Annette Kaiser

In view of the World Malaria Day 2025, the WHO and other partnerships started the campaign "Malaria Ends With Us: Reinvest, Reimagine, Reignite" to promote global policy and community action towards malaria elimination. Malaria control efforts have stalled in recent years due to climate changes, wars and economic decrease. Although there is profound knowledge in targeted prevention, treatment and detection in malaria people in endemic countries have limited access to these services. In 2020, people in low -and middle income countries spent 40% of their income in healthcare, a threat in pushing poverty. Malaria is affected by social inequities such as low education, work in agriculture, unprotected housing which exposes people to mosquito transmission (Carrasco-Escobar et al., 2021). Therefore, common global approaches have to be performed to overcome contemporary threats in global malaria control. The WHO has currently listed four main threats which comprise: i) invasive vector species (Singh et al., 2023) (ii) vector insecticide resistance (Suh et al., 2023) (iii) antimalarial drug efficacy and resistance (Rosenthal et al., 2024) iv) Parasite pfhrp2/3 gene deletions (Weiss et al., 2025).The Topical Issue addresses the urgency of novel control strategies either from the side of the parasite or the transmitting mosquito to ameliorate the reoccurrence of upcoming malaria cases.In that context, an alarming signal of global warming and climate change is the detection of four human Plasmodium species by Next Generation Sequencing (NGS) in a river (Heine et al.) West of Johannesburg, an area which is non endemic for malaria. Detection of the four different Plasmodium species might raise the question of accidential or Oddysee movement of the transmitting Anopheles mosquito into a former malaria free area. Hence, these findings illustrate the contemporary threat of endemic area expansion into non-endemic areas.A set of articles in this Topical Issue focuses on novel control strategies of the parasite and its transmission.The assessment of the malaria burden will be an important tool for prevention, control and eradication of the disease. In an integrative study based on retrieved data from the 2021 Global Burden of disease database (GBD), Zhou et al. assessed the malaria burden in the Comoros in 2021 including indicators like incidence, prevalence, and mortality, as well as disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs). Although the malaria burden decreased in the Comoros between 1999 to 2021 mainly due to epidemological changes, the study indicates that women under 40, school-aged children, and adults under 30 in the Comoros still have a higher malaria burden.Although malaria incidences have significantly declined in Indonesia, Lubis et al.recognize the necessicity to develop serum conversion rates to survey low level rates of transmission to immediately start elimination programmes. In a cross-sectional study conducted 2019 in Langkat district, North Sumatera Province, Indonesia, Lubis et al.applied two antigens, i.e. Merozoite Surface Protein-1 (MSP-1) and Apical Membrane Antigen 1 (PfAMA-1) in blood stages of P. falciparum and P.vivax. The seroprevalence for P. falciparum was 10.6% for PfAMA-1, 13% for PfMSP-119, respectively. In contrast, the measured serum conversion rates were 18.6% for PvAMA-1 and 7.4%for PvMSP-119. Based on these data the authors concluded that this assay is suitable for determing epidemological risk factors and surveillance in low transmission settings.Blocking transmission is an important issue to control asymptomatic gametocytemia. At least four articles in this Topical Issue focus on the threat of "insecticide resistance".Apart from the development of insecticides with novel scaffolds for ITNs, educational enrollment of the population (Mrema et al., 2023) is mostly important. In particular, highly endangered groups like children and pregnant women in rural areas have to be informed and convinced to use insecticide treated bednets.One article tackles the threat of invasive vector species i.e. the invasion of the malaria transmitting Anopheles mosquito into a non-endemic malaria free area West of Johannesburg. Six contributions in this Topical issue illustrate the necessity to implement novel control mechanisms to monitor malaria infections at an early stage in areas of low transmission.Conclusively, there are plenty of modern, scientific tools to combat the contemporary threats if we carefully observe and consequently implement them (World Malaria Report, 2025). Moreover, the collection demonstrates the need for direct and coordinated responses and strong quality assurance systems to overcome the current gaps. Apart from the progress in science and surveillance of malaria, reduction in international donor funding since 2025 from the US administration and other stakeholders for multiple years will have a critical impact on all achievements. This scenario has been recently modeled for tuberculosis with substantial impacts on mortality and morbidity due to reduced international donor support (Clark et al.,

Ticks are a group of arthropod vectors transmitting a variety of human pathogens, like Borrelia and the tick-borne Encephalitis virus. In Europe, Ixodes is the most important tick due to its wide distribution. Since the 20th century, Ixodes has significantly spread due to changes in biodiversity. Thus, there is an urgent need to decrease tick ubiquity in the environment to control tick-borne diseases.Deoxyhypusine Synthase (DHS) catalyzes the first step in the post translational modification (PTM) of the amino acid hypusine in eukaryotic initiation factor (eIF5A). Modified eIF5A plays a crucial role in cell proliferation of different parasites. Therefore, we cloned a putative DHS locus of 1098 bp from Ixodes by a reverse genetic approach from total RNA of salivary glands and expressed the protein in E. coli. Ixodes DHS encodes an ORF of 365 amino acids and is commonly spread in different Ixodes (98.36%) and Rhipicephalus species (99%), and fruit flies (70.92%). The expressed DHS protein has a molecular weight of 40.88 kDa and a determined pI of 5.12. In an activity assay the enzyme shows moderate activity. In the future, we intend to perform virtual docking experiments once a 3D structure of Ixodes ricinus has been resolved to evaluate DHS as a novel target and to discover potent inhibitors to define its role in infection.

The manuscript by Esumi presents an interesting hypothesis on how the essentiality of amino acids developed over the lineages. The Extracellular Protein Hypothesis (EPH) seems to be one explanation. In fact, humans seem to balance the deficiency of e...

The triamine spermidine is a key metabolite of the polyamine pathway. It plays a crucial role in many infectious diseases caused by viral or parasitic infections. Spermidine and its metabolizing enzymes, i.e., spermidine/spermine-N¹-acetyltransferase, spermine oxidase, acetyl polyamine oxidase, and deoxyhypusine synthase, fulfill common functions during infection in parasitic protozoa and viruses which are obligate, intracellular parasites. The competition for this important polyamine between the infected host cell and the pathogen determines the severity of infection in disabling human parasites and pathogenic viruses. Here, we review the impact of spermidine and its metabolites in disease development of the most important, pathogenic human viruses such as SARS-CoV-2, HIV, Ebola, and in the human parasites Plasmodium and Trypanosomes. Moreover, state-of-the-art translational approaches to manipulate spermidine metabolism in the host and the pathogen are discussed to accelerate drug development against these threatful, infectious human diseases.

Environmental stimuli can distress the internal reaction of cells and their normal function. To react promptly to sudden environmental changes, a cascade of heat shock proteins (Hsps) functions to protect and act as housekeepers inside the cells. In parallel to the heat shock response, the metabolic polyamine (PA) status changes. Here, we discuss possible ways of putative interactions between Hsps and polyamines in a wide lineage of eukaryotic model organisms with a particular focus on parasitic protozoa such as Plasmodium falciparum (P. falciparum). The supposed interaction between polyamines and Hsps may protect the parasite from the sudden change in temperature during transmission from the female Anopheles mosquito to a human host. Recent experiments performed with the spermidine mimetic inhibitor 15-deoxyspergualine in Plasmodium in vitro cultures show that the drug binds to the C-terminal EEVD motif of Hsp70. This leads to inhibition of protein biosynthesis caused by prevention of eIF5A2 phosphorylation and eukaryotic initiation factor 5A (eIF5A) modification. These observations provide further evidence that PAs are involved in the regulation of protein biosynthesis of Hsps to achieve a protective effect for the parasite during transmission.

The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (dhs) and deoxyhypusine hydroxylase (DOHH) enzymes. dhs from Plasmodium has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human dhs inhibitors led to 6-bromo-N-(1H-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC₅₀ value of 0.062 µM. We investigated this allosteric dhs inhibitor in Plasmodium. In vitro P. falciparum growth assays showed weak inhibition activity, with IC₅₀ values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the Pfdhs gene, as shown by chemogenomic profiling with transgenically modified P. falciparum lines. Moreover, in dose-dependent enzymatic assays with purified recombinant P. falciparum dhs protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled Pfdhs, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in P. falciparum dhs, which might foster the development of parasite-specific inhibitors.

Cancer drug resistance, in particular in advanced stages such as metastasis and invasion is an emerging problem. Moreover, drug resistance of parasites causing poverty-related diseases is an enormous, global challenge for drug development in the future. To circumvent this problem of increasing resistance, the development of either novel small compounds or Advanced Medicinal Therapies have to be fostered. Polyamines have many fundamental cellular functions like DNA stabilization, protein translation, ion channel regulation, autophagy, apoptosis and mostly important, cell proliferation. Consequently, many antiproliferative drugs can be commonly administered either in cancer therapy or for the treatment of pathogenic parasites. Most important for cell proliferation is the triamine spermidine, since it is an important substrate in the biosynthesis of the posttranslational modification hypusine in eukaryotic initiation factor 5A (EIF5A). To date, no small compound has been identified that directly inhibits the precursor protein EIF5A. Moreover, only a few small molecule inhibitors of the two biosynthetic enzymes, i.e. deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) have been functionally characterized. However, it is evident that only some of the compounds have been applied in translational approaches, i.e. in murine models to analyze the function of this modified protein in cell proliferation. In recent years, the pharmaceutical industry shifted from small molecules beyond traditional pharmacology to new tools and methods to treat disorders involving signaling deregulation. In this review, we evaluate translational approaches on inhibition of EIF5A hypusination in pathogenic parasites and therapy-resistant tumors and discuss its feasibility for an application in Advanced Medicinal Therapies.

Editorial: Heading Against Parasitic Resistance: A Screen for Next Generation Drugs Against Targets of cAMP- or cGMP-regulated Pathways

In this study, a determination of Troponin I and creatine kinase activity in whole-blood samples in a cohort of 100 small infants in the age of 2–5 years from Uganda with complicated Plasmodium falciparum malaria suggests the prevalence of cardiac symptoms in comparison to non-infected, healthy patients. Troponin I and creatine kinase activity increased during infection. Different reports showed that complicated malaria coincides with hypoxia in children. The obtained clinical data prompted us to further elucidate the underlying regulatory mechanisms of cardiac involvement in human cardiac ventricular myocytes. Complicated malaria is the most common clinical presentation and might induce cardiac impairment by hypoxia. Eukaryotic initiation factor 5A (eIF-5A) is involved in hypoxia induced factor (HIF-1α) expression. EIF-5A is a protein posttranslationally modified by hypusination involving catalysis of the two enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase. Treatment of human cardiomyocytes with GC7, an inhibitor of DHS, catalyzing the first step in hypusine biosynthesis led to a decrease in proinflammatory and proapoptotic myocardial caspase-1 activity in comparison to untreated cardiomyocytes. This effect was even more pronounced after co-administration of GC7 and GPI from P. falciparum simulating the pathology of severe malaria. Moreover, in comparison to untreated and GC7-treated cardiomyocytes, co-administration of GC7 and GPI significantly decreased the release of cytochrome C and lactate from damaged mitochondria. In sum, coadministration of GC7 prevented cardiac damage driven by hypoxia in vitro. Our approach demonstrates the potential of the pharmacological inhibitor GC7 to ameliorate apoptosis in cardiomyocytes in an in vitro model simulating severe malaria. This regulatory mechanism is based on blocking EIF-5A hypusination.