Autoantibodies inhibit Plasmodium falciparum growth and are associated with protection from clinical malaria.

Many infections, including malaria, are associated with an increase in autoantibodies (AAbs). Prior studies have reported an association between genetic markers of susceptibility to autoimmune disease and resistance to malaria, but the underlying mechanisms are unclear. Here, we performed a longitudinal study of children and adults (n = 602) in Mali and found that high levels of plasma AAbs before the malaria season independently predicted a reduced risk of clinical malaria in children during the ensuing malaria season. Baseline AAb seroprevalence increased with age and asymptomatic Plasmodium falciparum infection. We found that AAbs purified from the plasma of protected individuals inhibit the growth of blood-stage parasites and bind P. falciparum proteins that mediate parasite invasion. Protected individuals had higher plasma immunoglobulin G (IgG) reactivity against 33 of the 123 antigens assessed in an autoantigen microarray. This study provides evidence in support of the hypothesis that a propensity toward autoimmunity offers a survival advantage against malaria.

Gut microbiota elicits a protective immune response against malaria transmission.

Glycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the UDP-galactose:ß-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galß1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans.

A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation.

Immunity that controls parasitemia and inflammation during Plasmodium falciparum (Pf) malaria can be acquired with repeated infections. A limited understanding of this complex immune response impedes the development of vaccines and adjunctive therapies. We conducted a prospective systems biology study of children who differed in their ability to control parasitemia and fever following Pf infection. By integrating whole-blood transcriptomics, flow-cytometric analysis, and plasma cytokine and antibody profiles, we demonstrate that a pre-infection signature of B cell enrichment, upregulation of T helper type 1 (Th1) and Th2 cell-associated pathways, including interferon responses, and p53 activation associated with control of malarial fever and coordinated with Pf-specific immunoglobulin G (IgG) and Fc receptor activation to control parasitemia. Our hypothesis-generating approach identified host molecules that may contribute to differential clinical outcomes during Pf infection. As a proof of concept, we have shown that enhanced p53 expression in monocytes attenuated Plasmodium-induced inflammation and predicted protection from fever.

Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria.

BACKGROUND: Subcutaneous administration of the monoclonal antibody L9LS protected adults against controlled Plasmodium falciparum infection in a phase 1 trial. Whether a monoclonal antibody administered subcutaneously can protect children from P. falciparum infection in a region where this organism is endemic is unclear. METHODS: We conducted a phase 2 trial in Mali to assess the safety and efficacy of subcutaneous administration of L9LS in children 6 to 10 years of age over a 6-month malaria season. In part A of the trial, safety was assessed at three dose levels in adults, followed by assessment at two dose levels in children. In part B of the trial, children were randomly assigned, in a 1:1:1 ratio, to receive 150 mg of L9LS, 300 mg of L9LS, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection, as detected on blood smear performed at least every 2 weeks for 24 weeks. A secondary efficacy end point was the first episode of clinical malaria, as assessed in a time-to-event analysis. RESULTS: No safety concerns were identified in the dose-escalation part of the trial (part A). In part B, 225 children underwent randomization, with 75 children assigned to each group. No safety concerns were identified in part B. P. falciparum infection occurred in 36 participants (48%) in the 150-mg group, in 30 (40%) in the 300-mg group, and in 61 (81%) in the placebo group. The efficacy of L9LS against P. falciparum infection, as compared with placebo, was 66% (adjusted confidence interval [95% CI], 45 to 79) with the 150-mg dose and 70% (adjusted 95% CI, 50 to 82) with the 300-mg dose (P<0.001 for both comparisons). Efficacy against clinical malaria was 67% (adjusted 95% CI, 39 to 82) with the 150-mg dose and 77% (adjusted 95% CI, 55 to 89) with the 300-mg dose (P<0.001 for both comparisons). CONCLUSIONS: Subcutaneous administration of L9LS to children was protective against P. falciparum infection and clinical malaria over a period of 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT05304611.).

Structural basis of malaria RIFIN binding by LILRB1-containing antibodies.

Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)-variant surface antigens that are expressed on infected erythrocytes1-bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies2,3. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to ß2 microglobulin and RIFINs through their apical domains4,5. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable-constant (VH-CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN-LILRB1 D3 interaction that is similar to that of RIFIN-LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH-CH1 elbow without affecting VH-VL or CH1-CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH-CH1 elbow.

Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali.

BACKGROUND: CIS43LS is a monoclonal antibody that was shown to protect against controlled Plasmodium falciparum infection in a phase 1 clinical trial. Whether a monoclonal antibody can prevent P. falciparum infection in a region in which the infection is endemic is unknown. METHODS: We conducted a phase 2 trial to assess the safety and efficacy of a single intravenous infusion of CIS43LS against P. falciparum infection in healthy adults in Mali over a 6-month malaria season. In Part A, safety was assessed at three escalating dose levels. In Part B, participants were randomly assigned (in a 1:1:1 ratio) to receive 10 mg of CIS43LS per kilogram of body weight, 40 mg of CIS43LS per kilogram, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection detected on blood-smear examination, which was performed at least every 2 weeks for 24 weeks. At enrollment, all the participants received artemether-lumefantrine to clear possible P. falciparum infection. RESULTS: In Part B, 330 adults underwent randomization; 110 were assigned to each trial group. The risk of moderate headache was 3.3 times as high with 40 mg of CIS43LS per kilogram as with placebo. P. falciparum infections were detected on blood-smear examination in 39 participants (35.5%) who received 10 mg of CIS43LS per kilogram, 20 (18.2%) who received 40 mg of CIS43LS per kilogram, and 86 (78.2%) who received placebo. At 6 months, the efficacy of 40 mg of CIS43LS per kilogram as compared with placebo was 88.2% (adjusted 95% confidence interval [CI], 79.3 to 93.3; P<0.001), and the efficacy of 10 mg of CIS43LS per kilogram as compared with placebo was 75.0% (adjusted 95% CI, 61.0 to 84.0; P<0.001). CONCLUSIONS: CIS43LS was protective against P. falciparum infection over a 6-month malaria season in Mali without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04329104.).

NK cell-induced damage to P.falciparum-infected erythrocytes requires ligand-specific recognition and releases parasitophorous vacuoles that are phagocytosed by monocytes in the presence of immune IgG.

Natural killer (NK) cells lyse virus-infected cells and transformed cells through polarized delivery of lytic effector molecules into target cells. We have shown that NK cells lyse Plasmodium falciparum-infected red blood cells (iRBC) via antibody-dependent cellular cytotoxicity (ADCC). A high frequency of adaptive NK cells, with elevated intrinsic ADCC activity, in people chronically exposed to malaria transmission is associated with reduced parasitemia and resistance to disease. How NK cells bind to iRBC and the outcome of iRBC lysis by NK cells has not been investigated. We applied gene ablation in inducible erythrocyte precursors and antibody-blocking experiments with iRBC to demonstrate a central role of CD58 and ICAM-4 as ligands for adhesion by NK cells via CD2 and integrin αMß2, respectively. Adhesion was dependent on opsonization of iRBC by IgG. Live imaging and quantitative flow cytometry of NK-mediated ADCC toward iRBC revealed that damage to the iRBC plasma membrane preceded damage to P. falciparum within parasitophorous vacuoles (PV). PV were identified and tracked with a P.falciparum strain that expresses the PV membrane-associated protein EXP2 tagged with GFP. After NK-mediated ADCC, PV were either found inside iRBC ghosts or released intact and devoid of RBC plasma membrane. Electron microscopy images of ADCC cultures revealed tight NK-iRBC synapses and free vesicles similar in size to GFP+ PV isolated from iRBC lysates by cell sorting. The titer of IgG in plasma of malaria-exposed individuals that bound PV was two orders of magnitude higher than IgG that bound iRBC. This immune IgG stimulated efficient phagocytosis of PV by primary monocytes. The selective NK-mediated damage to iRBC, resulting in release of PV, and subsequent phagocytosis of PV by monocytes may combine for efficient killing and removal of intra-erythrocytic P.falciparum parasite. This mechanism may mitigate the inflammation and malaria symptoms during blood-stage P. falciparum infection.

Knowledge, attitudes and practices towards epilepsy in morocco: A cross-sectional study.

BACKGROUND: This study aims to assess knowledge, practices and attitudes of the general Moroccan population towards epilepsy and to highlight predictive factors. METHOD: A cross-sectional study was conducted in the Casablanca-Settat Moroccan region. A questionnaire was used to collect sociodemographic data and item answers from 400 people with epilepsy (PWE) and without epilepsy caregivers on dependent variables: knowledge, attitudes, and practices towards epilepsy. Bivariate and logistic regression analyses were performed using IBM SPSS Statistics 21.0. Statistical significance was set when P value < 0.05. RESULTS: The rates of poor knowledge, practices, and attitudes toward epilepsy were 11.5 %, 41 %, and 66.6 %, respectively. In the multivariate analysis, the risk of having poor knowledge about epilepsy was favored by lack of education (ORa = 4.31;CI95%:1.83-10.13;p = 0.001) and the absence of familiarity with epilepsy (ORa = 4.05;CI95%:1.92-8.54;p < 0.001). The risk of preferring allopathic practices to treat epilepsy was associated with lack of education (ORa = 2.21;CI95%:1.01-4.82;p = 0.046), residence in a city outside Casablanca (ORa = 2.33;CI95%:1.06-5.15;p = 0.035), age over 59 years (ORa = 2.50;CI95%:1.26-4.95; p = 0.008), residence in a rural areas (ORa = 4.41;CI95%:2.61-7.47;p < 0.001) and absence of familiarity with epilepsy (ORa = 4.08;CI95%:2.33-7.15;p < 0.001). Predictors of stigma towards epilepsy were female sex (ORa = 3.05;CI95%:2.04-4.56;p < 0.001) and the tendency to abandon anti-seizure medication for allopathic alternatives (ORa = 3.98;CI95%:2.21-7.17;p < 0.001), whereas advanced age was a protective factor (ORa = 0.57;CI95%:0.36-0.89;p = 0.014[39-59 years vs 18-29 years];ORa = 0.44;CI95%:0.23-0.82;p = 0.011[>59 years vs 18-29 years]). CONCLUSIONS: The rate of poor attitudes and treatment-seeking behavior was high. This socio-cultural context certainly impacts the quality of life and care of Moroccan PWE. These results should be considered to raise awareness in the Moroccan population.

Neither the African-Centric S47 Nor P72 Variant of TP53 Is Associated With Reduced Risk of Febrile Malaria in a Malian Cohort Study.

BACKGROUND: TP53 has been shown to play a role in inflammatory processes, including malaria. We previously found that p53 attenuates parasite-induced inflammation and predicts clinical protection to Plasmodium falciparum infection in Malian children. Here, we investigated whether p53 codon 47 and 72 polymorphisms are associated with differential risk of P. falciparum infection and uncomplicated malaria in a prospective cohort study of malaria immunity. METHODS: p53 codon 47 and 72 polymorphisms were determined by sequencing TP53 exon 4 in 631 Malian children and adults enrolled in the Kalifabougou cohort study. The effects of these polymorphisms on the prospective risk of febrile malaria, incident parasitemia, and time to fever after incident parasitemia over 6 months of intense malaria transmission were assessed using Cox proportional hazards models. RESULTS: Confounders of malaria risk, including age and hemoglobin S or C, were similar between individuals with or without p53 S47 and R72 polymorphisms. Relative to their respective common variants, neither S47 nor R72 was associated with differences in prospective risk of febrile malaria, incident parasitemia, or febrile malaria after parasitemia. CONCLUSIONS: These findings indicate that p53 codon 47 and 72 polymorphisms are not associated with protection against incident P. falciparum parasitemia or uncomplicated febrile malaria.

Accumulation of Neutrophil Phagocytic Antibody Features Tracks With Naturally Acquired Immunity Against Malaria in Children.

BACKGROUND: Studies have demonstrated the protective role of antibodies against malaria. Young children are known to be particularly vulnerable to malaria, pointing to the evolution of naturally acquired clinical immunity over time. However, whether changes in antibody functionality track with the acquisition of naturally acquired malaria immunity remains incompletely understood. METHODS: Using systems serology, we characterized sporozoite- and merozoite-specific antibody profiles of uninfected Malian children before the malaria season who differed in their ability to control parasitemia and fever following Plasmodium falciparum (Pf) infection. We then assessed the contributions of individual traits to overall clinical outcomes, focusing on the immunodominant sporozoite CSP and merozoite AMA1 and MSP1 antigens. RESULTS: Humoral immunity evolved with age, with an expansion of both magnitude and functional quality, particularly within blood-stage phagocytic antibody activity. Moreover, concerning clinical outcomes postinfection, protected children had higher antibody-dependent neutrophil activity along with higher levels of MSP1-specific IgG3 and IgA and CSP-specific IgG3 and IgG4 prior to the malaria season. CONCLUSIONS: These data point to the natural evolution of functional humoral immunity to Pf with age and highlight particular antibody Fc-effector profiles associated with the control of malaria in children, providing clues for the design of next-generation vaccines or therapeutics.

[Dermatoses of elderly inpatients in Casablanca: epidemiology and factors associated with length of stay]. / Dermatoses du sujet âgé en hospitalisation à Casablanca : épidémiologie et facteurs associés à la durée de séjour.

Geriatric in-patient dermatoses are diverse. Few data in Morocco describe the epidemiological profile and factors associated with average length of stay (LOS). Our aim was to identify these dermatoses and determine the factors associated with LOS.

Plasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype.

In malaria-naïve children and adults, Plasmodium falciparum-infected red blood cells (Pf-iRBCs) trigger fever and other symptoms of systemic inflammation. However, in endemic areas where individuals experience repeated Pf infections over many years, the risk of Pf-iRBC-triggered inflammatory symptoms decreases with cumulative Pf exposure. The molecular mechanisms underlying these clinical observations remain unclear. Age-stratified analyses of uninfected, asymptomatic Malian individuals before the malaria season revealed that monocytes of adults produced lower levels of inflammatory cytokines (IL-1ß, IL-6 and TNF) in response to Pf-iRBC stimulation compared to monocytes of Malian children and malaria-naïve U.S. adults. Moreover, monocytes of Malian children produced lower levels of IL-1ß and IL-6 following Pf-iRBC stimulation compared to 4-6-month-old infants. Accordingly, monocytes of Malian adults produced more IL-10 and expressed higher levels of the regulatory molecules CD163, CD206, Arginase-1 and TGM2. These observations were recapitulated in an in vitro system of monocyte to macrophage differentiation wherein macrophages re-exposed to Pf-iRBCs exhibited attenuated inflammatory cytokine responses and a corresponding decrease in the epigenetic marker of active gene transcription, H3K4me3, at inflammatory cytokine gene loci. Together these data indicate that Pf induces epigenetic reprogramming of monocytes/macrophages toward a regulatory phenotype that attenuates inflammatory responses during subsequent Pf exposure. Trial Registration: ClinicalTrials.gov NCT01322581.

Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection.

Infection of erythrocytes with Plasmodium species induces clinical malaria. Parasite-specific CD4(+) T cells correlate with lower parasite burdens and severity of human malaria and are needed to control blood-stage infection in mice. However, the characteristics of CD4(+) T cells that determine protection or parasite persistence remain unknown. Here we show that infection of humans with Plasmodium falciparum resulted in higher expression of the inhibitory receptor PD-1 associated with T cell dysfunction. In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.

Evidence for exposure dependent carriage of malaria parasites across the dry season: modelling analysis of longitudinal data.

BACKGROUND: In malaria endemic regions, transmission of Plasmodium falciparum parasites is often seasonal with very low transmission during the dry season and high transmission in the wet season. Parasites survive the dry season within some individuals who experience prolonged carriage of parasites and are thought to 'seed' infection in the next transmission season. METHODS: Dry season carriers and their role in the subsequent transmission season are characterized using a combination of mathematical simulations and data analysis of previously described data from a longitudinal study in Mali of individuals aged 3 months-12 years (n = 579). RESULTS: Simulating the life-history of individuals experiencing repeated exposure to infection predicts that dry season carriage is more likely in the oldest, most exposed and most immune individuals. This hypothesis is supported by the data from Mali, which shows that carriers are significantly older, experience a higher biting rate at the beginning of the transmission season and develop clinical malaria later than non-carriers. Further, since the most exposed individuals in a community are most likely to be dry season carriers, this is predicted to enable a more than twofold faster spread of parasites into the mosquito population at the start of the subsequent wet season. CONCLUSIONS: Carriage of malaria parasites over the months-long dry season in Mali is most likely in the older, more exposed and more immune children. These children may act as super-spreaders facilitating the fast spread of parasites at the beginning of the next transmission season.

Public antibodies to malaria antigens generated by two LAIR1 insertion modalities.

In two previously described donors, the extracellular domain of LAIR1, a collagen-binding inhibitory receptor encoded on chromosome 19 (ref. 1), was inserted between the V and DJ segments of an antibody. This insertion generated, through somatic mutations, broadly reactive antibodies against RIFINs, a type of variant antigen expressed on the surface of Plasmodium falciparum-infected erythrocytes. To investigate how frequently such antibodies are produced in response to malaria infection, we screened plasma from two large cohorts of individuals living in malaria-endemic regions. Here we report that 5-10% of malaria-exposed individuals, but none of the European blood donors tested, have high levels of LAIR1-containing antibodies that dominate the response to infected erythrocytes without conferring enhanced protection against febrile malaria. By analysing the antibody-producing B cell clones at the protein, cDNA and gDNA levels, we characterized additional LAIR1 insertions between the V and DJ segments and discovered a second insertion modality whereby the LAIR1 exon encoding the extracellular domain and flanking intronic sequences are inserted into the switch region. By exon shuffling, this mechanism leads to the production of bispecific antibodies in which the LAIR1 domain is precisely positioned at the elbow between the VH and CH1 domains. Additionally, in one donor the genomic DNA encoding the VH and CH1 domains was deleted, leading to the production of a camel-like LAIR1-containing antibody. Sequencing of the switch regions of memory B cells from European blood donors revealed frequent templated inserts originating from transcribed genes that, in rare cases, comprised exons with orientations and frames compatible with expression. These results reveal different modalities of LAIR1 insertion that lead to public and dominant antibodies against infected erythrocytes and suggest that insertion of templated DNA represents an additional mechanism of antibody diversification that can be selected in the immune response against pathogens and exploited for B cell engineering.

Structural and thermodynamic limits of layer thickness in 2D halide perovskites.

In the fast-evolving field of halide perovskite semiconductors, the 2D perovskites (A')2(A) n-1M n X3n+1 [where A = Cs+, CH3NH3+, HC(NH2)2+; A' = ammonium cation acting as spacer; M = Ge2+, Sn2+, Pb2+; and X = Cl-, Br-, I-] have recently made a critical entry. The n value defines the thickness of the 2D layers, which controls the optical and electronic properties. The 2D perovskites have demonstrated preliminary optoelectronic device lifetime superior to their 3D counterparts. They have also attracted fundamental interest as solution-processed quantum wells with structural and physical properties tunable via chemical composition, notably by the n value defining the perovskite layer thickness. The higher members (n > 5) have not been documented, and there are important scientific questions underlying fundamental limits for n To develop and utilize these materials in technology, it is imperative to understand their thermodynamic stability, fundamental synthetic limitations, and the derived structure-function relationships. We report the effective synthesis of the highest iodide n-members yet, namely (CH3(CH2)2NH3)2(CH3NH3)5Pb6I19 (n = 6) and (CH3(CH2)2NH3)2(CH3NH3)6Pb7I22 (n = 7), and confirm the crystal structure with single-crystal X-ray diffraction, and provide indirect evidence for "(CH3(CH2)2NH3)2(CH3NH3)8Pb9I28" ("n = 9"). Direct HCl solution calorimetric measurements show the compounds with n > 7 have unfavorable enthalpies of formation (ΔHf), suggesting the formation of higher homologs to be challenging. Finally, we report preliminary n-dependent solar cell efficiency in the range of 9-12.6% in these higher n-members, highlighting the strong promise of these materials for high-performance devices.

m-Phenylenediammonium as a New Spacer for Dion-Jacobson Two-Dimensional Perovskites.

Two-dimensional (2D) halide perovskites have several distinct structural classes and exhibit great tunability, stability, and high potential for photovoltaic applications. Here, we report a new series of hybrid 2D perovskites in the Dion-Jacobson (DJ) class based on aromatic m-phenylenediammonium (mPDA) dications. The crystal structures of the DJ perovskite materials (mPDA)MAn-1PbnI3n+1 (n = 1-3) were solved and refined using single-crystal X-ray crystallography. The results indicate a short I···I interlayer distance of 4.00-4.04 Å for the (mPDA)MAn-1PbnI3n+1 (n = 2 and 3) structures, which is the shortest among DJ perovskites. However, Pb-I-Pb angles are as small as 158-160°, reflecting the large distortion of the inorganic framework, which results in larger band gaps for these materials than those in other DJ analogues. Density functional theory calculations suggest appreciable dispersion in the stacking direction, unlike the band structures of the Ruddlesden-Popper phases, which exhibit flat bands along the stacking direction. This is a consequence of the short interlayer I···I distances that can lead to interlayer electronic coupling across the layers. The solution-deposited films (nominal (mPDA)MAn-1PbnI3n+1 compositions of n = 1-6) reveal improved surface coverage with increasing nominal n value with the higher n films being composed of a mixture of n = 1 and bulk three-dimensional MAPbI3 perovskites. The films made from solutions of these materials behave differently from those of other 2D iodide perovskites, and their solar cells have a mixture of n = 1 DJ and MAPbI3 as light-absorbing semiconductors.

Dendritic cell responses to Plasmodium falciparum in a malaria-endemic setting.

BACKGROUND: Plasmodium falciparum causes the majority of malaria cases worldwide and children in sub-Saharan Africa are the most vulnerable group affected. Non-sterile clinical immunity that protects from symptoms develops slowly and is relatively short-lived. Moreover, current malaria vaccine candidates fail to induce durable high-level protection in endemic settings, possibly due to the immunomodulatory effects of the malaria parasite itself. Because dendritic cells play a crucial role in initiating immune responses, the aim of this study was to better understand the impact of cumulative malaria exposure as well as concurrent P. falciparum infection on dendritic cell phenotype and function. METHODS: In this cross-sectional study, the phenotype and function of dendritic cells freshly isolated from peripheral blood samples of Malian adults with a lifelong history of malaria exposure who were either uninfected (n = 27) or asymptomatically infected with P. falciparum (n = 8) was assessed. Additionally, plasma cytokine and chemokine levels were measured in these adults and in Malian children (n = 19) with acute symptomatic malaria. RESULTS: With the exception of lower plasmacytoid dendritic cell frequencies in asymptomatically infected Malian adults, peripheral blood dendritic cell subset frequencies and HLA-DR surface expression did not differ by infection status. Peripheral blood myeloid dendritic cells of uninfected Malian adults responded to in vitro stimulation with P. falciparum blood-stage parasites by up-regulating the costimulatory molecules HLA-DR, CD80, CD86 and CD40 and secreting IL-10, CXCL9 and CXCL10. In contrast, myeloid dendritic cells of asymptomatically infected Malian adults exhibited no significant responses above the uninfected red blood cell control. IL-10 and CXCL9 plasma levels were elevated in both asymptomatic adults and children with acute malaria. CONCLUSIONS: The findings of this study indicate that myeloid dendritic cells of uninfected adults with a lifelong history of malaria exposure are able to up-regulate co-stimulatory molecules and produce cytokines. Whether mDCs of malaria-exposed individuals are efficient antigen-presenting cells capable of mounting an appropriate immune response remains to be determined. The data also highlights IL-10 and CXCL9 as important factors in both asymptomatic and acute malaria and add to the understanding of asymptomatic P. falciparum infections in malaria-endemic areas.

PD-1 Expression on NK Cells in Malaria-Exposed Individuals Is Associated with Diminished Natural Cytotoxicity and Enhanced Antibody-Dependent Cellular Cytotoxicity.

Natural killer (NK) cells are key effector cells of innate resistance capable of destroying tumors and virus-infected cells through cytotoxicity and rapid cytokine production. The control of NK cell responses is complex and only partially understood. PD-1 is an inhibitory receptor that regulates T cell function, but a role for PD-1 in regulating NK cell function is only beginning to emerge. Here, we investigated PD-1 expression on NK cells in children and adults in Mali in a longitudinal analysis before, during, and after infection with Plasmodium falciparum malaria. We found that NK cells transiently upregulate PD-1 expression and interleukin-6 (IL-6) production in some individuals during acute febrile malaria. Furthermore, the percentage of PD-1 expressing NK cells increases with age and cumulative malaria exposure. Consistent with this, NK cells of malaria-naive adults upregulated PD-1 following P. falciparum stimulation in vitro Additionally, functional in vitro studies revealed that PD-1 expression on NK cells is associated with diminished natural cytotoxicity but enhanced antibody-dependent cellular cytotoxicity (ADCC). These data indicate that PD-1+ NK cells expand in the context of chronic immune activation and suggest that PD-1 may contribute to skewing NK cells toward enhanced ADCC during infections such as malaria.

Cation Engineering in Two-Dimensional Ruddlesden-Popper Lead Iodide Perovskites with Mixed Large A-Site Cations in the Cages.

The Goldschmidt tolerance factor in halide perovskites limits the number of cations that can enter their cages without destabilizing their overall structure. Here, we have explored the limits of this geometric factor and found that the ethylammonium (EA) cations which lie outside the tolerance factor range can still enter the cages of the 2D halide perovskites by stretching them. The new perovskites allow us to study how these large cations occupying the perovskite cages affect the structural, optical, and electronic properties. We report a series of cation engineered 2D Ruddlesden-Popper lead iodide perovskites (BA)2(EAxMA1-x)2Pb3I10 (x = 0-1, BA is n-butylammonium, MA is methylammonium) by the incorporation of a large EA cation in the cage. An analysis of the single-crystal structures reveals that the incorporation of EA in the cage significantly stretches Pb-I bonds, expands the cage, and induces a larger octahedral distortion in the inorganic framework. Spectroscopic and theoretical studies show that such structural deformation leads to a blue-shifted bandgap, sub-bandgap trap states with wider energetic distribution, and stronger photoluminescence quenching. These results enrich the family of 2D perovskites and provide new insights for understanding the structure-property relationship in perovskite materials.