The innate immune system detects the presence of microbes in tissue by pattern recognition of conserved microbial structures, known as pathogen-associated molecular patterns (PAMPs). However PAMPs can be present in all microbes regardless of their pathogenic potential. To distinguish pathogens from other microbes with lower disease-causing potential the innate immune system can detect pathogen-induced processes, such as the presence of microbial products in the host cell cytosol, through mechanisms that are not fully resolved. Identification of signaling pathways involved in the detection of pathogen-induced processes is often difficult because PAMPs expressed by a pathogen can activate many pattern recognition receptors in parallel. Brucella abortus is a stealthy pathogen expressing modified PAMPs that no longer serve as agonists for pattern recognition receptors. As a result, host responses generated during B. abortus infection are entirely dependent on detecting the deployment of a virulence factor, the type IV secretion system (T4SS), as a pathogen-induced process. Here we propose to use this model organism to define a new signaling pathway involved in sensing the T4SS-dependent injection of proteins into the host cell cytosol as a pathogen-induced process. Our long-range goal is to determine the mechanisms and consequences of inducing inflammatory host responses during B. abortus infection. The objectives of this application are to study how translocation of the T4SS substrate VceC into host cells induces pro-inflammatory responses and alters the disease outcome. We hypothesize that translocation of the T4SS substrate VceC activates the unfolded protein response (UPR) with consequent induction of NF-?B-dependent inflammatory responses, thereby contributing to B. abortus- induced abortion. We will test key aspects of our hypothesis and accomplish the objectives of this application by pursuing two specific aims: (1) Elucidate the signaling pathway that detects targeting of VceC to the endoplasmic reticulum;and (2) Characterize the mechanism by which the UPR activates inflammatory responses in vivo. Successful completion of this work will move the field forward by establishing the UPR as a component of the innate immune system that detects microbial proteins targeting the ER as a pathogen- induced process. This new concept has important ramifications not only for bacterial pathogenesis, but also for host-virus interactions, innate immunity and the pathogenesis of certain inflammatory disorders, such as type 1 diabetes and inflammatory bowel disease.

Public Health Relevance

Brucellosis is a one of the most widespread zoonotic infections, with over 500,000 new cases each year. The disease, caused primarily by the bacterial pathogens Brucella melitensis and Brucella abortus, is acquired by consumption of unpasteurized dairy products or by contact with infected animals. Brucellosis is a multisystem disease characterized by fever, and frequently, osteoarticular disease. Our studies of how this pathogen interacts with host cells has revealed that one of its virulence factors activates a cellular response called the unfolded protein response. In this application, we propose to study how this Brucella virulence factor induces the unfolded protein response as an immune signaling pathway. The outcome of this work will be significant, because understanding how the unfolded protein response is linked to inflammation will have broad relevance for many different disease states in which the unfolded protein response has been implicated, including viral infections, type 1 diabetes and inflammatory bowel disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-S (02))
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Mukhopadhyay, Suman
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University of California Davis
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