Prof Alex Loukas
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STAFF PHOTO |
BSc (Hons), PhD
Professor Building E1, QTHA, CAIRNS CAMPUS,rm 102M |
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Research and Professional Interests Teaching Conference Presentations |
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Telephone: |
(07) 4042 1608 (Australia) |
+61 7 4042 1608 (International) |
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Facsimile: |
(07) 4042 1675 (Australia) |
+61 7 4042 1675 (International) |
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Email: |
Alex.Loukas@jcu.edu.au |
Research
Hookworm vaccines
Digestion of the blood meal - Work from our group has resulted in the unravelling of the semi-ordered proteolytic cascade of haemoglobin digestion in the gut of dog hookworms. We showed that recombinant aspartic, cysteine and metalloproteases act in synergy to cleave haemoglobin, and that these enzymes are excellent targets for vaccines. In particular, vaccination of dogs with the major aspartic haemoglobinase, Na-APR-1, significantly reduces worms burdens, egg counts and most importantly, prevents blood loss and anaemia.
With colleagues at George Washington University (GWU) in Washington DC, we are involved in a vaccine development project for the Human Hookworm Vaccine Initiative (Figure 1). The project focuses on the development and clinical testing of the Na-APR-1 vaccine. Our group discovered this vaccine and we are now taking it through process development so that it can be tested in clinical trails.
Immunomodulation by helminth parasites
We are identifying the proteins secreted by hookworms that allow them to evade immune clearance. In particular, we are isolating and characterising proteins that interact with host cells and skew the immune phenotype to promote parasite survival. With colleagues in Townsville and Brisbane, we are involved in a clinical trial assessing the therapeutic value of human hookworms in suppressing the inflammation associated with celiac disease. Studies in our laboratories are exploring the mechanisms by which hookworms can down-modulate immune responses directed towards them and other bystander antigens. The ultimate aim of this research is to identify proteins secreted by hookworms that can be used as therapeutic agents to treat a range of auto-immune disorders.
Developmental biology of hookworms
With colleagues in Melbourne, we are exploring the molecular changes associated with the transition of hookworm larvae from a free-living to a parasitic state, with a major focus on the SCP/TAPS (or ASP) family of proteins. Using subtractive hybridisation and microarrays we identified genes that are up-regulated when hookworm larvae fist penetrate a mammalian host. These genes are potential (and known) targets for vaccines and drugs. One group of proteins that we are particularly interested in is the SCP/TAPS (also known as ASPs) family of secreted proteins that are extremely abundant in the hookworm secretome, and were the most abundant family of secreted proteins expressed upon host entry.We are exploring the functions of these proteins using a range of molecular and immunological techniques.
Recombinant vaccines for schistosomiasis
Using signal sequence trapping, we identified genes encoding novel transmembrane proteins that are expressed on the surface of this blood-dwelling parasite. The extracellular regions of two of these proteins provide excellent protection in a mouse model of schistosomaisis mansoni, and one antigen in particular, Sm-TSP-2, was recognized uniquely by antibodies from putatively immune people in Brazil but not by chronically infected people from the same area (Figure 2). This work is conducted as a collaboration with colleagues in Brazil and the U.S. Clinical trials with the Sm-TSP-2 vaccine in Brazil will begin within the next 12-18 months. We are also using protein microarrays consisting of schistosome tegument proteins screened with sera from resistant vs. chronically infected humans and animals to identify new vaccine antigens.
Cholangiocarcinoma caused by liver fluke
We are exploring the molecular basis of cholangiocarcinoma induction by the human liver fluke, Opisthorchis viverrini. This parasite infects millions of people throughout South-East Asia, particlularly northern Thailand, where uncooked fish is eaten. Many of those people infected eventually progress to cancer of the bile ducts (cholangiocarcinoma) and this is thought to be a direct consequence of proteins secreted by the parasites. With our Thai colleagues, we are identifying the molecules responsible for pathogenesis and establishing a tumourigenic environment.
Proteomics
In collaboration with Dr Jason Mulvenna at JCU Cairns, we have established a proteomics facility to explore the host-parasite interface at the protein level.This work involves characterising the protein composition of parasite secretomes and the changes they induce in host tissues.
Grants
NHMRC Senior Research Fellowship . C.I. A. Loukas; 01/07 – 12/11; $511,000 for 5 years.
Bill and Melinda Gates Foundation Research Grant . C.I.’s - P. Hotez, J. Bethony, D. Diemert, A. Loukas. Development and clinical testing of the Na-APR-1 Hookworm Vaccine. 08/06 –07/10
NHMRC program grant (496600) . C.I.’s – D. Kemp, M. Good, D. McManus, I. Toth, N. Anstey, K. Sriprakash, D. Doolan, C. Engwerda, A. Loukas . Immunity and pathogenesis in tropical and infectious diseases: implications for vaccines and drug development. 01/08 – 12/12
NHMRC project grant (613668) . C.I.’s – A. Loukas, J. Bethony . Apical membrane proteins as targets for a schistosomiasis vaccine. 01/10 – 12/12
NHMRC project grant in global health (613669) . C.I.’s – A. Loukas, B. Sripa, J. Mulvenna, M. Jones. Interactions between excretory/secretory proteins of the carcinogenic liver fluke and host cells. 01/10 – 12/12
ARC Linkage Project grant (LP100100092). C.I.’s – R. Gasser, A. Hofmann, A. Loukas, P. Sternberg . Elucidating structure and function of activation-associated secreted proteins (ASPs) in blood-feeding hookworms – toward new methods of control.01/10 – 12/12
ARC Discovery Project grant (DP1092444). C.I.’s - R. Gasser, P. Sternberg, A. Loukas. Elucidating a key developmental switch in Haemonchus contortus using a massively parallel picolitre reactor sequencing-coupled genomic and bioinformatic platform. 01/10 – 12/12
NIH- NIAID International Collaborations in Infectious Diseases Research (U01 AI065871-01) . C.I.s - P. Brindley, B. Sripa, A. Loukas.Pathogenesis of liver fluke induced cancer in Thailand.10/05 – 09/10
Broad Foundation . C.I.’s – J. Croese, J. McCarthy, A. Loukas . Inoculating celiac subjects with Necator americanus, a human hookworm: does contrived parasitisation of naive adults inhibit autoimmunity?01/08 – 06/10
Laboratory Members - current
Postdocs with fellowships – M. Pearson (CJ Martin fellow currently in UK), J. Mulvenna (Peter Doherty fellow), P. Giacomin (CJ Martin fellow currently in USA)
Postdocs – S. Gaze, L. St Pierre, M. Smout, A. Dougall, H. McSorley, N. Ruyssers
Research Assistants – A. Aziz
PhD students – L. Tribolet, I. Ferreira
Fellowships, Prizes, Awards
1991 – Wenkart Foundation PhD scholarship
1999 – Howard Florey postdoctoral award (NHMRC)
1999 – Univ. Qld postdoctoral fellowship offered but declined to accept Florey award
2004 – NHMRC R. Douglas Wright career development award– 5 yrs salary
2006 - Bancroft-Mackerras medal awarded by the Australian Society for Parasitology for outstanding contributions to parasitology in the past 5 years
2006 – Ralph Doherty prize awarded by QIMR for leadership/excellence in medical research
2007 – NHMRC Senior Research Fellowship
Editorial Duties
Editor-in-Chief - International Journal for Parasitology (2009-)
Editorial Board Member for Expert Review of Vaccines (2007-)
Advisory Editorial Board member - PLoS Neglected Tropical Diseases (2009-)
Deputy Editor - PLoS Neglected Tropical Diseases – (2007-2009)
Publications (selected)
Loukas A, Bethony JM, Mendez S, Fujiwara RT, Goud GN, Zhan B, Bottazzi ME, Hotez PJ (2005) Vaccination with recombinant aspartic hemoglobinase reduces parasite load and protects against anemia after challenge infection with blood-feeding hookworms in dogs.PLoS Med 2(10): e295.
Bethony J, Brooker S, Albonico M, Geiger SM, Loukas A, Diemert D, Hotez PJ (2005) The soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm infection.Lancet 367: 1521–32.
Technologies for the Control of Human Hookworm Infection.Trends Parasitol 22: 327-31
Loukas A, Bethony J, Brooker S, Hotez PJ (2006) Hookworm Vaccines – past, present and future.Lancet Infect Dis 6(11):733-41. paper featured on front cover of issue.
Williamson AL, Lustigman S, Oksov Y, Deumic V, Plieskatt J, Mendez S, Zhan B, Bottazzi ME, Hotez PJ, Loukas A (2006) Ac- MTP-1, an astacin-like metalloprotease secreted by infective hookworm larvae, is involved in tissue migration. Infect Immun 74: 961-967.
Ranjit N, Jones MK, Stenzel DJ, Gasser RB, Loukas A (2006)A survey of the intestinal transcriptomes of the hookworms, Necator americanus and Ancylostoma caninum, using tissues isolated by laser microdissection microscopy. Int J Parasitol 36: 701-10.Invited paper for thematic issue.
Tran MH, Pearson MS*, Bethony JM*, Smyth DJ, Jones MK, Duke M, Don TA, McManus DP, Correa-Oliveira R, Loukas A (2006) Tetraspanins on the surface of Schistosoma mansoni are protective vaccine antigens in mice and Sm-TSP-2 is selectively recognized by naturally resistant individuals.Nature Med 12: 835-40.Paper was featured on the front cover.
Loukas A, Tran M, Pearson MS (2007) Schistosome membrane proteins as vaccines. Int J Parasitol. 37: 257-63.
Sripa B, Kaewkes S, Sithithaworn P, Mairiang E, Laha T, Smout M, Pairojkul C, Bhudhisawasdi V, Tesana S, Thinkamrop B, Bethony JM, Loukas A, Brindley PJ (2007) Liver fluke induces cholangiocarcinoma. PLoS Med4(7):e201.
Laha T, Pinlaor P, Mulvenna J, Sripa B, Sripa M, Smout MJ, Gasser RB, Brindley PJ, Loukas A (2007) Gene discovery for the carcinogenic human liver fluke, Opisthorchis viverrini. BMC Genomics 22;8:189.
Datu B, Gasser RB, Nagaraj SH, Ong EK, O’Donoghue P, McInnes R, Ranganathan, S, Loukas A (2008) Transcriptional changes in the hookworm, Ancylostoma caninum, during the transition from a free-living to a parasitic larva. PLoS Neglect Trop Dis 2(1) e130.
Loukas A, Bethony JM (2008) New drugs for an ancient parasite. Nature Med 14: 365-7.
Ruyssers NE, De Winter BY, De Man JG, Loukas A, Herman AG, Pelckmans PA, Moreels TG (2008) Worms and the treatment of inflammatory bowel disease: are molecules the answer? Clin Dev Immunol 2008:567314.
Gasser RB, Cantacessi C, Loukas A (2008) DNA technological progress toward advanced diagnostic tools to support human hookworm control. Biotechnol Adv26: 35-45
McManus DP, Loukas A (2008) The current status of vaccines for schistosomiasis. Clin Microbiol Rev 21: 225-42
Hotez PJ, Bethony JM, Oliveira SC, Brindley PJ, Loukas A. (2008) Multivalent anthelminthic vaccine to prevent hookworm and schistosomiasis. Expert Rev Vaccines 7: 745-52.
Mulvenna J, Hamilton B, Nagaraj S, Smyth D, Loukas A, Gorman J (2009).Proteomic analysis of the excretory/secretory component of the blood-feeding stage of the hookworm, Ancylostoma caninum. Mol Cell Proteomics8: 109-21
Ruyssers NE, De Winter BY, De Man JG, Loukas A, Pearson MS, Weinstock JV, Van den Bossche RM, Martinet W, Pelckmans PA, Moreels TG (2009) Therapeutic potential of helminth soluble proteins in TNBS-induced colitis in mice. Inflamm Bowel Dis. 15: 491-500.
Ranjit N, Zhan B, Hamilton B, Stenzel DJ, Lowther J, Pearson MS, Gorman J, Hotez PJ, Loukas A (2009) Proteolytic degradation of hemoglobin in the intestine of the human hookworm, Necator americanus. J Infect Dis 199: 904-12
Pearson MS, Bethony JM, Pickering DA, de Oliveira LM, Jariwala A, Santiago H, Miles AP, Zhan B, Jiang D, Ranjit N, Mulvenna J, Tribolet L, Plieskatt J, Smith T, Bottazzi ME, Jones K, Keegan B, Hotez PJ, Loukas A (2009) An enzymatically inactivated hemoglobinase from Necator americanus induces neutralizing antibodies against multiple hookworm species and protects dogs against heterologous hookworm infection. FASEB J 23: 3007-19.
Sripa B, Mairiang E, Thinkhamrop B, Laha T, Kaewkes S, Sithithaworn P, Tessana S, Loukas A, Brindley PJ, Bethony JM (2009) Parasite specific IL-6 increases the risk of advanced periductal fibrosis in infection with the carcinogenic human liver fluke, Opisthorchis viverrini. Hepatology 50:1273-81.
Smout MJ, Laha T, Mulvenna J, Sripa B, Suttiprapa S, Brindley PJ, Loukas A (2009) A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells. PLoS Path 5(10):e1000611.
Gobert GN, Tran MH, Moertel L, Mulvenna J, Jones MK, McManus DP, Loukas A. (2010) Transcriptional changes in Schistosoma mansoni during early schistosomula development and in the presence of erythrocytes.PLoS Neglect Trop Dis 4(2): e600.
Mulvenna J, Sripa B, Brindley PJ, Gorman J, Jones MK, Colgrave ML, Jones A, Nawaratna S, Laha T, Suttiprapa S, Smout MJ, Loukas A. (2010) The secreted and surface proteomes of the adult stage of the carcinogenic human liver fluke Opisthorchis viverrini. Proteomics 10: 1063-78.
Pearson MS, Pickering DA, Tribolet L, Cooper L, Mulvenna J, Oliveira LM, BethonyJM, Hotez PJ, Loukas A (2010)Neutralizing antibodies to the hookworm hemoglobinase, Na-APR-1: implications for a multivalent vaccine against hookworm infection and schistosomiasis. J Infect Dis in press [Dec 15, 2009].
Tran MH, Freitas TC, Cooper L, Gaze S, Gatton ML, Jones MK, Lovas E, Pearce EJ, Loukas A. (2010) Suppression of mRNAs encoding tegument tetraspanins from Schistosoma mansoni results in impaired tegument turnover.PLoS Path in press [Feb 17, 2010].