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Full NameProfessor Miguel A. Valvano

Department:Wellcome-Wolfson Institute of Experimental Medicine

Organisation:Queen's University Belfast

Email Address:Email hidden; Javascript is required.

Research Fields

  • genetics, genomics and molecular biology
  • infectious disease and the immune system
  • Other

Other Research Fields:

Macrophage biology

Postgrad Medical Specialties

  • Medicine
  • Surgery
  • Emergency Medicine
  • Paediatrics
  • Pathology

Medical Subspecialties

  • Infectious diseases
  • Immunology
  • Respiratory Medicine
  • Vascular Medicine

My Work

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antimicrobial resistance, and discovered all the components of a general protein glycosylation pathway in Burkholderia (unpublished work).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.

- 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.
- Khodai-Kalaki, M., A. Andrade, Y. Fathy Mohamed, and M.A. Valvano*. 2015. Burkholderia cenocepacia lipopolysaccharide modification and flagellin glycosylation affect virulence but not innate immune recognition in plants. mBio Jun 4;6(3).

Potential Projects

Sample Project
Burkholderia cenocepacia is an opportunistic pathogen of cystic fibrosis patients whose underlying mechanisms of infectivity are relatively poorly understood. Recent work has implicated a type 6 secretion system (T6SS) secreted effector molecule, known as TecA, as a key player in the disease process of this organism by causing severe cytoskeletal dysregulation in macrophages. Previous studies showed a link between the gene cluster of a plasmid-encoded type IV secretion system (T4SS-2) and lack of morphological disruption in infected macrophages, together with a dramatic reduction of TecA production. We speculated that genes within the T4SS-2 cluster might be involved in the regulation of T6SS or TecA expression. This project will test the hypothesis that the deletion of two co-transcribed genes (pBCA054 and pBC055) encoding putative global transcriptional regulators located within the T4SS-2 gene cluster are responsible for the reduced expression of T6SS and/or TecA.

The aim of this project is to elucidate the regulation of infectivity in B. cenocepacia, an opportunistic pathogen that causes a severe and intractable pneumonia accompanied by sepsis in cystic fibrosis (CF). Research in the Valvano lab has shown that the bacterium reproduces intracellularly within macrophages of CF patients, causing actin cytoskeletal disruption via the deamination of RhoGTPases. The type VI secretion system effector known as TecA, described by Aubert et al. (2016), appears to be responsible for this; consequently, understanding the regulation of both the aforementioned type VI secretion system (T6SS) and of the expression of tecA is of paramount importance to fully elucidate how B. cenocepacia causes disease. Previous mutagenic studies show that macrophage cytoskeletal disruption is significantly diminished by the deletion of a plasmid encoded type IV secretion system (T4SS-2) (Tolman et al., unpublished). Located within the T4SS-2 cluster are two co-transcribed genes (pBCA054 and pBCA055) which encode putative global transcriptional regulators; the hypothesis being tested is that these are involved in the regulation of either T6SS activity, tecA expression, or both.

The plan is to create two deletion mutants, one lacking pBCA054 and pBCA055 and another lacking a large stretch of the T4SS-2 gene cluster, rendering T4SS-2 non-functional but leaving the genes under scrutiny intact and expressible- this is to rule out any sort of interaction between T4SS-2 and T6SS. The mutants will be examined for TecA/T6SS expression using several phenotypic markers and also biochemically characterized by determining the role of the second messenger cyclic-di-GMP in the regulation of T6SS.