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Full NameProfessor Miguel A. Valvano
Department:Wellcome-Wolfson Institute for Experimental Medicine
Organisation:Queen's University Belfast
- genetics, genomics and molecular biology
- infectious disease and the immune system
Postgrad Medical Specialties
- Emergency Medicine
- Infectious diseases
- Respiratory Medicine
We have made seminal contributions in the molecular pathogenesis of the opportunistic CF pathogen Burkholderia cenocepacia and gained international recognition as a leader in Burkholderia research. We described for the first time the biology of the Burkholderia cenocepacia infection in macrophages. We also developed novel genetic tools that allow us to manipulate and better understand this difficult organism, elucidated the role of lipopolysaccharide in antimicrobial resistance, and discovered all the components of a general protein glycosylation pathway in Burkholderia (unpublished work). Pioneering studies demonstrated that Burkholderia strains could survive in macrophages within a specialized vacuole that delays the fusion with the phagolysosome and has properties of an arrested autophagosome. We also identified the T6SS effector protein TecA, which disarms Rho type GTPases and causes the activation of the pyrin inflammasome. Also, we have contributed to elucidate mechanisms of high-level multidrug antibiotic resistance in B. cenocepacia, in particular a novel mechanism of extracellular resistance based on bacterially secreted molecules that can scavenge antibiotics outside the cell.
An, S-q., J. Murtagh, K.B. Twomey, M.K. Gupta, T.P. O'Sullivan, R. Ingram, M.A. Valvano*,Ji-l. Tang. 2019. Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies diffusible signal factor analogues. Nature Communications 10:2334. doi: 10.1038/s41467-019-10271.
El-Halfawy, O.E., J. Klett, R.J. Ingram, S.A. Loutet, M.E.P. Murphy, S. Martín-Santamaría, and M.A. Valvano*. 2017. Antibiotic capture by bacterial lipocalins uncovers an extracellular mechanism of intrinsic antibiotic resistance. mBio 017 Mar 14;8(2). pii: e00225-17. doi: 10.1128/mBio.00225-17.
Aubert, D.F., X. Hao, J. Yang, X. Shi, W. Gao, L. Li, F. Bisaro, S. Chen, M.A. Valvano*, and F. Shao*. 2016. A Burkholderia Type VI Effector Deamidates Rho GTPases to Activate the Pyrin Inflammasome. Cell Host & Microbe 19:664-674.
Infection and chronic inflammation in patients with cystic fibrosis (CF) lead to progressive lung damage. CF-defective macrophages fail to kill engulfed opportunistic pathogens such as Burkholderia cenocepacia. Engulfed pathogens disarm macrophages and counteract immunity by deploying proteins (effectors) that alter central cellular pathways including actin cytoskeleton remodeling. Pathogen-induced disorganization of the actin cytoskeleton is both a remarkable anti-host strategy and a danger signal driving inflammation and cell death. However, the actin cytoskeleton dynamics in the context of the CF defect has not been explored. We hypothesize that intracellular opportunistic pathogens engulfed by macrophages, in combination with the CF genetic defect, induce disorganization of the actin cytoskeleton that leads to a highly proinflammatory state. Our research established B. cenocepacia as a model organism for cellular microbiology. We discovered that a B. cenocepacia type VI-secretion system (T6SS) disrupts the macrophage's actin cytoskeleton and elicits pyroptosis (proinflammatory cell death), and we recently identified TecA as the T6SS protein responsible for these phenotypes by causing the direct inactivation of Rho GTPases, which in turn activates the Pyrin inflammasome and the ASC complex formation. We will investigate here the relationship between inflammation and B. cenocepacia-mediated modulation of macrophages' actin cytoskeleton in CFTR-defective human monocytic macrophages. We will address 2 specific aims: (1) To assess the status of the pyrin inflammasome in B. cenocepacia-infected, CFTR-defective peripheral monocytes; and (2) To evaluate the role of the B. cenocepacia T4SS and T2SS systems in the activation of ASC-dependent inflammasomes upon infection in human macrophages.