New Paper on Leukotriene B4 Inhibition During Plague
JANUARY 26, 2024
Eager to share our first foray into inflammatory lipids during plague published in PLoS Pathogens! Amanda Brady led these studies, but we couldn’t have done it without our collaborators. Continue reading for a crash course into Amanda’s exciting discoveries about Y. pestis manipulation of LTB4.
Y. pestis induces an early non-inflammatory environment during plague that is required to establish a foothold in its host. Therefore, many researchers are interested the mechanisms used by Y. pestis to evade and inhibit the immune system. Inflammation is controlled by a tightly regulated sequence of events, initiated by the production of inflammatory lipids and sustained and amplified by the subsequent production of cytokines and chemokines.
Others have shown that cytokine/chemokine production and neutrophil recruitment is delayed during plague, but until Amanda hit the scene, the role of inflammatory lipids during plague had not been thoroughly investigated.
During a global lipidomics analysis, Amanda discovered that the lipid LTB4 is not synthesized during the early stages of plague. This caught her attention because LTB4 is critical for the timely initiation of the inflammatory cascade and leukocyte activation and chemotaxis.
Moreover, Katelyn Sheneman showed that exogenous administration of LTB4 inhibited Y. pestis proliferation in vivo, further supporting a hypothesis that Y. pestis inhibits the production of LTB4 to delay neutrophil recruitment and activation during early colonization.
Using human and mouse neutrophils, Amanda went on to further support this hypothesis by showing that Y. pestis actively inhibits LTB4 production by leukocytes through the injection of bacterial proteins called Yops into the host cells.
However, Amanda also discovered that the T3SS, which the bacteria use to inject these Yop proteins into cells, is actually the PAMP recognized by leukocytes to initiate LTB4 synthesis – another great example in Y. pestis highlighting the evolutionary arms race between immune cells and bacteria.
Taken together, these studies expand on our current working model of Y. pestis manipulation of the innate immune system to include rapid inhibition of the first steps of the inflammatory cascade need for timely recruitment of neutrophils to control infection.