Reduced T Regulatory Cell Response during Acute Plasmodium falciparum Infection in Malian Children Co-Infected with Schistosoma haematobium

Regulatory T cells (Tregs) suppress host immune responses and participate in immune homeostasis. In co-infection, secondary parasite infections may disrupt the immunologic responses induced by a pre-existing parasitic infection. We previously demonstrated that schistosomiasis-positive (SP) Malian children, aged 4-8 years, are protected against the acquisition of malaria compared to matched schistosomiasis-negative (SN) children.To determine if Tregs contribute to this protection, we performed immunologic and Treg depletion in vitro studies using PBMC acquired from children with and without S. haematobium infection followed longitudinally for the acquisition of malaria. Levels of Tregs were lower in children with dual infections compared to children with malaria alone (0.49 versus 1.37%, respectively, P = 0.004) but were similar months later, during a period with negligible malaria transmission. The increased levels of Tregs in SN subjects were associated with suppressed serum Th1 cytokine levels, as well as elevated parasitemia compared to co-infected counterparts.These results suggest that lower levels of Tregs in helminth-infected children correlate with altered circulating cytokine and parasitologic results which may play a partial role in mediating protection against falciparum malaria

The expanding dusty bipolar nebula around the nova V1280 Sco

V1280 Sco is one of the slowest dust-forming nova ever historically observed. We performed multi-epoch high-spatial resolution observations of the circumstellar dusty environment of V1280 Sco to investigate the level of asymmetry of the ejecta We observed V1280 Sco in 2009, 2010 and 2011 using unprecedented high angular resolution techniques. We used the NACO/VLT adaptive optics system in the J, H and K bands, together with contemporaneous VISIR/VLT mid-IR imaging that resolved the dust envelope of V1280 Sco, and SINFONI/VLT observations secured in 2011. We report the discovery of a dusty hourglass-shaped bipolar nebula. The apparent size of the nebula increased from 0.30" x 0.17" in July 2009 to 0.64" x 0.42" in July 2011. The aspect ratio suggests that the source is seen at high inclination. The central source shines efficiently in the K band and represents more than 56+/-5% of the total flux in 2009, and 87+/-6% in 2011. A mean expansion rate of 0.39+/-0.03 mas per day is inferred from the VISIR observations in the direction of the major axis, which represents a projected upper limit. Assuming that the dust shell expands in that direction as fast as the low-excitation slow ejecta detected in spectroscopy, this yields a lower limit distance to V1280 Sco of 1kpc; however, the systematic errors remain large due to the complex shape and velocity field of the dusty ejecta. The dust seems to reside essentially in the polar caps and no infrared flux is detected in the equatorial regions in the latest dataset. This may imply that the mass-loss was dominantly polar

Antigen-Specific B Memory Cell Responses to Plasmodium falciparum Malaria Antigens and Schistosoma haematobium Antigens in Co-Infected Malian Children

Polyparasitism is common in the developing world. We have previously demonstrated that schistosomiasis-positive (SP) Malian children have age-dependent protection from malaria compared to matched schistosomiasis-negative (SN) children. Evidence of durable immunologic memory to malaria antigens is conflicting, particularly in young children and the effect of concomitant schistomiasis upon acquisition of memory is unknown. We examined antigen-specific B memory cell (MBC) frequencies (expressed as percentage of total number of IgG-secreting cells) in 84 Malian children aged 4–14 to malaria blood-stage antigens, apical membrane antigen 1 (AMA-1) and merozoite surface protein 1 (MSP-1) and to schistosomal antigens, Soluble Worm Antigenic Preparation (SWAP) and Schistosoma Egg Antigen (SEA), at a time point during the malaria transmission season and a follow-up dry season visit. We demonstrate, for the first time, MBC responses to S. haematobium antigens in Malian children with urinary egg excretion and provide evidence of seasonal acquisition of immunologic memory, age-associated differences in MBC acquisition, and correlation with circulating S. haematobium antibody. Moreover, the presence of a parasitic co-infection resulted in older children, aged 9–14 years, with underlying S. haematobium infection having significantly more MBC response to malaria antigens (AMA1 and MSP1) than their age-matched SN counterparts. We conclude that detectable MBC response can be measured against both malaria and schistosomal antigens and that the presence of S. haematobium may be associated with enhanced MBC induction in an age-specific manner

Safety and Allele-Specific Immunogenicity of a Malaria Vaccine in Malian Adults: Results of a Phase I Randomized Trial

OBJECTIVES: The objectives were to evaluate the safety, reactogenicity, and allele-specific immunogenicity of the blood-stage malaria vaccine FMP1/AS02A in adults exposed to seasonal malaria and the impact of natural infection on vaccine-induced antibody levels. DESIGN: We conducted a randomized, double-blind, controlled phase I clinical trial. SETTING: Bandiagara, Mali, West Africa, is a rural town with intense seasonal transmission of Plasmodium falciparum malaria. PARTICIPANTS: Forty healthy, malaria-experienced Malian adults aged 18–55 y were enrolled. INTERVENTIONS: The FMP1/AS02A malaria vaccine is a 42-kDa recombinant protein based on the carboxy-terminal end of merozoite surface protein-1 (MSP-1(42)) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The control vaccine was a killed rabies virus vaccine (Imovax). Participants were randomized to receive either FMP1/AS02A or rabies vaccine at 0, 1, and 2 mo and were followed for 1 y. OUTCOME MEASURES: Solicited and unsolicited adverse events and allele-specific antibody responses to recombinant MSP-1(42) and its subunits derived from P. falciparum strains homologous and heterologous to the 3D7 vaccine strain were measured. RESULTS: Transient local pain and swelling were more common in the malaria vaccine group than in the control group (11/20 versus 3/20 and 10/20 versus 6/20, respectively). MSP-1(42) antibody levels rose during the malaria transmission season in the control group, but were significantly higher in malaria vaccine recipients after the second immunization and remained higher after the third immunization relative both to baseline and to the control group. Immunization with the malaria vaccine was followed by significant increases in antibodies recognizing three diverse MSP-1(42) alleles and their subunits. CONCLUSIONS: FMP1/AS02A was well tolerated and highly immunogenic in adults exposed to intense seasonal malaria transmission and elicited immune responses to genetically diverse parasite clones. Anti-MSP-1(42) antibody levels followed a seasonal pattern that was significantly augmented and prolonged by the malaria vaccine

High levels of Plasmodium falciparum rosetting in all clinical forms of severe malaria in African children

Plasmodium falciparum rosetting (the spontaneous binding of infected erythrocytes to uninfected erythrocytes) is a well-recognized parasite virulence factor. However, it is currently unclear whether rosetting is associated with all clinical forms of severe malaria, or only with specific syndromes such as cerebral malaria. We investigated the relationship between rosetting and clinical malaria in 209 Malian children enrolled in a case-control study of severe malaria. Rosetting was significantly higher in parasite isolates from severe malaria cases compared with non-severe hyperparasitemia and uncomplicated malaria controls (F(2,117) = 8.15, P < 0.001). Analysis of sub-categories of severe malaria (unrousable coma, severe anemia, non-comatose neurological impairment, repeated seizures or a small heterogeneous group with signs of renal failure or jaundice) showed high levels of rosetting in all sub-categories, and no statistically significant differences in rosetting between sub-categories (F(4,67) = 1.28, P = 0.28). Thus rosetting may contribute to the pathogenesis of all severe malaria syndromes in African children, and interventions to disrupt rosetting could be potential adjunctive therapies for all forms of severe malaria in Africa

The Early Spectrophotometric Evolution of V1186 Scorpii (Nova Scorpii 2004 #1)

We report optical photometry and optical through mid-infrared spectroscopy of the classical nova V1186 Sco. This slowly developing nova had an complex light curve with multiple secondary peaks similar to those seen in PW Vul. The time to decline 2 magnitudes, t$_2$, was 20 days but the erratic nature of the light curve makes determination of intrinsic properties based on the decline time (e.g., luminosity) problematic, and the often cited MMRD relationship of Della Valle and Livio (1995) fails to yield a plausible distance. Spectra covering 0.35 to 35 $\mu$m were obtained in two separate epochs during the first year of outburst. The first set of spectra, taken about 2 months after visible maximum, are typical of a CO-type nova with narrow line emission from \ion{H}{1}, \ion{Fe}{2}, \ion{O}{1} and \ion{He}{1}. Later data, obtained between 260 and 380 days after maximum, reveal an emerging nebular spectrum. \textit{Spitzer} spectra show weakening hydrogen recombination emission with the emergence of [\ion{Ne}{2}] (12.81 $\mu$m) as the strongest line. Strong emission from [\ion{Ne}{3}] (15.56 $\mu$m) is also detected. Photoionization models with low effective temperature sources and only marginal neon enhancement (Ne $\sim$ 1.3 Ne$_{\odot}$) are consistent with these IR fine-structure neon lines indicating that V1186 Sco did not occur on a ONeMg white dwarf. In contrast, the slow and erratic light curve evolution, spectral development, and photoionization analysis of the ejecta imply the outburst occurred on a low mass CO white dwarf. We note that this is the first time strong [\ion{Ne}{2}] lines have been detected so early in the outburst of a CO nova and suggests that the presence of mid-infrared neon lines is not directly indicative of a ONeMg nova event.Comment: 7 figures, 37 pages. Astronimocal Journal accepte

Platelet-mediated clumping of Plasmodium falciparum infected erythrocytes is associated with high parasitemia but not severe clinical manifestations of malaria in African children

Platelet-mediated clumping of Plasmodium falciparum infected erythrocytes is an adhesive phenotype commonly found in field isolates that has previously been associated with severe malaria. Here, clumping was assessed in 131 isolates from Malian children. The clumping phenotype was seen in 6% (n=51) of uncomplicated malaria, 24% (n=51) of severe malaria, and 45% (n=29) of high parasitemia non-severe malaria isolates. Multivariate analysis indicated that clumping was strongly positively associated with parasitemia (F(1,122)=24.1, p<0.001) but not with disease category (F(2,122)=1.8, p=0.17). Therefore platelet-mediated clumping in Malian P. falciparum isolates is primarily associated with high parasitemia and not with severe clinical manifestations of malaria

Increased levels of anti-PfCSP antibodies in post-pubertal females versus males immunized with PfSPZ Vaccine does not translate into increased protective efficacy

BACKGROUND: While prior research has shown differences in the risk of malaria infection and sickness between males and females, little is known about sex differences in vaccine-induced immunity to malaria. Identifying such differences could elucidate important aspects of malaria biology and facilitate development of improved approaches to malaria vaccination. METHODS: Using a standardized enzyme-linked immunosorbent assay, IgG antibodies to the major surface protein on Plasmodium falciparum (Pf) sporozoites (SPZ), the Pf circumsporozoite protein (PfCSP), were measured before and two weeks after administration of a PfSPZ-based malaria vaccine (PfSPZ Vaccine) to 5-month to 61-year-olds in 11 clinical trials in Germany, the US and five countries in Africa, to determine if there were differences in vaccine elicited antibody response between males and females and if these differences were associated with differential protection against naturally transmitted Pf malaria (Africa) or controlled human malaria infection (Germany, the US and Africa). RESULTS: Females >/= 11 years of age made significantly higher levels of antibodies to PfCSP than did males in most trials, while there was no indication of such differences in infants or children. Although adult females had higher levels of antibodies, there was no evidence of improved protection compared to males. In 2 of the 7 trials with sufficient data, protected males had significantly higher levels of antibodies than unprotected males, and in 3 other trials protected females had higher levels of antibodies than did unprotected females. CONCLUSION: Immunization with PfSPZ Vaccine induced higher levels of antibodies in post-pubertal females but showed equivalent protection in males and females. We conclude that the increased antibody levels in post-pubertal females did not contribute substantially to improved protection. We hypothesize that while antibodies to PfCSP (and PfSPZ) may potentially contribute directly to protection, they primarily correlate with other, potentially protective immune mechanisms, such as antibody dependent and antibody independent cellular responses in the liver

Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia

Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, suggesting selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we demonstrate that Sl2 and McCb have opposing malaria associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identified an unexpected interaction between Sl2 and α+thalassaemia, revealing that the protective association of Sl2 was greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, and the data highlight the importance of considering genetic interactions in disease-association studies