Brucellosis is one of the world's most frequent zoonotic diseases with over 500,000 new human infections every year. Brucella abortus strain 19 vaccine, developed in the 1930s, is the principal vaccine used to prevent transmission of brucellosis from cattle to humans worldwide and in Brazil. The mechanisms that mediate protection by strain 19 are poorly understood. Host mechanisms of innate immunity induced by the vaccine that control infection remain obscure. Indeed, the vaccine contains several properties that are inhibitory to host immunity. Our research group was the first to implicate the role of inflammasome receptors in the control of Brucella abortus infection. Further, our team has demonstrated that IFN-aR KO mice are more resistant to infection suggesting that type I IFN signaling favors Brucella multiplication in the host. Therefore, our long-term goal is to resolve the conundrum of how Brucella activates innate immune components that results in host resistance versus bacterial subversion of the immune response. Brucella spp are one of the few bacterial pathogens that use the endoplasmic reticulum (ER) as its replicative niche. The Unfolded Protein Response (UPR) is a conserved signaling pathway in eukaryotes that mediates cellular adaptation to protein-folding stress in the ER. The UPR also modulates innate immunity. Recently, our collaborators have demonstrated that Brucella induces the UPR that enables its intracellular replication. Based on these compelling preliminary data, we propose to test the central hypothesis that Brucella abortus strain 19 activates protective innate immune mediators and triggers the UPR to secure intracellular replication. Further, we propose that the strain 19 induced UPR regulates cytokine production.
Our specific aims are to determine whether: 1) NLRP3 inflammasome activation and IL-1? secretion induced by Brucella requires the UPR; 2) the bacterial virulence factor ? TcpB that modulates host cell microtubules activates the NLRP3 inflammasome and IL-1? and 3) the UPR activated by Brucella abortus strain 19 regulates STING expression and type I interferon production to facilitate bacterial persistence. We believe that our approach will shed light on the mechanisms of immunity against this important human and animal pathogen. Additionally, critical information gained from these specific aims will begin to bridge the gap between what we know about mechanisms of protection induced by B. abortus vaccine strain 19 and how bacterial persistence is regulated. Finally, the investigators on this proposal have a strong track record in brucellosis research and a unique combination of key expertise in whole animal models, immunology, human brucellosis, cell biology, and analysis of the UPR.

Public Health Relevance

Brucellosis is one of the world's most frequent zoonotic diseases with over 500,000 new human infections every year. This proposal defines the pathways of innate immune activation or inhibition by Brucella abortus strain 19 vaccine. Identifying activation or inhibition of innate immune mechanisms used by strain 19 will determine the issues with the current vaccine and suggest changes to enhance its efficacy and disease control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116453-05
Application #
9841875
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mukhopadhyay, Suman
Project Start
2016-01-20
Project End
2020-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Foundation for Research Development
Department
Type
DUNS #
898723903
City
Belo Horizonte
State
Country
Brazil
Zip Code
31270901
Smith, Judith A (2018) Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity. Front Immunol 9:422
Guimarães, Gabriela; Gomes, Marco Túlio R; Campos, Priscila C et al. (2018) Immunoproteasome Subunits Are Required for CD8+ T Cell Function and Host Resistance to Brucella abortus Infection in Mice. Infect Immun 86:
Smith, Judith A (2018) Brucella Lipopolysaccharide and pathogenicity: The core of the matter. Virulence 9:379-382
Canesso, M C C; Lemos, L; Neves, T C et al. (2018) The cytosolic sensor STING is required for intestinal homeostasis and control of inflammation. Mucosal Immunol 11:820-834
Corsetti, Patrícia P; de Almeida, Leonardo A; Gonçalves, André Nicolau Aquime et al. (2018) miR-181a-5p Regulates TNF-? and miR-21a-5p Influences Gualynate-Binding Protein 5 and IL-10 Expression in Macrophages Affecting Host Control of Brucella abortus Infection. Front Immunol 9:1331
Hielpos, M Soledad; Fernández, Andrea G; Falivene, Juliana et al. (2018) IL-1R and Inflammasomes Mediate Early Pulmonary Protective Mechanisms in Respiratory Brucella Abortus Infection. Front Cell Infect Microbiol 8:391
Costa Franco, Miriam Maria Silva; Marim, Fernanda Martins; Alves-Silva, Juliana et al. (2018) AIM2 senses Brucella abortus DNA in dendritic cells to induce IL-1? secretion, pyroptosis and resistance to bacterial infection in mice. Microbes Infect :
Costa Franco, Miriam M; Marim, Fernanda; Guimarães, Erika S et al. (2018) Brucella abortus Triggers a cGAS-Independent STING Pathway To Induce Host Protection That Involves Guanylate-Binding Proteins and Inflammasome Activation. J Immunol 200:607-622
Marinho, Fabio V; Benmerzoug, Sulayman; Oliveira, Sergio C et al. (2017) The Emerging Roles of STING in Bacterial Infections. Trends Microbiol 25:906-918
Campos, Priscila C; Gomes, Marco Túlio R; Guimarães, Erika S et al. (2017) TLR7 and TLR3 SenseBrucella abortusRNA to Induce Proinflammatory Cytokine Production but They Are Dispensable for Host Control of Infection. Front Immunol 8:28

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