Defining the impact of prostaglandins on yersinia pestis infection

The National Institute of Allergy and Infectious Diseases awarded the University of Louisville $152,600 on October 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to define the impact of prostaglandins on Yersinia pestis infection.

The research addresses how prostaglandins—host-derived lipid mediators—modulate the immune response during plague infection. Yersinia pestis uses a type 3 secretion system to suppress the host inflammatory cascade, delaying immune activation and creating a non-inflammatory environment favorable to bacterial proliferation. Preliminary studies show that prostaglandins are elevated early in infection while leukotriene B4, a pro-inflammatory lipid, is inhibited in a type 3 secretion system-dependent manner. The research will investigate whether early-synthesized prostaglandins are beneficial or detrimental to the host, the molecular mechanisms underlying differential prostaglandin synthesis across neutrophils, macrophages, and mast cells, and whether Yersinia pestis actively subverts prostaglandin production.

The University of Louisville Office of Research & Innovation serves as the recipient. Performance occurs in Louisville, Kentucky from October 1, 2026, through June 30, 2029. This is a Project Grant, an assistance type supporting biomedical research and research training in infectious diseases.

Abstract

Inflammation is a tightly regulated cascade of events that recruits and activates immune cells to the site of infection. Yersinia pestis is the etiologic agent of the human disease known as plague. A hallmark of this disease is the suppression of the host immune system, leading to a dramatic delay in inflammation. During infection, Y. Pestis uses its type 3 secretion system (T3SS) to inject effector proteins into host cells, disrupting signaling pathways critical for bacterial clearance and inflammation. As a result, early infection is characterized by the maintenance of a non-inflammatory environment in which the bacterium can proliferate without significant host intervention. Host-derived lipid mediators are critical in initiating the inflammatory response, triggering the production of inflammatory proteins, such as cytokines and chemokines, but can also play a role in resolving inflammation. However, the impact these lipids have on the host response during plague, and whether the bacterium subverts their production, remains poorly understood. Preliminary studies show that the synthesis of the potent pro-inflammatory lipid leukotriene B4 (LTB4) is delayed until 36 hours post-infection, with its production actively inhibited in neutrophils, macrophages, and mast cells in a T3SS-dependent manner. In contrast, several prostaglandins are elevated by 6 hours post-infection and maintained for at least 24 hours. While Y. Pestis inhibits prostaglandin E2 (PGE2) synthesis in neutrophils and macrophages in a T3SS-dependent manner, IT causes robust T3SS-independent PGE2 production in mast cells. This raises important questions about the role of early- synthesized prostaglandins during plague, including whether they are beneficial or detrimental to the host, and the molecular mechanisms behind their differential synthesis in leukocytes. The proposed studies aim to address these gaps by investigating the impact of prostaglandins on disease progression and inflammation (aim 1) and defining the molecular mechanisms underlying differential PGE2 synthesis during Y. Pestis infection (aim 2). These studies will be the first to define the role of prostaglandins in Y. Pestis infection and the interaction between mast cells and Y. Pestis. Completion of these aims will provide novel insights into how Y. Pestis establishes a non-inflammatory environment during early plague, delineate the dynamics of PGE2 synthesis in different leukocytes, and may offer broader insights into the role of inflammatory lipids during infection by other bacteria.