Explore the vast range of titles available.

Factors governing the clinical trajectory of Plasmodium falciparum infection remain an important area of investigation. Here we present transcriptomic, proteomic and metabolomic analyses comparing clinical subtypes of severe Plasmodium falciparum malaria to matched controls with uncomplicated disease in 79 children from Mali. MMP8 , IL1R2 , and ARG1 transcription is higher across cerebral malaria, severe malarial anemia, and concurrent cerebral malaria and severe malarial anemia, indicating a shared inflammatory signature. Tissue inhibitor of metalloproteinases 1 is the most upregulated protein in cerebral malaria, which along with elevated MMP8 and MMP9 transcription, underscores the importance of the metalloproteinase pathway in central nervous system pathophysiology. L-arginine metabolites are decreased in cerebral malaria, which coupled with increased ARG1 transcription suggests a putative mechanism impairing cerebral vasodilation. Using multi-omics approaches, we thus describe the inflammatory cascade in severe malaria syndromes, and identify potential therapeutic targets and biological markers. Infection by Plasmodium falciparum can manifest as diverse symptoms and outcomes with different treatment requirements. Here the authors use metabolomics, proteomics and transcriptomics data from 79 children to identify potential omics signatures that correlate with different extent and nature of inflammation to provide insights into the development of future treatments.

Shigella is a major cause of moderate-to-severe diarrhea, the most affected being young children from poor resource countries. Shigella species easily acquire antibiotic resistance, presenting a challenge to infection control. The development of vaccines for young children has been hindered by a lack of understanding of what constitutes protective immunity. Here, for the first time, we investigated the magnitude and specificity of Shigella humoral immunity evoked by natural exposure in children 6 months to 2 years old living in Mali and Ethiopia ( Shigella -endemic areas) using a qualified multiplex assay. Antibody profiles varied with age and region, revealing epidemiological trends. Children 12–17 months old were identified as the most vulnerable to infection. Antibodies specific for conserved Shigella proteins were higher in older children, affirming their potential as vaccine candidates. Shigella serosurveillance is useful in guiding public health interventions.

•rCSP/GLA-LSQ malaria vaccine was associated with only mild/moderate adverse events.•Geometric mean (GM) anti-CSP IgG rose > 4-fold 28 days after 1st dose in all groups.•rCSP/GLA-LSQ resulted in ~90-fold rise GM anti-CSP IgG 28 days after 3rd dose.•GLA-LSQ, a novel adjuvant, showed favorable safety and immunostimulatory results. Plasmodium falciparum circumsporozoite protein (CSP) is a major sporozoite surface protein and a key target of pre-erythrocytic malaria subunit vaccines. A full-length recombinant CSP (rCSP) based strategy could be advantageous, as this antigen includes a region critical to sporozoite cell attachment and hepatocyte invasion. The adjuvant Glucopyranosyl Lipid A-liposome Quillaja saponaria 21 (GLA-LSQ) functions as a TLR4 agonist, promotes antigen-specific TH1 responses and stimulates cytotoxic T cell production. To date, one study has reported the clinical acceptability of GLA-LSQ. We present interim results of a phase 1 first-in-human dose-escalation clinical trial of full-length rCSP vaccine given with or without GLA-LSQ adjuvant. Participants experienced only mild to moderate related solicited adverse events. The lowest adjuvanted vaccine dose achieved >90-fold rise in geometric mean anti-CSP IgG antibody titer. These favorable safety and immunogenicity results confirm the immunostimulatory capacity of this relatively new adjuvant and support next steps in clinical product development. Trial registration: ClinicalTrials.gov Identifier NCT03589794 (registered 18 July 2018)

In Bandiagara, Mali, children experience on average two clinical malaria episodes per year. However, even in the same transmission area, the number of uncomplicated symptomatic infections, and their parasitemia, can vary dramatically among children. We simultaneously characterize host and parasite gene expression profiles from 136 Malian children with symptomatic falciparum malaria and examine differences in the relative proportion of immune cells and parasite stages, as well as in gene expression, associated with infection and or patient characteristics. Parasitemia explains much of the variation in host and parasite gene expression, and infections with higher parasitemia display proportionally more neutrophils and fewer T cells, suggesting parasitemia-dependent neutrophil recruitment and/or T cell extravasation to secondary lymphoid organs. The child’s age also strongly correlates with variations in gene expression: Plasmodium falciparum genes associated with age suggest that older children carry more male gametocytes, while variations in host gene expression indicate a stronger innate response in younger children and stronger adaptive response in older children. These analyses highlight the variability in host responses and parasite regulation during P. falciparum symptomatic infections and emphasize the importance of considering the children’s age when studying and treating malaria infections. Here the authors use dual RNA sequencing to characterize host and parasite gene expression from 136 Malian children with symptomatic Plasmodium falciparum infection. They find that parasitemia levels correlate with neutrophil and T cell levels and that the child’s age correlates with innate immune gene expression as well as gametocyte levels.

SARS-CoV-2 vaccines are useful tools to combat the Coronavirus Disease 2019 (COVID-19) pandemic, but vaccine reluctance threatens these vaccines’ effectiveness. To address COVID-19 vaccine reluctance and ensure equitable distribution, understanding the extent of and factors associated with vaccine acceptance and uptake is critical. We report the results of a large nationwide study in the US conducted December 2020-May 2021 of 36,711 users from COVID-19-focused smartphone-based app How We Feel on their willingness to receive a COVID-19 vaccine. We identified sociodemographic and behavioral factors that were associated with COVID-19 vaccine acceptance and uptake, and we found several vulnerable groups at increased risk of COVID-19 burden, morbidity, and mortality were more likely to be reluctant to accept a vaccine and had lower rates of vaccination. Our findings highlight specific populations in which targeted efforts to develop education and outreach programs are needed to overcome poor vaccine acceptance and improve equitable access, diversity, and inclusion in the national response to COVID-19.

Plasmodium parasites caused 241 million cases of malaria and over 600,000 deaths in 2020. Both P . falciparum and P . ovale are endemic to Mali and cause clinical malaria, with P . falciparum infections typically being more severe. Here, we sequenced RNA from nine pediatric blood samples collected during infections with either P . falciparum or P . ovale , and characterized the host and parasite gene expression profiles. We found that human gene expression varies more between individuals than according to the parasite species causing the infection, while parasite gene expression profiles cluster by species. Additionally, we characterized DNA polymorphisms of the parasites directly from the RNA-seq reads and found comparable levels of genetic diversity in both species, despite dramatic differences in prevalence. Our results provide unique insights into host-pathogen interactions during malaria infections and their variations according to the infecting Plasmodium species, which will be critical to develop better elimination strategies against all human Plasmodium parasites.

Background RIFINs and STEVORs are variant surface antigens expressed by P. falciparum that play roles in severe malaria pathogenesis and immune evasion . These two highly diverse multigene families feature multiple paralogs, making their classification challenging using traditional bioinformatic methods. Results STRIDE (STevor and RIfin iDEntifier) is an HMM-based, command-line program that automates the identification and classification of RIFIN and STEVOR protein sequences in the malaria parasite Plasmodium falciparum . STRIDE is more sensitive in detecting RIFINs and STEVORs than available PFAM and TIGRFAM tools and reports RIFIN subtypes and the number of sequences with a FHEYDER amino acid motif, which has been associated with severe malaria pathogenesis. Conclusions STRIDE will be beneficial to malaria research groups analyzing genome sequences and transcripts of clinical field isolates, providing insight into parasite biology and virulence.

Extensive genetic diversity plays a role in immune evasion, and antibody responses can be strain-specific or broadly reactive depending on the epitope. Controlled human malaria infection (CHMI) allows investigation of immune responses to variant parasite proteins after a single infection with a known strain. We designed a novel diversity-reflecting peptide microarray containing 638,817 unique peptides representing 22,655 variants of 227 proteins from 23 P genome assemblies and 379 field isolates. Using this array, we probed sera from 38 malaria naïve adults before and 28 days after CHMI with one of two genetically distinct strains, NF54 (n = 21) or 7G8 (n = 17). We examined fold-increase in antibody response (intensity) and cross-reactivity to protein variants (breadth). ABCPred was used to predict linear epitopes for all 227 proteins. We used MEME to identify enriched motifs in regions of high intensity or breadth, which were presumed to be potential epitopes. While the two CHMI groups had similar intensity of responses to all proteins on the array, 20 proteins on the array had differential breadth of responses and participants infected with 7G8 strain had a higher breadth of responses to 17 of them. Of 543 ABCPred-predicted epitopes, 66 overlapped with MEME-identified epitopes, six of which were highly cross-reactive with >95% of peptide variants serorecognized by at least one CHMI group. Overall, we found most antibody responses to be comparable after infection with the NF54 strain or 7G8 strain, but we saw notable differences for ~10% of proteins on the array. While many MEME-identified epitopes from highly cross-reactive proteins were asparagine rich, an epitope from PF3D7_1033200 (ETRAMP10.2) was not. Highly cross-reactive responses to ETRAMP10.2 could be further characterized and ETRAMP10.2 could be considered for inclusion in a next generation vaccine.

Plasmodium falciparum erythrocyte membrane protein-1s (PfEMP1s), diverse malaria proteins expressed on the infected erythrocyte surface, play an important role in pathogenesis, mediating adhesion to host vascular endothelium. Antibodies to particular non-CD36-binding PfEMP1s are associated with protection against severe disease. We hypothesized that given lifelong P. falciparum exposure, Malian adults would have broad PfEMP1 serorecognition and high seroreactivity levels during follow-up, particularly to non-CD36-binding PfEMP1s such as those that attach to endothelial protein C receptor (EPCR) and intercellular adhesion molecule-1 (ICAM-1). Using a protein microarray, we determined serologic responses to 166 reference PfEMP1 fragments during a dry and subsequent malaria transmission season in Malian adults. Malian adult sera had PfEMP1 serologic responses throughout the year, with decreased reactivity to a small subset of PfEMP1 fragments during the dry season and increases in reactivity to a different subset of PfEMP1 fragments during the subsequent peak malaria transmission season, especially for intracellular PfEMP1 domains. For some individuals, PfEMP1 serologic responses increased after the dry season, suggesting antigenic switching during asymptomatic infection. Adults were more likely to experience variable serorecognition of CD36-binding PfEMP1s than non-CD36-binding PfEMP1s that bind EPCR or ICAM-1, which remained serorecognized throughout the year. Sustained seroreactivity to non-CD36-binding PfEMP1s throughout adulthood amid seasonal fluctuation patterns may reflect underlying protective severe malaria immunity and merits further investigation.