|INOMATA, MEGUMI - Tufts University
|XU, SHUYING - Tufts University
|CHANDRA, PALLAVI - Washington University School Of Medicine
|MEYDANI, SIMIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
|TAKEMURA, GENZOU - Asahi University
|PHILIPS, JENNIFER - Washington University School Of Medicine
|LEONG, JOHN - Tufts University
Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/17/2020
Publication Date: 12/21/2020
Citation: Inomata, M., Xu, S., Chandra, P., Meydani, S.N., Takemura, G., Philips, J.A., Leong, J.M. 2020. Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging. Proceedings of the National Academy of Sciences (PNAS). 117(52):33561-33569. https://doi.org/10.1073/pnas.2015368117.
Interpretive Summary: Streptococcus pneumoniae (pneumococcus) can be commonly found in the nasopharynx, where it often causes no symptoms, but it can infect the lower respiratory tract, leading to pneumonia and potentially spreading to the bloodstream and brain. Inflammatory cells such as macrophages are important for immune defense against pneumococcal infection, but very high levels of inflammation are associated more serious disease. The elderly have higher levels of inflammation and more likely to develop serious infection caused by S. pneumoniae. In aged mice, S. pneumoniae lung infection is linked to more robust inflammatory responses and higher bacterial numbers. In this study, we investigated how mouse macrophages interact with S. pneumoniae. One means by which macrophages both kill microorganisms and control inflammation through a process called LC3-associated phagocytosis (LAP). We found that macrophages that were isolated from young mice utilized LAP to both eliminate S. pneumoniae and downregulated the production of molecules that cause inflammation. In contrast to macrophages from young mice, macrophages from aged mice were deficient for LAP, resulting in less efficient bacterial killing and higher levels of inflammatory molecules. Thus, LAP decreases with age and may contribute to the observed susceptibility of the elderly to infectious diseases such a pneumococcal pneumonia.
Technical Abstract: Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.