Brucella melitensis are intracellular bacteria that invade and replicate within macrophages and dendritic cells. With over 500,000 new infections per year, brucellosis is the most prevalent zoonosis worldwide and incurs significant human morbidity and economic loss. The intracellular location of Brucella renders the organism resistant to antibiotics. A safe and effective human vaccine does not exist. Thus, better understanding of the host-pathogen interactions supporting establishment of the intracellular replicative niche is critical. B. melitensis is a stealthy bacterium that expresses atypical smooth lipopolysaccharides and enters macrophages via lipid rafts rather than traditional phagocytosis. These Brucella-containing vacuoles (BCV) avoid degradation by end stage lysomsomes and fuse with the endoplasmic reticulum (ER). Reorganization of the host ER occurs within 48 hours of BCV fusion. The UPR is a conserved, cellular stress response comprised of three pathways that maintains ER homeostasis. ER perturbations such as calcium depletion, increased polypeptide load, and viral infection initiate the UPR. We recently published that infection of macrophages with Brucella induces all three arms of the UPR both in vitro and in vivo in a murine model of infection. Furthermore, our data suggest that intracellular replication is supported by the host UPR. Here, our goal is to better refine the host-pathogen interactions promoting chronic infection by interrogating the role of individual UPR pathways during Brucella intracellular infection (Aim 1) and by investigating the role of the IRE1? pathway in supporting nutrient acquisition (Aim 2). The UPR enhances amino acid transport and induces authophagy, a process of organelle recycling. These attributes of the UPR might contribute to the survival of B. melitensis in macrophages. We hypothesize that by inducing the UPR, and specifically the IRE1? pathway, B. melitensis promotes its infectious success. Achievement of these aims will lead to a more complete understanding of how a conserved, host response supports intracellular replication of Brucella. This will allow for an informed approach for the development of novel therapeutics that target the UPR to prevent and treat brucellosis. Achieving the scientific goals of this proposal is the first of many steps in developing into an independent academic research scientist. The mentorship of my sponsor and co-sponsor will help me grow in the areas of critical thinking, communication, and responsible conduct of research. This fellowship will aid in my development as a future academic research professor so I may establish my own research group investigation host-pathogen interactions and to train future scientists.

Public Health Relevance

Brucella melitensis is an intracellular bacterial pathogen that is the causative agent of Brucellosis, the most prevalent zoonosis worldwide. Investigating the mechanism by which Brucella melitensis establishes its intracellular niche will allow for increased understanding of the pathogen as well as the development of novel therapeutics.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Mukhopadhyay, Suman
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University of Wisconsin Madison
Schools of Medicine
United States
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