Exosome-derived long noncoding RNAs: Mediators of host-Plasmodium parasite communication.

Overcoming challenges associated with malaria eradication proves to be a formidable task due to the complicated life cycle exhibited by the malaria parasite and the lack of safe and enduring vaccines against malaria. Investigating the interplay between Plasmodium parasites and their mammalian hosts is crucial for the development of novel vaccines. Long noncoding RNAs (lncRNAs) derived from Plasmodium parasites or host cells have emerged as potential signaling molecules involved in the trafficking of proteins, RNA (mRNAs, miRNAs, and ncRNAs), and DNA. These lncRNAs facilitate the interaction between hosts and parasites, impacting normal physiology or pathology in malaria-infected individuals. Moreover, they possess the capacity to regulate immune responses and associated signaling pathways, thus potentially influencing chromatin organization, epigenetic modifications, mRNA processing, splicing, and translation. However, the functional role of exosomal lncRNAs in malaria remains poorly understood. This review offers a comprehensive analysis of lncRNA and exosomal lncRNA profiles during malaria infection. It presents an overview of recent progress in elucidating the involvement of exosomal lncRNAs in host-parasite interactions. Additionally, potential exosomal lncRNAs linked to the domains of innate and adaptive immunity in the context of malaria are proposed. These findings may contribute to the discovery of new diagnostic and therapeutic strategies for malaria. Furthermore, the need for additional research was highlighted that aimed to elucidate the mechanisms underlying lncRNA transportation into host cells and their targeting of specific genes to regulate the host's immune response. This knowledge gap presents an opportunity for future investigations, offering innovative approaches to enhance malarial control. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Small Molecule-RNA Interactions RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.

Extracellular Vesicles Derived from Plasmodium-infected Hosts as Stimuli of "Trained" Innate Immunity.

Although the burden of malaria has been successfully controlled globally, this disease remains a major public health issue. To date, neither existing drugs nor vaccines against malaria are sufficient in eliminating malaria worldwide. To achieve the eradication of malaria by 2040, effective interventions targeting all Plasmodium species are urgently needed. As the cornerstone of vaccine design, immune memory serves a significant role in the host's defense against Plasmodium infections. It has long been considered that innate immunity is non-specific and lacks immunologic memory. However, emerging evidence has suggested that innate immunity can be trained following exposure of the body to infectious agents, such as Plasmodium or its products, which, in turn, promotes the onset of a type of memory in innate immune cells. The above "trained" innate immune cells, whose phenotype is modified in response to epigenetic modifications, metabolic recombination, or cytokine secretion, exhibit differential pathophysiology after the exposure of the body to a pathogen. In addition, Plasmodium-infected red blood cells and other host cells can secrete exosomes that contain conserved parasite-specific information, such as proteins, RNA, non-coding RNA molecules, and nucleic acids. These molecules can act as stimuli for promoting the establishment of "trained" innate immunity against malaria, thereby altering the onset and progression of the parasitic disease. A deeper understanding of the role of exosomes in the development of "trained" innate immunity during Plasmodium infection could provide novel therapeutic and prevention strategies against malaria infections.

Plasmodium manipulates the expression of host long non-coding RNA during red blood cell intracellular infection.

BACKGROUND: Parasites interact with their host through "direct" and/or "indirect" mechanisms. Plasmodium, for example, either mediates direct physical interactions with host factors or triggers the immune system of the host indirectly, leading to changes in infectious outcomes. Long non-coding RNAs (lncRNAs) participate in regulating biological processes, especially host-pathogen interactions. However, research on the role of host lncRNAs during Plasmodium infection is limited. METHODS: A RNA sequencing method (RNA-seq) was used to confirm the differential expression profiles of lncRNAs in Plasmodium yeolii 17XL (P.y17XL)-infected BALB/c mice. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to elucidate the potential functions of Plasmodium-induced genes. Subsequently, the effect of specific lncRNAs on the modulation of immune-related signaling pathways in malaria was determined by fluorescence-activated cell sorting, western blot and enzyme-linked immunosorbent assay. RESULTS: The data showed that in P.y17XL-infected BALB/c mice, Plasmodium upregulated the expression of 132 lncRNAs and downregulated the expression of 159 lncRNAs. Differentially expressed lncRNAs clearly associated with malaria infection were annotated, including four novel dominant lncRNAs: ENMSUSG00000111521.1, XLOC_038009, XLOC_058629 and XLOC_065676. GO and KEGG pathway analyses demonstrated that these four differentially expressed lncRNAs were associated with co-localized/co-expressed protein-coding genes that were totally enriched in malaria and with the transforming growth factor beta (TGF-ß) signaling pathway. Using the models of P.y17XL-infected BALB/c mice, data certified that the level of TGF-ß production and activation of TGF-ß/Smad2/3 signaling pathway were obviously changed in malaria infection. CONCLUSIONS: These differentially expressed immune-related genes were deemed to have a role in the process of Plasmodium infection in the host via dendritic/T regulatory cells and the TGF-ß/Smad2/3 signaling pathway. The results of the present study confirmed that Plasmodium infection-induced lncRNA expression is a novel mechanism used by Plasmodium parasites to modify host immune signaling. These results further enhance current understanding of the interaction between Plasmodium and host cells.

Comprehensive analysis of CXCR family members in lung adenocarcinoma with prognostic values.

BACKGROUND: The expression profiles and molecular mechanisms of CXC chemokine receptors (CXCRs) in Lung adenocarcinoma (LUAD) have been extensively explored. However, the comprehensive prognostic values of CXCR members in LUAD have not yet been clearly identified. METHODS: Multiple available datasets, including Oncomine datasets, the cancer genome atlas (TCGA), HPA platform, GeneMANIA platform, DAVID platform and the tumor immune estimation resource (TIMER) were used to detect the expression of CXCRs in LUAD, as well as elucidate the significance and value of novel CXCRs-associated genes and signaling pathways in LUAD. RESULTS: The mRNA and/or protein expression of CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CXCR6 displayed predominantly decreased in LUAD tissues as compared to normal tissues. On the contrary, compared with the normal tissues, the expression of CXCR7 was significantly increased in LUAD tissues. Subsequently, we constructed a network including CXCR family members and their 20 related genes, and the related GO functions assay showed that CXCRs connected with these genes participated in the process of LUAD through several signal pathways including Chemokine signaling pathway, Cytokine-cytokine receptor interaction and Neuroactive ligand-receptor interaction. TCGA and Timer platform revealed that the mRNA expression of CXCR family members was significantly related to individual cancer stages, cancer subtypes, patient's gender and the immune infiltration level. Finally, survival analysis showed that low mRNA expression levels of CXCR2 (HR = 0.661, and Log-rank P = 1.90e-02), CXCR3 (HR = 0.674, and Log-rank P = 1.00e-02), CXCR4 (HR = 0.65, and Log-rank P = 5.01e-03), CXCR5 (HR = 0.608, and Log-rank P = 4.80e-03) and CXCR6 (HR = 0.622, and Log-rank P = 1.85e-03) were significantly associated with shorter overall survival (OS), whereas high CXCR7 mRNA expression (HR = 1.604, and Log-rank P = 4.27e-03) was extremely related with shorter OS in patients. CONCLUSION: Our findings from public databases provided a unique insight into expression characteristics and prognostic values of CXCR members in LUAD, which would be benefit for the understanding of pathogenesis, diagnosis, prognosis prediction and targeted treatment in LUAD.

Adaptive immune responses mediated age-related Plasmodium yoelii 17XL and 17XNL infections in 4 and 8-week-old BALB/c mice.

BACKGROUD: It is important to expound the opposite clinical outcomes between children and adulthood for eradicate malaria. There remains unknown about the correlation between adaptive immune response and age-related in malaria. METHODS: 4 and 8-week-old mice were used to mimic children and adulthood, respectively. Parasitemia and the survival rate were monitored. The proportion and function of Th1 and Th2 cells were detected by FACS. The levels of IFN-γ, IL-4, total IgG, IgG1, IgG2a and Plasmodium yoelii MSP-1-specific IgG were measured by ELISA. RESULTS: The adult group showed greater resistance to P. yoelii 17XL infection, with lower parasitemia. Compared with 4-week-old mice, the percentage of CD4+T-bet+IFN-γ+ Th1 cells as well as IFN-γ production were significantly increased on day 5 p.i. in the 8-week-old mice after P. yoelii 17XNL infection. The percentage of CD4+GATA3+IL-4+ Th2 cells and CD4+CXCR5+ Tfh cells, and IL-4 production in the 8-week-old mice significantly increased on day 5 and day 10 after P. yoelii 17XNL infection. Notably, the levels of total IgG, IgG1, IgG2a and P. yoelii MSP-1-specific IgG were also significantly increased in the 8-week-old mice. PD-1, a marker of exhaustion, was up-regulated on CD4+ or activated CD4+ T cells in the 8-week-old mice as compared to the 4-week-old group. CONCLUSIONS: Thus, we consider that enhanced cellular and humoral adaptive immunity might contribute to rapid clearance of malaria among adults, likely in a PD-1-dependent manner due to induction of CD4+ T cells exhaustion in P. yoelii 17XNL infected 8-week-old mice.

Plasmodium yoelii 17XL infection modified maturation and function of dendritic cells by skewing Tregs and amplificating Th17.

BACKGROUND: Emerging data has suggested that Tregs, Th17, Th1 and Th2 are correlated with early immune mechanisms by controlling Plasmodium infection. Plasmodium infection appeared to impair the antigen presentation and maturation of DCs, leading to attenuation of specific cellular immune response ultimately. Hence, in this study, we aim to evaluate the relevance between DCs and Tregs/Th17 populations in the process and outcomes of infection with Plasmodium yoelii 17XL (P.y17XL). METHODS: DCs detection/analysis dynamically was performed by Tregs depletion or Th17 neutralization in P.y17XL infected BALB/c mice via flow cytometry. Then the levels of cytokines production were detected using enzyme-linked mmunosorbent assay (ELISA). RESULTS: Our results indicated that Tregs depletion or Th17 neutralization in BALB/c mice infected with P.y17XL significantly up-regulated the percentages of mDC and pDC, increased the expressions of major histocompatibility complex (MHC) class II, CD80, CD86 on DCs and the levels of IL-10/IL-12 secreted by DCs, indicating that abnormal amplification of Tregs or Th17 may damage the maturation and function of DCs during the early stage of malaria infection. Interestingly, we also found that the abnormal amplification of Th17, as well as Tregs, could inhibit the maturation of DCs. CONCLUSIONS: Tregs skewing or Th17 amplification during the early stage of malaria infection may inhibit the maturation and function of DCs by modifying the subsets of DCs, expressions of surface molecules on DCs and secretion mode of cytokines.

Modulation of anti-malaria immunity by vitamin A in C57BL/6J mice infected with heterogenic plasmodium.

Vitamin A (VA) is an anti-inflammatory agent that is important in modulating and balancing the immune system. The present study aimed to investigate the immunoregulatory effects of vitamin A supplement (VAS) in C57BL/6J mice infected with Plasmodium yoelii 17XL (P.y17XL) or Plasmodium berghei ANKA (P.bANKA). Following VA treatment, parasitaemia decreased, but survival rate did not significantly change during P.y17XL infection. However, in P.bANKA infected C57BL/6J mice, VA pretreatment decreased parasitaemia, and a lag in cerebral malaria (CM) was observed during the early stages of infection. Furthermore, VA pretreatment was also demonstrated to upregulate MHCII expression in dendritic cells (DCs), downregulate Th1 and Tregs, and downregulate TNF-α and IFN-γ production. The results of the current study indicated that VAS downregulated the inflammation response in CM, but did not exhibit an immunoregulatory effect against P.y17XL infection. VAS protected the onset of CM by reducing inflammation, and was also correlated with the downregulation of Th1 by modifying the function of DCs and Tregs. However, no significant effect was observed during P.y17XL infection.

MXene/Graphene Heterostructures as High-Performance Electrodes for Li-Ion Batteries.

Recently, MXene/graphene heterostructures have been successfully fabricated and found to exhibit outstanding performance as electrodes for Li-ion batteries. However, insights into the mechanism behind the encouraging experimental results are missing. We use first-principles calculations to systematically investigate the electrochemical properties of MXene/graphene heterostructures, choosing Ti2CX2 (X = F, O, and OH) as representative MXenes. Our calculations disclose that the presence of graphene not only avoids restacking effects of MXene layers but also enhances the electric conductivity, Li adsorption strength (while maintaining a high Li mobility), and mechanical stiffness. These favorable attributes collectively lead to the excellent performance of MXene/graphene electrodes observed experimentally. While the Ti2CO2/graphene heterostructure is proposed to be the most promising candidate within the studied materials, the developed comprehensive understanding is of significance also for the future rational design of MXene-based electrodes.

Bacillus Calmette-Guérin-inoculation at different time points influences the outcome of C57BL/6 mice infected with Plasmodium chabaudi chabaudi AS.

Bacillus Calmette-Guérin (BCG) is an attenuated Mycobacterium tuberculosis vaccine. We performed a series of co-infection experiments with BCG-Plasmodium chabaudi chabaudi Landau, 1965 AS using C57BL/6 mice to analyse whether BCG can affect the development of protective immunity to infection with Plasmodium spp. and the mechanism of this protection. We divided mice into four groups: BCG-inoculation 4 weeks prior to P. c. chabaudi AS infection (B-4w-Pc); simultaneous BCG-inoculation and P. c. chabaudi AS infection (Pc+B); BCG-inoculation 3 days post P. c. chabaudi AS (Pc-3-B) infection; and mono-P. c. chabaudi AS infection as control (Pc). The parasitemia level in the B-4w-Pc group was noticeably higher than control group at 6-19 days post infection (dpi). Compared with the control group, the proportion of CD4(+)CD69(+) T cells was significantly reduced 5, 8 and 12 dpi, but the proportion of CD4(+)CD25(+)Foxp3(+) Tregs was significantly increased in the B-4w-Pc group on 5 and 8 dpi. The B-4w-Pc group also demonstrated reduced levels of IFN-γ and TNF-α on 5 and 8 dpi and significantly elevated level of IL-10 on 12 dpi. There were significantly fewer mDCs (CD11c(+)CD11b(+)) and pDCs (CD11c(+)B220(+)) in the B-4w-Pc group than the control group at all the time points post infection and the expression of MHC II was noticeably reduced on day 8 pi. Our findings confirmed that BCG inoculation prior to Plasmodium infection resulted in excessive activation and proliferation of Tregs and upregulation of anti-inflammatory mediators, which inhibited establishment of a Th1-dominant immune response during the early stages of Plasmodium infection by inhibiting dendritive cells response. BCG inoculation prior to P. c. chabaudi AS infection may contribute to overgrowth of parasites as well as mortality in mice.