The Role of Lipoate Dependent Metabolism During Intracellular Growth andPathogenesis of Listeria monocytogenes.

[摘要] The Gram-positive bacterial pathogen Listeria monocytogenes replicates rapidly in the host cytosol, indicating it efficiently utilizes host-derived nutrients. The critical co-factor lipoate is one nutrient this bacterium must scavenge for optimal intracellular growth. Although the L. monocytogenes genome encodes two putative lipoate ligases, LplA1 and LplA2, intracellular replication and virulence require only LplA1. The thesis research described here shows that LplA1 enables L. monocytogenes to use small host derived lipoyl-peptides, revealing an adaptive mechanism to exploit the host cytosol for essential nutrients.Furthermore, I provide evidence that a single amino acid residue on the surface of LplA1 is required for L. monocytogenes growth with lipoyl-peptides, as well as LplA1 mediated intracellular growth and spread. Lipoate dependent metabolism in L. monocytogenes controls the amino acid and anteiso-branched chain fatty acid (BCFA) composition of the bacterium, which is critical for intracellular replication. My thesis studies demonstrate that a bacterial enzyme, LplA1, enables usage of host-derived lipoate and plays a key role in the metabolism and pathogenesis of L. monocytogenes. The ability to utilize diverse sources of lipoate is likely to be a common theme in pathogenesis, as some parasites, while capable of synthesizing their own lipoate, must also scavenge lipoate from the host environment. This thesis has illustrated that understanding how microbes specifically alter their metabolism to exploit the host as a replicative environment will lead to a better understanding of disease processes and will reveal targets for development of theraputics.

[发布机构] University of Michigan

[效力级别] Listeria Monocytogenes

[关键词] Lipoate;Listeria Monocytogenes;Pathogenesis;Metabolism;Branched Chain Fatty Acids;Lipoic Acid Ligase;Health Sciences;Science;Microbiology & Immunology