No abstract

Malaria is a tropical parasitic disease caused by the Plasmodium genus, which resulted in an estimated 219 million cases of malaria and 435 000 malaria-related deaths in 2017. Despite the availability of the Plasmodium falciparum genome since 2002, 74% of the genes remain uncharacterized. To remedy this paucity of functional information, we used transcriptomic data to build gene co-expression networks for two Plasmodium species (P. falciparum and P. berghei), and included genomic data of four other Plasmodium species, P. yoelii, P. knowlesi, P. vivax and P. cynomolgi, as well as two non-Plasmodium species from the Apicomplexa, Toxoplasma gondii and Theileria parva. The genomic and transcriptomic data were incorporated into the resulting database, malaria.tools, which is preloaded with tools that allow the identification and cross-species comparison of co-expressed gene neighbourhoods, clusters and life stage-specific expression, thus providing sophisticated tools to predict gene function. Moreover, we exemplify how the tools can be used to easily identify genes relevant for pathogenicity and various life stages of the malaria parasite. The database is freely available at www.malaria.tools.

Abiotic stresses negatively impact ecosystems and the yield of crops, and climate change will increase their frequency and intensity. Despite progress in understanding how plants respond to individual stresses, our knowledge of plant acclimatization to combined stresses typically occurring in nature is still lacking. Here, we used a plant with minimal regulatory network redundancy, Marchantia polymorpha, to study how seven abiotic stresses, alone and in 19 pairwise combinations, affect the phenotype, gene expression, and activity of cellular pathways. While the transcriptomic responses show a conserved differential gene expression between Arabidopsis and Marchantia, we also observe a strong functional and transcriptional divergence between the two species. The reconstructed high-confidence gene regulatory network demonstrates that the response to specific stresses dominates those of others by relying on a large ensemble of transcription factors. We also show that a regression model could accurately predict the gene expression under combined stresses, indicating that Marchantia performs arithmetic multiplication to respond to multiple stresses. Lastly, two online resources (https://conekt.plant.tools and http://bar.utoronto.ca/efp_marchantia/cgi-bin/efpWeb.cgi) are provided to facilitate the study of gene expression in Marchantia exposed to abiotic stresses.

Suboptimal immune responses to pathogens contribute to chronic infections. One way to improve immune responses is to boost Ag presentation. In this study, we investigate the potential of the tripartite motif-containing 21 (TRIM21) pathway. TRIM21 is a ubiquitously expressed cytosolic protein that recognizes the Fc region of Abs. When Abs that are bound to pathogens enter the cell as immune complexes, binding of TRIM21 to Fc initiates downstream inflammatory signaling and targets the immune complexes for proteasomal degradation. In APCs, peptides generated by proteasomes are loaded onto MHC class I molecules to stimulate CD8 T cell responses, which are crucial for effective immunity to pathogens. We hypothesized that increasing the affinity between immune complexes and TRIM21 might markedly improve CD8 T cell responses to Ags processed by the TRIM21 pathway. Using phage display technology, we engineered the human IgG1 Fc to increase its affinity for TRIM21 by 100-fold. Adenovirus immune complexes with the engineered Fc induced greater maturation of human dendritic cells (DC) than immune complexes with unmodified Fc and stimulated increased Ag-specific CD8 T cell proliferation and IFN-γ release in cocultures of DC-PBMC. Thus, by increasing the affinity between Fc and TRIM21, Ags from immune complexes undergo enhanced cross-presentation on DC, leading to greater CD8 T cell responses. Our study reveals an approach that could potentially be used in vaccines to increase cytotoxic T cell responses against Ags that are targeted or delivered by Fc-modified Abs.