A. La Flamme

Peloruside A enhances apoptosis in H-ras-transformed cells and is cytotoxic to proliferating T cells.

Peloruside A (peloruside), a compound isolated from the marine sponge Mycale hentscheli, inhibits growth of human (HL-60) and mouse (32D-ras) myeloid leukemic cells, as well as non-transformed 32D cells. Using the MTT cell proliferation assay and trypan blue dye exclusion tests, little difference was seen in growth inhibition between 32D and 32D-ras cells; however, peloruside was more cytotoxic to the oncogene-transformed cells. Peloruside also blocked 32D-ras cells more readily in G2/M of the cell cycle, leading to apoptosis. Annexin-V/propidium iodide staining of 32D and 32D-ras cells showed that 1.6 μM peloruside induced significant cell death by 36 hours in 32D cells (16% survival), but to comparable levels as early as 14 hours in 32D-ras cells (11% survival). There was no evidence for activation of either of the initiator caspases-8 or -9 by 0.1 μM peloruside following 12 hours of exposure. Peloruside inhibited T cell proliferation and IL-2 and IFN γ production in both the mixed lymphocyte reaction and following CD3 cross-linking, and this effect was shown to be a non-specific cytotoxic effect. It is concluded that peloruside preferentially targets oncogene-transformed cells over non-transformed cells by inducing transformed cells to undergo apoptosis.

Chronic exposure to schistosome eggs reduces serum cholesterol but has no effect on atherosclerotic lesion development

Previous studies have shown that people infected with schistosomiasis have lower levels of serum cholesterol than uninfected controls. To better understand the impact of this parasitic infection on serum cholesterol levels and on atherosclerotic lesion development induced by hypercholesterolemia, apolipoprotein E (ApoE)‐deficient mice were chronically exposed to the eggs of Schistosoma mansoni over a period of 16 weeks. Total serum cholesterol and low‐density lipoprotein (LDL) were reduced in egg‐exposed ApoE‐deficient mice fed a diet high in cholesterol compared to unexposed controls. However, exposure to eggs had no effect on atherosclerotic lesion size or progression in ApoE‐deficient mice. Macrophages isolated from egg‐exposed mice had an enhanced ability to take up LDL but not acetylated LDL (acLDL). This study suggests that schistosome eggs alone may alter serum lipid profiles through enhancing LDL uptake by macrophages, but these changes do not ultimately affect atherosclerotic lesion development.

Prevalence and significance of CYP2C19*2 and CYP2C19*17 alleles in a New Zealand acute coronary syndrome population.

BACKGROUND High on-treatment platelet reactivity has been associated with poor outcomes following acute coronary syndromes (ACS). Both the loss of function CYP2C19*2 allele and the gain of function CYP2C19*17 allele along with a range of clinical characteristics have been associated with variation in the response to clopidogrel. AIM The study aims to examine the frequency of CYP2C19 variants and understand the factors associated with on-treatment platelet reactivity in a New Zealand ACS population. METHODS We prospectively enrolled 312 ACS patients. We collected clinical characteristics and measured on-treatment platelet reactivity using two validated point-of-care assays, VerifyNow and Multiplate. DNA was extracted and CYP2C19*2 and *17 alleles were identified using real-time polymerase chain reaction. RESULTS CYP2C19*2 or CYP2C19*17 alleles were observed in 101 (32%) and 106 (34%) of patients, respectively, with significant differences in distribution by ethnicity. In Maori and Pacific Island patients, 47% (confidence interval (CI) 31-63%) had CYP2C19*2 and 11% (CI 4-19%) CYP2C19*17 compared with 26% (CI 19-32%) and 41% (CI 32-49%) in white people. Carriage of CYP2C19*2 alleles was associated with higher levels of platelet reactivity measured by either assay, but we observed no relationship between platelet reactivity and CYP2C19*17. In multivariate analysis diabetes, clopidogrel dose and CYP2C19*2 status were all significant independent predictors of platelet reactivity. CONCLUSIONS Both CYP2C19*2 and *17 were common in a New Zealand ACS population, with CYP2C19*2 observed in almost half the Maori and Pacific Island patients. CYP2C19*2, diabetes and clopidogrel dose were independent contributors to on-treatment platelet reactivity.

The ontogeny of New Zealand groper (Polyprion oxygeneios) lymphoid organs and IgM.

This study investigates the ontogeny of New Zealand groper (Polyprion oxygeneios) immune system, a new species for aquaculture in the Southern Pacific Ocean. In the eggs, both lysozyme and IgM were detected. Egg IgM was found at 1.07-1.56 μg/g wet weight and consisted of monomers compared to the polymerized IgM found in adult serum. In larvae, the head-kidney (HK) was first observed at 6 dph, followed by the spleen at 16 dph, and thymus at 20 dph, and within these organs IgM(+) cells were first detected in the HK (12 dph), then the spleen (32 dph) and finally in the thymus and the gastrointestinal tract (45 dph). Low levels of Igμ heavy chain transcripts were detected at 2 and 3 dph and they increased at 9 dph. Igμ expression further increased from day 45 onwards. In juveniles (115 dph), the HK and blood showed similar percentages of IgM(+) cells as the adult groper. These results highlight the important maturation steps that occur during the development of the immune system in the marine teleost P. oxygeneios.

The platinum age of parasitology: harnessing the power of the parasite

The 19th century has been termed the ‘Golden Age of Parasitology’ as during this period the life cycles of many parasites were identified, public health strategies were proposed to prevent transmission, and therapeutic strategies initiated to provide a cure for those infected (1). However, if the 19th century was the Golden Age, surely we should declare that in the last decade, we have entered into a Platinum Age of Parasitology where we appreciate not only how parasitic infection negatively impacts humans, but also how humans and parasites have co-evolved, in many cases, to minimize the pathological impact of infection on the host (2). From this co-evolution or ‘parasitic compromise’, we have begun to uncover potential benefits from hosting a parasite (2). The clearest examples of the benefits identified so far come from helminth infections, which have been shown to reduce the incidence or severity of specific autoimmune (e.g. multiple sclerosis, type 1 diabetes) or chronic inflammatory disorders (e.g. Crohn’s disease, ulcerative colitis) (3–5). Thus, we have started to identify the pathways by which helminths provide this protective immunomodulation with the ultimate goal of using this information to develop new therapeutic agents or products to treat immune-mediated disorders. Can it be denied that we are now in the Platinum Age of Parasitology – harnessing helminths for our own health? This issue of Parasite Immunology is devoted to this exciting idea – how helminths modulate the immune system to reduce the incidence or severity of chronic immune-mediated diseases. It is fitting then that the first report of helminth infection directly preventing autoimmune disease was published in Parasite Immunology in 1999 (4). In this study, Cooke et al. demonstrated that infection with the trematode, Schistosoma mansoni, or injection of S. mansoni eggs alone reduced the incidence of diabetes in NOD mice, which spontaneously develop type 1 diabetes. Reports of helminth infections or helminth products preventing or reducing other immune-mediated diseases such as inflammatory bowel disease (5), multiple sclerosis (3, 6, 7) and even allergy (8) in animal models quickly followed. Given the overwhelming evidence from animal models, the question is no longer if helminth infections reduce immune-mediated disease pathology but how best to use helminth-mediated immunomodulation to treat patients. Thus, this edition of Parasite Immunology begins by focusing on recent progress in the use of live helminths in humans. Fleming and Weinstock (9) summarize the results of recent clinical trials and discuss the lessons learned from these trials including clinical trial design, the choice of helminth, the possibility of epigenetic imprinting and the reversibility of disease pathology in patients. In addition to the use of live helminth infections for the treatment of immune-mediated diseases, concurrent studies have shown that purified helminth products are immunoregulatory and have therapeutic potential. In this issue, Shepherd et al. (10) take a drug discovery approach to identify and develop the immunomodulatory components of helminths for use in treating immune-mediated diseases. This review not only details the wide range of helminth products that have been identified and their immunoregulatory properties, but also highlights the pleiotropic nature of these immunomodulatory components and the difficulties in developing these products as therapeutics. Additionally, the potential of nonprotein components and especially small organic molecules is explored with a look towards future development of their therapeutic promise. Correspondence: Anne C. La Flamme, School of Biological Sciences, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New Zealand (e-mail: anne.laflamme@vuw.ac.nz). Received: 13 April 2015 Accepted for publication: 13 April 2015