Research Areas

Discovery of novel modulators of Innate Immunity

Pattern recognition receptors (PRRs) on cells of the innate immune system mediate many of our essential responses to infection. These include Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-1 like receptors (RLRs). A major area of investigation within the IRC is to identify specific novel pathogen-derived molecules which modulate the responses of these receptor families. Many pathogens have also evolved strategies to prolong their survival in the host by evading or suppressing protective immune responses. Scientists within the IRC are focused on identifying novel immunomodulators derived from specific bacterial pathogens such as Bordetella pertussis (1), Mycobacterium tuberculosis (2) and Helicobacter pylori, as well as from the parasitic helminth Fasciola hepatica and the Vaccinia virus (3).

As well as pathogen-derived molecules, it is also established that the release of intracellular factors during necrotic cell death can function as natural adjuvants to promote immune responses and possibly initiate tumor rejection and autoimmunity. Scientists within the IRC are also focusing on the identification of novel endogenous immunomodulators which occur upon tissue damage or sterile cell injury (4,5).

Basic Biology of Innate Immune Sensing

The indentification of different PRRs has led to resurgence in interest in innate immunity, but still many of the mechanisms underlying their functions have yet to be fully characterised and understood. The second major area of focus of scientists within the IRC is to investigate the cellular mechanisms and signalling pathways which regulate the effects on TLRs, NLRs and RLRs in response to both pathogen-derived and endogenous immunomodulators. To date, work by IRC scientists has led to numerous new discoveries related to these pathways (6-11). These studies will lead to a greater overall understanding of the sensing and signalling mechanisms of the innate immune system.

Validation of identified Immunomodulators

As work on the discovery of novel immunomodulators and signalling pathways advances, so scientists within the IRC, in conjunction with our industrial partners, are investigating the function of novel modulators of innate immunity in driving the adaptive immune response. These studies will promote a greater understanding of the influence of the innate immune system in promoting adaptive responses and involve the evaluation and exploitation of both pathogen-derived and endogenous regulators as potential immunotherapeutics for autoimmunity and cancer, as well as for novel adjuvants for vaccines.

References

(1) Dunne, A., Ross, P.J., Pospisilova, E., Masin, J., Meaney, A., Sutton, C.E., Iwakura, Y., Tschopp, J., Sebo, P., Mills, K.H. Inflammasome activation by adenylate cyclase toxin directs Th17 responses and protection against Bordetella pertussis. J Immunol 185: 1711-1719. (2010)

(2) Macdonald, S.H., Woodward, E., Coleman, M.M., Nadarajan, P., Chew, W.M., McLaughlin, A. M., Keane, J. Networked T Cell Death following Macrophage Infection by Mycobacterium tuberculosis. PLoS One 7(6): e38488 (2012)

(3) Lysakova-Devine, T., Keogh, B., Harrington, B., Nagpal, K., Halle, A., Golenbock, D.T., Monie, T., Bowie, A.G.
Viral inhibitory peptide of TLR4, a peptide derived from vaccinia protein A46, specifically inhibits TLR4 by directly targeting MyD88 adaptor-like and TRIF-related adaptor molecule. J Immunol 185: 4261-4271. (2010)

(4) Afonina, I.S., Tynan, G.A., Logue, S.E., Cullen, S.P., Bots, M., Luthi, A.U., Reeves, E.P., McElvaney, N.G., Medema, J.P., Lavelle, E.C., Martin, S.J. Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1alpha. Mol Cell 44: 265-278. (2011)

(5) Masters, S.L., Dunne, A., Subramanian, S.L., Hull, R.L., Tannahill, G.M., Sharp, F.A., Becker, C., Franchi, L., Yoshihara, E., Chen, Z., Mullooly, N., Mielke, L.A., Harris, J., Coll, R.C., Mills, K.H., Mok, K.H., Newsholme, P., Nunez, G., Yodoi, J., Kahn, S.E., Lavelle, E.C., O'Neill, L.A. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 11: 897-904. (2010)

(6) Harris, J., Hartman, M., Roche, C., Zeng, S.J.G., O'Shea, A., Sharp, F.A., Lambe, E.M., Creagh, E.M., Golenbock, D.T., Tschopp, J., Kornfeld, H., Fitzgerald, K.A., Lavelle, E.C. Autophagy Controls IL-1 beta Secretion by Targeting Pro-IL-1 beta for Degradation. J Biol Chem 286: 9587-9597. (2011)

(7) Peral de Castro, C., Jones, S.A., Ni Cheallaigh, C., Hearnden, C.A., Williams, L., Winter, J., Lavelle, E.C., Mills, K.H.G., Harris, J. Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion. Journal of Immunology in press. (2012).

(8) Masters, S.L., Mielke, L.A., Cornish, A.L., Sutton, C.E., O'Donnell, J., Cengia, L.H., Roberts, A.W., Wicks, I.P., Mills, K.H., Croker, B.A. Regulation of interleukin-1beta by interferon-gamma is species specific, limited by suppressor of cytokine signalling 1 and influences interleukin-17 production. EMBO Rep 11: 640-646. (2010)

(9) Mellett, M., Atzei, P., Jackson, R., O'Neill, L.A., Moynagh P.N. Mal mediates TLR-induced activation of CREB and expression of IL-10. J Immunol 186: 4925-4935. (2011)

(10) Smith, S.M., Moran, A.P., Duggan, S.P., Ahmed, S.E., Mohamed, A.S., Windle, H.J., O'Neill, L.A., Kelleher, D.P. Tribbles 3: a novel regulator of TLR2-mediated signaling in response to Helicobacter pylori lipopolysaccharide. J Immunol 186: 2462-2471. (2011)

(11) Doyle, S.L., Campbell, M., Ozaki, E., Salomon, R.G., Mori, A., Kenna, P.F., Farrar, G.J., Kiang, A.S., Humphries, M.M., Lavelle, E.C., O'Neill, L.A., Hollyfield, J.G., Humphries, P. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nature Medicine 18(5): 791-798. (2012)