Metabolic and innate immune cues merge into a specific inflammatory response via unfolded protein response (UPR). Cell, Elsevier, In press, 177 (5), pp. SummaryInnate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DC) are exacerbated by a high fatty acid (FA) metabolic environment. FA suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR) leading to a distinct transcriptomic signature, with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response.Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

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Abstract. Antimalarial drugs are a key tool in malaria elimination programs. With the emergence of artemisinin resistance in southeast Asia, an effort to identify molecular markers for surveillance of resistant malaria parasites is underway. Non-synonymous mutations in the kelch propeller domain (K13-propeller) in Plasmodium falciparum have been associated with artemisinin resistance in samples from southeast Asia, but additional studies are needed to characterize this locus in other P. falciparum populations with different levels of artemisinin use. Here, we sequenced the K13-propeller locus in 82 samples from Haiti, where limited government oversight of non-governmental organizations may have resulted in low-level use of artemisinin-based combination therapies. We detected a single-nucleotide polymorphism (SNP) at nucleotide 1,359 in a single isolate. Our results contribute to our understanding of the global genomic diversity of the K13-propeller locus in P. falciparum populations.Discussions of global malaria elimination programs have been renewed in light of the decline in malaria-associated morbidity and mortality resulting from scaled-up vector-and parasite-targeted interventions over the past decade.1 A key strategy in malaria elimination programs is effective use of antimalarial drugs, particularly artemisinin-based combination therapies (ACTs), which are the first-line therapies in most malaria-endemic countries.1 However, malaria elimination goals face a new threat with the emergence of artemisinin resistance in southeast Asia.2-5 A recent study used both in vivo and in vitro methods to identify non-synonymous singlenucleotide polymorphisms (SNPs) at the PF3D7_1343700 kelch propeller domain (K13-propeller) in Cambodian Plasmodium falciparum associated with artemisinin resistance. 6Subsequent investigations at the K13-propeller locus in other southeast Asian populations, including those of Vietnam, Myanmar, Laos, and Thailand, confirm the association of non-synonymous SNPs at the K13-propeller with artemisinin resistance.7 However, these polymorphisms were not detected in sub-Saharan Africa P. falciparum samples from Gambia, Mali, Ghana, Burkina Faso, Congo, Democratic Republic of Congo, Kenya, Tanzania, Malawi, and Uganda, where little to no artemisinin resistance has been reported. [7][8][9] Furthermore, other non-synonymous SNPs were identified in the sub-Saharan African samples that were not observed in the southeast Asian P. falciparum samples. These findings suggest that polymorphisms in the K13-propeller could vary geographically, and therefore, genetic studies on the K13-propeller in other malaria-endemic countries are needed to assess the use of this locus as a tool to monitor the global emergence and spread of artemisinin resistance.Haiti is one of two remaining malaria-endemic countries in the Caribbean. It has several favorable elimination characteristics. 10 (1) One parasite species (P. falciparum) accounts for the majority, if not all, cases of malaria.11 (2) Malaria transmission is low.12...