Helminth Biology

Staff
Funding
Collaborators
Student Projects
Key Publications
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Lab Head: Dr Alex Loukas

CURRENT RESEARCH

Hookworm developmental biology, immunology and vaccinology

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.

Vaccines - 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 - With colleagues at GWU, 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. tudies in our laboratories are exploring the mechanisms by which hookworms can downmodulate 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 - 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. This project utilises subtractive hybridisation and microarrays to identify genes that are upregulated 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.

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.

Cholangiocarcinoma caused by liver fluke
We have funding to explore 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 the pathology and concurrently exploring the transcriptome and proteome of the parasite.

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Staff

Funding

Bill and Melinda Gates Foundation
Sabin Vaccine Institute
NHMRC
NIH (R01 and ICIDR) 
ARC
Broad Foundation

Collaborators (outside of QIMR)

• Dr Jeff Bethony (George Washington Univ, USA and Instituto Fiocruz, Brazil)
• Professor Peter Hotez & the Human Hookworm Vaccine Initiative (George Washington Univ, USA)
• Professor Paul Brindley (Tulane University, USA)
• Professor Robin Gasser (The University of Melbourne)
• Dr Andreas Hofmann (Griffith University)
• Dr Stephanie Constant (George Washinton Univ, USA)
• Drs Thewarach Laha and Banchob Sripa (Khon Kaen University, Thailand)
• Professor Istvan Toth (The University of Queensland)
• Professor Nick Anstey (Menzies School of Health Research)
• Prof John Dalton (University of Technology, Sydney)
• Dr John Croese (Townsville General Hospital)
• Prof Edward Pearce (University of Pennsylvania, USA)

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Key Publications

Recent Selected Research Articles
Datu BJ, 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 Negl Trop Dis 9;2(1):e130. 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.

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.

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.

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.

Bethony JM, Loukas A, Smout MJ, Bottazzi ME, Lustigman S, Goud GN, Mendez S, Hotez PJ (2005). Anti-ASP-2 antibodies reduce the intensity of hookworm infection in humans and laboratory animals. FASEB J 19: 1743-5.

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.

Recent Selected Reviews
McManus DP, Loukas A. (2008) Current status of vaccines for schistosomiasis. Clin Microbiol Rev 2008 21: 225-42.

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 Med 4(7):e201.

Loukas A, Tran M, Pearson MS (2007) Schistosome membrane proteins as vaccines. Int J Parasitol 37(3-4):257-63.

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.

Loukas A, Bethony J, Brooker S, Hotez PJ (2006) Hookworm Vaccines - past, present and future. Lancet Infect Dis 6(11):733-41.

Hotez PJ, Brooker, S, Bethony, JM, Bottazzi ME, Loukas A, Xiao S (2004) Current concepts: Hookworm infection. New Eng J Med 351:799-80.

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