Protein secretion, Cell envelope biology, Bacterial pathogenesis, Immune response to Bacterial infections, Antimicrobials
My research interests focus on the bacterial cell surface. This focus is based on the philosophy that the bacterial cell surface offers a rich source of molecules which can be utilized and adapted to treat or prevent infections.
Protein secretion machines are the instruments of microbial warfare! Using these machines bacteria produce adhesins, toxins, enzymes and mediators of motility. These proteins are either secreted to or beyond the bacterial cell surface. These secreted proteins may interact directly with host cells resulting in disease. The simplest and most widely utilised secretion systems fall under the rubric of Type 5 secretion systems (T5SS). This category comprises those proteins secreted by the classical Autotransporter system, the two-partner system and the trimeric Autotransporter system. The importance of proteins secreted via the T5SS is illustrated by the fact that in some cases they form part of current human vaccines; thus filamentous haemagglutinin and pertactin are essential components of the acellular whooping cough vaccine. Furthermore, Autotransporters are often essential virulence factors and in the case of Shigella, the agent of bacillary dysentery, abolition of the gene encoding the Autotransporter IcsA results in an attenuated strain which forms the basis for a live attenuated Shigella vaccine. Thus, further understanding of these proteins may lead to greater healthcare benefits. For the last 17 years Prof. Henderson’s work has focussed on group the Autotransporter proteins. This work has ranged from investigating the mechanisms of gene regulation, the molecular mechanisms of biogenesis, interaction of proteins with host cells and exploiting the system for commercial protein production.
Outer membrane protein biogenesis
The outer membranes of Gram-negative bacteria are lipid bilayers. They consist of a phospholipid inner leaflet and a lipopolysaccharide outer leaflet with two major classes of protein: -barrel proteins (OMPs) and peripheral lipoproteins. These four major components provide an interface between the bacterium and its environment; they work in concert to protect the organism from noxious substances while permitting the selective uptake of nutrients. To survive bacteria must produce OMPs that directly or indirectly allow the organism to sense the environment, to move, to stick to inanimate surfaces, host cells or each other, to exchange genetic material, to evade host defences and in the case of pathogens, to cause disease. Furthermore, OMPs are exposed, elicit immune responses and are targets of antibody and therefore a source of antigens for vaccines. In Gram-negative bacteria Antibiotic resistance is often dependent on the OMP diffusion porins (e.g. OmpF/C) and transenvelope spanning efflux complexes (e.g. ArcAB-TolC). Therefore, understanding the nature of outer membrane is crucial to the development of strategies to prevent and treat infections. For the last 5 years Prof. Henderson’s group has investigated the molecular basis for outer membrane protein biogenesis.
Pathogenesis of Infection
Secreted proteins are the main nodes of interaction between pathogens and the host. Prof. Henderson’s group utilises a variety of approaches to study the different mechanisms by which secreted proteins influence infection. Key outcomes to these investigations include (i) elucidating why HIV patients are more susceptible to non-typhoidal Salmonella infections (Dr. Cal MacLennan’s group led this study); (ii) understanding how the immune system senses and responds to particular surface antigens (Dr. Adam Cunningham’s group have led these studies); and (iii) demonstrating that not all surface proteins can elicit a protective immune response.
Prof. Henderson’s group have been involved in sequencing bacterial genomes for over 10 years. Utilising Sanger, Illumina and 454 technologies Prof. Henderson’s group have completed the genomes of the type strains for several diarrheal pathogens. These organisms place a huge societal and economic burden on populations in developing countries and afflict the youngest disproportionately. They are among the largest killers of children under age 5. The genome sequences provide the basis for developing strategies to tackle these sinister organisms.
Beatson SA, MG de Luna, AC Freitas, PA dos Santos, JTB de Melo, DL Squire, AF Cunningham, JR Fitzgerald and IR Henderson. 2011. Genome sequence of the emerging pathogen Aeromonas caviae.J. Bacteriol. 193:1286-1287.
Siggins MK, AF Cunningham, JL Marshall, TR Hughes, IR Henderson, CA MacLennan. 2011. Absent bactericidal activity of mouse serum against invasive African non-typhoidal Salmonella results from impaired complement function but not lack of antibody. J. Immunol. 186:2365-71.
Knowles TJ, D Browning, M Jeeves, R Maderbocus, D Squires, DL Leyton, IR Henderson and M Overduin. 2011. Structure and function of BamE, a member of the b-barrel assembly machinery. EMBO Reports. 12:123-8 (highlighted in EMBO Reports with associated comment article).
Tsai JC, M Yen, R Castillo, DL Leyton, IR Henderson and MH Saier, Jr. 2010. The bacterial Intimins and Invasins: a large and novel family of secreted proteins. PLoS ONE. 5: e14403.
Lehr U, M Schütz, P Oberhettinger, F Ruiz-Perez, J Donald, T Palmer, D Linke, IR Henderson, IB Autenrieth. 2010. C-terminal amino acid residues of the trimeric autotransporter adhesin YadA of Yersinia enterocolitica are decisive for its recognition and assembly by BamA. Mol. Microbiol. 78:932-46.
Ruiz-Perez F, IR Henderson and JP Nataro. 2010. Involvement of FkpA, a peptidyl-prolyl cis/trans isomerase in the biogenesis of EspP autotransporter protein. Gut Microbe. 1:339-344.
Crossman LC, RR Chaudhuri, SA Beatson, TJ Wells, M Desvaux, AF Cunningham, NK Petty, V Mahon, C Brinkley, JL Hobman, SJ Savarino, SM Turner, MJ Pallen, CW Penn, J Parkhill, AK Turner, TJ Johnson, NR Thomson, SGJ Smith and IR Henderson. 2010. A commensal gone bad: complete genome sequence of the prototypical enterotoxigenic Escherichia coli strainH10407. J. Bacteriol. 192:5822-31
Leyton DL, MG de Luna, YR Sevastsyanovich, K Tveen Jensen, DF Browning, A Scott-Tucker and IR Henderson. 2010. The unusual extended signal peptide region is not required for secretion and function of an Escherichia coli autotransporter. FEMS Microbiol. Letts. 311:133-9.