Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function.

Approximately 619,000 malaria deaths were reported in 2021, and resistance to recommended drugs, including artemisinin-combination therapies (ACTs), threatens malaria control. Treatment failure with ACTs has been found to be as high as 93% in northeastern Thailand, and parasite mutations responsible for artemisinin resistance have already been reported in some African countries. Therefore, there is an urgent need to identify alternative treatments with novel targets. In this Perspective, we discuss some promising antimalarial drug targets, including enzymes involved in proteolysis, DNA and RNA metabolism, protein synthesis, and isoprenoid metabolism. Other targets discussed are transporters, Plasmodium falciparum acetyl-coenzyme A synthetase, N-myristoyltransferase, and the cyclic guanosine monophosphate-dependent protein kinase G. We have outlined mechanistic details, where these are understood, underpinning the biological roles and hence druggability of such targets. We believe that having a clear understanding of the underlying chemical interactions is valuable to medicinal chemists in their quest to design appropriate inhibitors.

High-fat diet-induced resistance to helminth infection via alternative induction of type 2 immunity.

Gastrointestinal nematode infections cause morbidity and socioeconomic loss in the most deprived communities. The shift in the context of obesity has led to spatial overlap with endemic gastrointestinal nematode regions resulting in the emergence of a novel comorbidity. Despite this, the impact of a high-fat diet (HFD) on immune-regulated protection against gastrointestinal infections remains largely unknown. We employed the murine model of nematode infection, Trichuris muris, to investigate the effect of an HFD on the immune response against chronic infection. Surprisingly, diet-induced obesity drove parasite expulsion in both single and repeated trickle low doses of T. muris eggs. Mechanistically, an HFD increased the expression of the ST2 receptor on CD4+ T cells, priming an enhanced type 2 helper T (Th2) cell cytokine production following interleukin (IL)-33 stimulation ex vivo. Despite IL-33-/- mice demonstrating that IL-33 is not critical for host protective immunity to T. muris under a conventional diet, HFD-fed T-cell deplete mice adoptively transferred with ST2-/- CD4 T cells were unable to expel a T. muris infection unlike those transferred with ST2-sufficient cells. Collectively, this study demonstrates that an HFD primes CD4+ T cells to utilize the IL-33-ST2 axis in a novel induction of type 2 immunity, providing insights into the emerging comorbidities of obesity and nematode infection.

Prevalence and intensity of Schistosoma haematobium infection among schoolchildren in central Zambia before and after mass treatment with a single dose of praziquantel.

INTRODUCTION: Urinary schistosomiasis caused by Schistosoma haematobium is common in some parts of Lusaka Province, Zambia, where water contact activity is high and sanitation is poor. We conducted a longitudinal study in Ng'ombe Compound of Lusaka, between 2007 and 2015, to observe the prevalence and intensity of S. haematobium infection among community primary school children, before and after receiving a single dose of praziquantel. MATERIALS AND METHODS: A total of 975 (445 females and 530 males) pupils, aged 9-16 years, were tested for S. haematobium at baseline. After mass treatment with praziquantel in 2010, 1570 pupils (785 females and 785 males), aged 9-15 years, were examined for S. haematobium eggs, from 2011 to 2015. RESULTS: At baseline, 279 out of 975 of the children were infected, with light infections constituting 84.9% and 15.1% classified as heavy infection. After mass treatment with praziquantel, the prevalence rate dropped, slightly, to 20.3% (63 out of 310) in 2011. However, it increased the following years up to 38% (133 out of 350) in 2015, with prevalence rates higher in males than females. The average number of heavy infection cases increased to 24.3% (120 out of 494) after treatment, reducing cases of light infections to 75.7% (374 out of 494). CONCLUSION: This study revealed that mass treatment with a single dose of praziquantel was not sufficient to significantly reduce the transmission of schistosomiasis. Further studies will need to evaluate whether multiple praziquantel treatments will be more therapeutically effective in limiting future incidences.

Retinoic acid elicits a coordinated expression of gut homing markers on T lymphocytes of Zambian men receiving oral Vivotif, but not Rotarix, Dukoral or OPVERO vaccines.

All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4ß7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, in healthy adult volunteers, ATRA induced an increase of these gut homing markers on T cells in vivo in a time dependent manner. The coordinated increase of α4ß7 and CCR9 by ATRA was seen in 57% (12/21) of volunteers and only when given together with an oral Vivotif vaccine. When this coordinated response to ATRA and Vivotif vaccine was present, it was strongly correlated with the gut immunoglobulin A (IgA) specific response to vaccine LPS (ρ = 0.82; P = 0.02). Using RNA-Seq analysis of whole blood transcription, patients receiving ATRA and Vivotif in conjunction showed transcriptomic changes in immune-related pathways, particularly including interferon α/ß signaling pathway, membrane-ECM interactions and immune hubs. These results suggest that exogenous ATRA can be used to manipulate responses to a subclass of oral vaccines, so far limited to a live attenuated Vivotif vaccine.