Research in the Darveau Lab

Our lab focuses on lipopolysaccharide (LPS), a molecule found in the outer membrane of Gram-negative bacteria, and how it manipulates the host innate immune response.  LPS is a complex strucutre, made up of a highly variable polysaccharide region (O-Antigen), a less variable oligosaccharide region (core), and a relatively conserved lipid region (Lipid A).  Lipid A is the structure our lab is primarily concerned with.

Dept. of Pathology and Microbiology,
University of South Carolina

The "classical" Lipid A structure is represented by Lipid A extracted from Escherichia coli.  The structure is a 1,4'-biphosphorylated glucosamine disaccharide.  Attached to this sugar moiety are 6 fatty acids, and hence, this form of Lipid A is also called "hexa-acylated."  Not all Lipid A structures are identical; different bacterial species exhibit Lipid A structures with differing amounts and types of fatty acids, phosphate groups, etc.

One of the ways that the mammalian innate immune system recognizes bacteria is via Toll-like receptors (TLRs).  These TLRs are able to detect "molecular patterns" that are commonly associated with pathogens.  For instance, TLR-5 is able to detect flagellin (which indicates the presence of motile bacteria), and TLR-3 is able to detect the presence of double-stranded RNA (which indicates the presence of viral infection).  Our lab, however, is interested in TLR-4, a molecule which is able to detect and respond to LPS and Lipid A.  Upon recognition of LPS, the host is able to activate an inflammatory pathway, which (ideally) will clear the host of the invading bacterial pathogen.

Some bacteria, however, have found ways of manipulating this host innate immune response.  By altering their Lipid A structures, some bacteria have been shown to drastically change how the host responds to infection.  Two such organisms that have been known to do this are Porphyromonas gingivalis and Bacteroides spp.

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Porphyromonas gingivalis is associated with periodontitis, i.e., gum inflammation.  This is the leading cause of tooth loss in the world and, as one could imagine, a severe economic burden on our health care system.  P. gingivalis has been shown to manipulate the host innate immune response by deacylating (i.e., removing fatty acids from) its Lipid A structure.  In particular, it reduces the number of fatty acids from five to four.  It does this by sensing hemin concentration.  Hemin is the component of hemoglobin that is responsible for binding oxygen.  When P. gingivalis detects a high concentration of hemin in its microenvironment, it responds by removing a fatty acid from its Lipid A structure.  This slight alteration in the structure of P. gingivalis Lipid A has been demonstrated to drastically reduce the host's ability to mount an immune response.  In particular, the ability of the host to express E-selectin (a molecule important in bringing neutrophils to the site of an infection) is greatly reduced.

We are also investigating Lipid A deacylation in a human intestinal opportunistic pathogen, Bacteroides fragilis, and in a human intestinal symbiont, Bacteroides thetaiotaomicron, and how these changes impact the host response to colonization/infection.

In summary, the research focus of our lab is on the Lipid A modifications that take place during host infection and how those changes manipulate the host innate immune response.