Sweet and sour: Uncovering bacterial antigen biosynthesis and the mechanism of host protection by iNKT cells
Immunology
Final Report Abstract
Invariant natural killer T cells (iNKT cells) express an invariant TCR α chain and they can recognize self-derived as well as microbial glycolipid antigens presented by CD1d. Mice lacking iNKT cells are impaired in their early immune response against Streptococcus pneumoniae, a gram-positive bacterium responsible for pneumonia, sepsis and other diseases. It has been shown that S. pneumoniae synthesizes a glycolipid that is both a major component of the bacterial membrane and an antigen for iNKT cells. This compound is a glucosylated diacylglycerol (DAG) containing vaccenic acid, a mono-unsaturated, 18 carbon fatty acid (C18:1) with a cis-unsaturated bond between carbons 9 and 10. An identical antigen has been found in Group B Streptococcus (GBS). The in vitro and in vivo assays point towards a strategy used by S. pneumoniae, and maybe by other Streptococcus species, to evade the host immune system. Generating a mutant strain with reduced iNKT cell antigens showed that a foreign antigen is important for iNKT cell responses during pulmonary infection. However, it also pointed towards the idea of testing this system with the wild-type S. pneumoniae strain. Thus, I could show that wild-type bacteria in an oleic acid-rich environment downregulate fab expression and lose their iNKT cell antigen. As host tissue is supposed to have high oleic acid levels, wild-type bacteria might shutdown endogenous fatty acid synthesis and rather take up host fatty acids. By incorporating those host fatty acids into bacterial glycolipids, S. pneumoniae might create a molecular chimera by replacing bacterial vaccenic acid with host oleic acid and thus rendering its abundant glycolipids non-antigenic. Accordingly, the suppression of oleic acid biosynthesis in the host by treatment with an SCD1-inhibitor, decreased bacterial growth. These data not only deliver a greater understanding of the requirements for iNKT cell activation, but also, they elucidate a pathogen immune evasion mechanism that is tied to the availability of an important nutrient.
