'Preconditioning' with Low Dose Lipopolysaccharide Aggravates the Organ Injury/Dysfunction Caused by Hemorrhagic Shock in Rats

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedRS is supported by the Program Science without Borders, CAPES Foundation, Ministry of Education of Brazil, Brasilia/DF, Brazil; NSAP is, in part, supported by the Bart’s and The London Charity (753/1722). The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no 608765, from the William Harvey Research Foundation and University of Turin (Ricerca Locale ex-60%). This work contributes to the Organ Protection research theme of the Barts Centre for Trauma Sciences, supported by the Barts and The London Charity (Award 753/1722

The Synthetic Plasmodium falciparum Circumsporozoite Peptide PfCS102 as a Malaria Vaccine Candidate: A Randomized Controlled Phase I Trial

BACKGROUND: Fully efficient vaccines against malaria pre-erythrocytic stage are still lacking. The objective of this dose/adjuvant-finding study was to evaluate the safety, reactogenicity and immunogenicity of a vaccine candidate based on a peptide spanning the C-terminal region of Plasmodium falciparum circumsporozoite protein (PfCS102) in malaria naive adults. METHODOLOGY AND PRINCIPAL FINDINGS: Thirty-six healthy malaria-naive adults were randomly distributed into three dose blocks (10, 30 and 100 microg) and vaccinated with PfCS102 in combination with either Montanide ISA 720 or GSK proprietary Adjuvant System AS02A at days 0, 60, and 180. Primary end-point (safety and reactogenicity) was based on the frequency of adverse events (AE) and of abnormal biological safety tests; secondary-end point (immunogenicity) on P. falciparum specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well tolerated and their safety profile was good. Most AEs were local and, when systemic, involved mainly fatigue and headache. Half the volunteers in AS02A groups experienced severe AEs (mainly erythema). After the third injection, 34 of 35 volunteers developed anti-PfCS102 and anti-sporozoite antibodies, and 28 of 35 demonstrated T-cell proliferative responses and IFN-gamma production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-gamma secreting CD8(+) T cell responses. Responses were only marginally boosted after the 3(rd) vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 microg was less immunogenic in comparison to 30 and 100 microg that induced similar responses. AS02A formulations with 30 microg or 100 microg PfCS102 induced about 10-folds higher antibody and IFN-gamma responses than Montanide formulations. CONCLUSIONS/SIGNIFICANCE: PfCS102 peptide was safe and highly immunogenic, allowing the design of more advanced trials to test its potential for protection. Two or three immunizations with a dose of 30 microg formulated with AS02A appeared the most appropriate choice for such studies. TRIAL REGISTRATION: Swissmedic.ch 2002 DR 1227

A Major Role for the Plasmodium falciparum ApiAP2 Protein PfSIP2 in Chromosome End Biology

The heterochromatic environment and physical clustering of chromosome ends at the nuclear periphery provide a functional and structural framework for antigenic variation and evolution of subtelomeric virulence gene families in the malaria parasite Plasmodium falciparum. While recent studies assigned important roles for reversible histone modifications, silent information regulator 2 and heterochromatin protein 1 (PfHP1) in epigenetic control of variegated expression, factors involved in the recruitment and organization of subtelomeric heterochromatin remain unknown. Here, we describe the purification and characterization of PfSIP2, a member of the ApiAP2 family of putative transcription factors, as the unknown nuclear factor interacting specifically with cis-acting SPE2 motif arrays in subtelomeric domains. Interestingly, SPE2 is not bound by the full-length protein but rather by a 60kDa N-terminal domain, PfSIP2-N, which is released during schizogony. Our experimental re-definition of the SPE2/PfSIP2-N interaction highlights the strict requirement of both adjacent AP2 domains and a conserved bipartite SPE2 consensus motif for high-affinity binding. Genome-wide in silico mapping identified 777 putative binding sites, 94% of which cluster in heterochromatic domains upstream of subtelomeric var genes and in telomere-associated repeat elements. Immunofluorescence and chromatin immunoprecipitation (ChIP) assays revealed co-localization of PfSIP2-N with PfHP1 at chromosome ends. Genome-wide ChIP demonstrated the exclusive binding of PfSIP2-N to subtelomeric SPE2 landmarks in vivo but not to single chromosome-internal sites. Consistent with this specialized distribution pattern, PfSIP2-N over-expression has no effect on global gene transcription. Hence, contrary to the previously proposed role for this factor in gene activation, our results provide strong evidence for the first time for the involvement of an ApiAP2 factor in heterochromatin formation and genome integrity. These findings are highly relevant for our understanding of chromosome end biology and variegated expression in P. falciparum and other eukaryotes, and for the future analysis of the role of ApiAP2-DNA interactions in parasite biology

Evaluation of the effectiveness of topical repellent distributed by village health volunteer networks against Plasmodium spp. infection in Myanmar: A stepped-wedge cluster randomised trial

BACKGROUND: The World Health Organization has yet to endorse deployment of topical repellents for malaria prevention as part of public health campaigns. We aimed to quantify the effectiveness of repellent distributed by the village health volunteer (VHV) network in the Greater Mekong Subregion (GMS) in reducing malaria in order to advance regional malaria elimination. METHODS AND FINDINGS: Between April 2015 and June 2016, a 15-month stepped-wedge cluster randomised trial was conducted in 116 villages in Myanmar (stepped monthly in blocks) to test the effectiveness of 12% N,N-diethylbenzamide w/w cream distributed by VHVs, on Plasmodium spp. infection. The median age of participants was 18 years, approximately half were female, and the majority were either village residents (46%) or forest dwellers (40%). No adverse events were reported during the study. Generalised linear mixed modelling estimated the effect of repellent on infection detected by rapid diagnostic test (RDT) (primary outcome) and polymerase chain reaction (PCR) (secondary outcome). Overall Plasmodium infection detected by RDT was low (0.16%; 50/32,194), but infection detected by PCR was higher (3%; 419/13,157). There was no significant protection against RDT-detectable infection (adjusted odds ratio [AOR] = 0.25, 95% CI 0.004-15.2, p = 0.512). In Plasmodium-species-specific analyses, repellent protected against PCR-detectable P. falciparum (adjusted relative risk ratio [ARRR] = 0.67, 95% CI 0.47-0.95, p = 0.026), but not P. vivax infection (ARRR = 1.41, 95% CI 0.80-2.47, p = 0.233). Repellent effects were similar when delayed effects were modelled, across risk groups, and regardless of village-level and temporal heterogeneity in malaria prevalence. The incremental cost-effectiveness ratio was US$256 per PCR-detectable infection averted. Study limitations were a lower than expected Plasmodium spp. infection rate and potential geographic dilution of the intervention. CONCLUSIONS: In this study, we observed apparent protection against new infections associated with the large-scale distribution of repellent by VHVs. Incorporation of repellent into national strategies, particularly in areas where bed nets are less effective, may contribute to the interruption of malaria transmission. Further studies are warranted across different transmission settings and populations, from the GMS and beyond, to inform WHO public health policy on the deployment of topical repellents for malaria prevention. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12616001434482)