alveolar macrophage is a sentinel pulmonary host defense cell, but the human alveolar macrophage in B. pseudomallei infection has never been studied. The objective of this study was to investigate the host-pathogen interaction of B. pseudomallei infection with the human alveolar macrophage and to determine the role of flagellin in modulating inflammasome-mediated pathways. We found that B. pseudomallei infects primary human alveolar macrophages but is gradually restricted in the setting of concurrent cell death. Electron microscopy revealed cytosolic bacteria undergoing division, indicating that B. pseudomallei likely escapes the alveolar macrophage phagosome and may replicate in the cytosol, where it triggers immune responses. In paired human blood monocytes, uptake and intracellular restriction of B. pseudomallei are similar to those observed in alveolar macrophages, but cell death is reduced. The alveolar macrophage cytokine response to B. pseudomallei is characterized by marked interleukin (IL)-18 secretion compared to monocytes. Both cytotoxicity and IL-18 secretion in alveolar macrophages are partially flagellin dependent. However, the proportion of IL-18 release that is driven by flagellin is greater in alveolar macrophages than in monocytes. These findings suggest differential flagellin-mediated inflammasome pathway activation in the human alveolar macrophage response to B. pseudomallei infection and expand our understanding of intracellular pathogen recognition by this unique innate immune lung cell.

The Parker B. Francis Fellowship Program: analysis of 31 years of career development support.

RATIONALE: The Parker B. Francis (PBF) Fellowship Program has supported more than 750 M.D., M.D./Ph.D., and Ph.D. fellows since 1976, but there is little information about the effectiveness of the program in fostering successful careers and producing important research. OBJECTIVES: To survey all past PBF Fellows to obtain information about their productivity and career pathways. METHODS: We obtained e-mail addresses for 526 (74%) of the 712 PBF awardees from 1976 to 2006, then sent an e-mail survey to the 526 past fellows and received 365 replies (69% response rate, 49% overall). Survey questions addressed time in research, areas of research, current position and responsibilities, and research funding. MEASUREMENTS AND MAIN RESULTS: Seventy percent of the 365 respondents spend 25% or greater effort in research and 56% report 50% or more effort in research. Respondents have published an average of 2.7 peer-reviewed publications per year, totaling more than 15,678 peer-reviewed publications, of which 1,875 appeared in high-impact journals. Respondents have received more than $1.8 billion in direct research funding since their PBF Fellowships began. Ph.D. awardees spend more time in research than M.D. awardees, and current research effort did not differ by gender. PBF awardees have become prominent leaders in universities, the National Institutes of Health, health care, and industry. CONCLUSIONS: The PBF Program has been highly successful in producing a large number of scientific and clinical leaders in pulmonary and critical care medicine. The results provide comprehensive data about the success of this career development program and provide a model for programs designed to build the workforce in pulmonary and critical care medicine.