Macrophage-infectivity potentiator of Trypanosoma cruzi (TcMIP) is a new pro-type 1 immuno-stimulating protein for neonatal human cells and vaccines in mice.

peer reviewedThis work identifies the protein "macrophage infectivity potentiator" of Trypanosoma cruzi trypomastigotes, as supporting a new property, namely a pro-type 1 immunostimulatory activity on neonatal cells. In its recombinant form (rTcMIP), this protein triggers the secretion of the chemokines CCL2 and CCL3 by human umbilical cord blood cells from healthy newborns, after 24h in vitro culture. Further stimulation for 72h results in secretion of IFN-γ, provided cultures are supplemented with IL-2 and IL-18. rTcMIP activity is totally abolished by protease treatment and is not associated with its peptidyl-prolyl cis-trans isomerase enzymatic activity. The ability of rTcMIP to act as adjuvant was studied in vivo in neonatal mouse immunization models, using acellular diphtheria-tetanus-pertussis-vaccine (DTPa) or ovalbumin, and compared to the classical alum adjuvant. As compared to the latter, rTcMIP increases the IgG antibody response towards several antigens meanwhile skewing antibody production towards the Th-1 dependent IgG2a isotype. The amplitude of the rTcMIP adjuvant effect varied depending on the antigen and the co-presence of alum. rTcMIP did by contrast not increase the IgE response to OVA combined with alum. The discovery of the rTcMIP immunostimulatory effect on neonatal cells opens new possibilities for potential use as pro-type 1 adjuvant for neonatal vaccines. This, in turn, may facilitate the development of more efficient vaccines that can be given at birth, reducing infection associated morbidity and mortality which are the highest in the first weeks after birth

Malaria cérébrale expérimentale (de la microvésiculation aux gènes de sensibilité)

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Fertility, gestation outcome and parasite congenital transmissibility in mice infected with TcI, TcII and TcVI genotypes of Trypanosoma cruzi.

This work aims to compare the effects of acute or chronic infections with the T. cruzi genotypes TcI (X10 strain), TcII (Y strain) and TcVI (Tulahuen strain) on fertility, gestation, pup growth and the possible vertical transmission of parasites in BALB/c mice. The occurrence of congenital infection was evaluated by microscopic examination of blood and/or qPCR on blood and heart in newborn pups and/or older offspring submitted to cyclophosphamide-induced immunosuppression in order to detect possible cryptic congenital infection. Altogether, the results show that: i) for the three strains tested, acute infection occurring after the embryo implantation in the uterus (parasite inoculation 4 days before mating), or close to delivery (parasite inoculation on day 13 of gestation), prevents or severely jeopardizes gestation outcome (inducing pup mortality and intra-uterine growth retardation); ii) for the three strains tested, gestation during chronic infection results in intra-uterine growth retardation, whereas re-inoculation of TcVI parasites during gestation in such chronically infected mice, in addition, strongly increases pup mortality; iii) congenital infection remains a rare consequence of infection (occurring in approximately 4% of living pups born to acutely infected dams); iv) PCR, detecting parasitic DNA and not living parasites, is not convenient to detect congenial infection close to delivery; v) transmission of parasites by breast milk is unlikely. This study should encourage further investigations using other parasite strains and genotypes to explore the role of virulence and other factors, as well as the mechanisms of such effects on gestation and on the establishment of congenital infection.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Cerebral malaria: A neurovascular pathology with many riddles still to be solved

Cerebral malaria (CM), one of the most common fatal complications of the heterogenous syndrome named severe malaria, is indubitably a post-infectious neurovascular pathology, as evidenced by histopathological analyses. This neurological syndrome is characterised not only by the cytoadherence of Plasmodium falciparum-infected erythrocytes, but also by morphological and functional alterations of brain microvascular endothelial cells subsequent to their interactions with circulating cells, such as platelets, monocytes, lymphocytes, and dendritic cells. During CM, host cells, in particular immune cells, are found recruited and activated at the site of sequestration, where they release various soluble molecules. Among these, cytokines play a major role in CM pathogenesis. Indeed, cerebral complications appear to be due to an imbalance between pro-inflammatory and anti-inflammatory mediators. Cytokines (notably interferon-gamma, tumour necrosis factor, lymphotoxin) and chemokine receptors (notably CCR5) are also responsible for blood-brain barrier alterations and biochemical changes leading to the brain parenchymal lesions that can be observed in CM. In return, glial cells can influence blood-borne elements, and thereby worsen the pathology. Numerous problems remain to be solved, especially the sequence of pathological events, namely the order in which the circulating cells sequester on the endothelial wall. A better understanding of the molecular mechanisms involved in CM pathogenesis is needed if we are capable of preventing cerebral complications and improving the quality of patient management.info:eu-repo/semantics/publishe

Pathogenèse du neuropaludisme: Faits et hypothèses

Cerebral malaria (CM) is one of the most serious complications of Plasmodium falciparum infection. It is characterized by sequestration of parasitized red blood cells (PRBC) in cerebral capillaries and venules. Although the exact cause of CM remains unclear, current evidence has clearly implicated metabolic disturbances and host immune responses. Studies on mouse CM models suggest the involvement of host cells and in particular platelets. These results led us to study the role of platelets in human CM. Our findings demonstrated that significantly greater accumulation of platelets occurred in capillaries and venules of Malawian patients who died from CM than from other diseases. We also assessed the role of platelets in cytoadherence of PRBCs using PRBC adhering only on CD36, platelets and endothelial cells (EC) constitutively devoid of CD36. Cultures using the three components showed that platelets played a role in inducing cytoadherence of PRBC on EC via a cellular bridging resistant to physiological flow conditions. Having established the link between platelets and sequestration, the next step will be to examine the link between platelets and CM. A combination of approaches from different disciplines will be needed to gain further insight into the mechanisms underlying the complications of malaria.info:eu-repo/semantics/publishe

Mouse groups and AmBisome treatment schedules.

a<p>Mice were either non treated (NT) or treated (T) with AmBisome during the acute (A) and/or chronic (C) phases of infection by intraperitoneal injections (<i>i.p.</i>) on alternate days. Some mice of indicated groups received cyclophosphamide administred on alternate days from dpi 60. Data in brackets indicate the first and the last post-inoculation day (dpi) of treatment.</p

Parasitemias in dams acutely or chronically infected with TcI, TcII or TcVI.

<p>ING = infected and non-gravid mice; see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002271#pntd-0002271-g001" target="_blank">Figure 1</a> for nomenclature of IAM, CI and CI² groups; parasitemias were recorded at delivery for IAM (dpi 7–9), CI (dpi 94–96), CI² dams (dpi 9–11 of reinfection) and at dpi 7 for ING mice; parasitemias in TcI acute-infection and TcII and TcVI chronic infections were recorded by qPCR, whereas those of acute TcII and TcVI infections were determined by blood microscopic investigation. * = P<0.05 by comparison to the ING group.</p

Gene-expression profiling discriminates between cerebral malaria (CM)-susceptible mice and CM-resistant mice.: Gene expression profiles in mouse malaria

International audienceThe development of cerebral malaria (CM) in mice with Plasmodium berghei ANKA infection is under genetic control. Brain gene-expression patterns were investigated in well-defined genetically CM-resistant (CM-R; BALB/c and DBA/2) and CM-susceptible (CM-S; C57BL/6 and CBA/J) mice by use of cDNA microarrays. By combining transcriptional profiling with rigorous statistical methods and cluster analysis, we identified a set of 69 genes that perfectly discriminated between mouse strains and between CM-R and CM-S mice. The analysis of gene ontological terms revealed that the genes that clustered and were related to susceptibility to CM preferentially belonged to some biological process classes, such as those pertaining to immune responses. Using a false discovery rate of 5% and the Welch t test, we identified 31 genes with consistent differential expression between CM-R and CM-S mice. These data indicate that microarray analysis may be useful for identification of candidate genes that are potentially responsible for resistance or susceptibility to mouse CM and suggest that candidate genes identified in mice could be specifically tested in humans for an association with disease severity