FoxP3+ regulatory CD4 T cells (Tregs) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. ...falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ Tregs in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations.
Cytokine-producing CD4 T cells have important roles in immunity against
malaria. However, the factors influencing functional differentiation of
specific CD4 T cells in naturally exposed children are ...not well understood. Moreover, it is not known which CD4 T-cell cytokine-producing subsets are most critical for protection. We measured
specific IFNγ-, IL10-, and TNFα-producing CD4 T-cell responses by multi-parametric flow cytometry in 265 children aged 6 months to 10 years enrolled in a longitudinal observational cohort in a high malaria transmission site in Uganda. We found that both age and parasite burden were independently associated with cytokine production by CD4 T cells. IL10 production by IFNγ
CD4 T cells was higher in younger children and in those with high-parasite burden during recent infection. To investigate the role of CD4 T cells in immunity to malaria, we measured associations of
-specific CD4 cytokine-producing cells with the prospective risk of
infection and clinical malaria, adjusting for household exposure to
-infected mosquitos. Overall, the prospective risk of infection was not associated with the total frequency of
specific CD4 T cells, nor of any cytokine-producing CD4 subset. However, the frequency of CD4 cells producing IL10 but not inflammatory cytokines (IFNγ and TNFα) was associated with a decreased risk of clinical malaria once infected. These data suggest that functional polarization of the CD4 T-cell response may modulate the clinical manifestations of malaria and play a role in naturally acquired immunity.
Vδ2
γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. ...The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2
T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2
counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vδ2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vδ2
T cell pro-inflammatory cytokine production. Higher Vδ2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vδ2
T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria.
γδ T cells expressing Vδ2 may be instrumental in the control of malaria, because they inhibit the replication of blood-stage parasites in vitro and expand during acute malaria infection. However, Vδ2 ...T-cell frequencies and function are lower among children with heavy prior malaria exposure. It remains unclear whether malaria itself is driving this loss. Here we measure Vδ2 T-cell frequency, cytokine production, and degranulation longitudinally in Ugandan children enrolled in a malaria chemoprevention trial from 6 to 36 months of age. We observed a progressive attenuation of the Vδ2 response only among children incurring high rates of malaria. Unresponsive Vδ2 T cells were marked by expression of CD16, which was elevated in the setting of high malaria transmission. Moreover, chemoprevention during early childhood prevented the development of dysfunctional Vδ2 T cells. These observations provide insight into the role of Vδ2 T cells in the immune response to chronic malaria.
CRISPR-Cas systems have proven effective in a variety of applications due to their ease of use and relatively high editing efficiency. Yet, any individual CRISPR-Cas system has inherent limitations, ...necessitating a diversity of RNA-guided nucleases to suit applications with distinct needs. We searched through metagenomic sequences to identify RNA-guided nucleases and found enzymes from diverse CRISPR-Cas types and subtypes, the most promising of which we developed into gene-editing platforms. Based on prior annotations of the metagenomic sequences, we establish the likely taxa and sampling locations where Class 2 CRISPR-Cas systems active in eukaryotes may be found. The newly discovered systems show robust capabilities as gene editors and base editors.
Background. Experimental inoculation of viable Plasmodium falciparum sporozoites administered with chemoprevention targeting blood-stage parasites results in protective immunity. It is unclear ...whether chemoprevention similarly enhances immunity following natural exposure to malaria. Methods. We assessed P. falciparum-speciuc T-cell responses among Ugandan children who were randomly assigned to receive monthly dihydroartemisinin-piperaquine (DP; n = 87) or no chemoprevention (n = 90) from 6 to 24 months of age, with pharmacologie assessments for adherence, and then clinically followed for an additional year. Results. During the intervention, monthly DP reduced malaria episodes by 55% overall (P < .001) and by 97% among children who were highly adherent to DP (P < .001). In the year after the cessation of chemoprevention, children who were highly adherent to DP had a 55% reduction in malaria incidence as compared to children given no chemoprevention (P = .004). Children randomly assigned to receive DP had higher frequencies of blood-stage specific CD4⁺ T cells coproducing interleukin-2 and tumor necrosis factor α(P= .003), which were associated with protection from subsequent clinical malaria and parasitemia, and fewer blood-stage specific CD4⁺ T cells coproducing interleukin-10 and interferon γ (P= .001), which were associated with increased risk of malaria. Conclusions. In this setting, effective antimalarial chemoprevention fostered the development of CD4⁺ T cells that coproduced interleukin 2 and tumor necrosis factor á and were associated with prospective protection, while limiting CD4⁺ T-cell production of the immunoregulatory cytokine IL-10.
Background. Mechanisms mediating immunity to malaria remain unclear, but animal data and experimental human vaccination models suggest a critical role for CD4⁺ T cells. Advances in multiparametric ...flow cytometry have revealed that the functional quality of pathogen-specific CD4⁺ T cells determines immune protection in many infectious models. Little is known about the functional characteristics of Píasmodium-specific CD4⁺ T-cell responses in immune and nonimmune individuals. Methods. We compared T-cell responses to Plasmodium falciparum among household-matched children and adults residing in settings of high or low malaria transmission in Uganda. Peripheral blood mononudear cells were stimulated with P. falciparum antigen, and interferon γ (IFN-γ), interleukin 2, interleukin 10, and tumor necrosis factor α (TNF-α) production was analyzed via multiparametric flow cytometry. Results. We found that the magnitude of the CD4⁺ T-cell responses was greater in areas of high transmission but similar between children and adults in each setting type. In the high-transmission setting, most P. falciparum-specific CD4⁺ T-cells in children produced interleukin 10, while responses in adults were dominated by IFN-γ and TNF-α. In contrast, in the low-transmission setting, responses in both children and adults were dominated by IFN-γ and TNF-α. Conclusions. These findings highlight major differences in the CD4⁺ T-cell response of immune adults and nonimmune children that may be relevant for immune protection from malaria.
Abstract only
Genetic association studies have long been used to connect traits of interest to loci in crop genomes and guide breeding of superior plants. This technology has been used to increase ...yield, shelf life, sensory appeal, and environmental stress resistance. Our recent work has shown that human health modifying regions (HMRs) can be identified using the same approach and incorporated into commercial crops to maximize the health potential of food. The genes found within an HMR can be investigated for contribution to bioactive metabolite synthesis and regulation in the plant. Inflammatory Bowel Disease (IBD) is a non‐curable pathology of the gastrointestinal system characterized by recurring bouts of inflammation and persistent damage to the lining of the gastrointestinal tract. Treatments for IBD are designed to help manage symptoms and maintain remission by preventing bouts of unencumbered inflammation or promoting healing of damaged tissue regions. Little is known about how various bioactive components from food impact IBS, but bioactive compounds in oats have shown ability to reduce inflammation and have been associated to promoting overall gastrointestinal health. We screened oat extracts from 115 genetically diverse breeding lines for their ability to modulate inflammation and induce cell migration into areas of injury in cell culture models of gastrointestinal health. Using a genome wide association study (GWAS), we associated each phenotype to loci on the oat genetic linkage map and identified specific candidate genes connected to metabolite biosynthesis and regulation. The identification of these HMRs will help guide future efforts to improve oat nutritional value for gastrointestinal health.
Intimate partner violence (IPV) is a ubiquitous and serious problem, the prevalence of which varies greatly around the world. Previous research shows that cultural factors interact with personality ...and that this interaction influences cognitions, attitudes, and behaviors that are related to personal and individual styles of resolving conflicts. In relation to this, the present study has three aims: comparing the self-reported IPV (physical, psychological and sexual) of English and Spanish offenders, comparing the Millon Clinical Multiaxial Inventory III (MCMI-III) scores of the two groups, and examining the association between country of origin, psychopathology, and IPV. The sample consists of 147 IPV offenders (80 English and 67 Spanish). The measures used were the MCMI-III and the Conflict Tactics Scale 2. The Mann−Whitney U tests were used to compare the English and Spanish sample, and independent logistic regressions were used to examine the relationship between personality patterns, psychopathology and culture, and IPV. Higher frequencies of physical and psychological aggression were found in the English group compared with the Spanish group as well as several differences in personality patterns and psychopathology between the groups. Some MCMI-III subscales also interact with nationality and predict physical and psychological aggression. The relevance of these results for intervention is discussed.
FoxP3+ regulatory CD4 T cells (Tregs) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. ...falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ Tregs in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations.
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