A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases.

Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell-autologous mechanism to prevent such damage. However, IL-10-producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. This work provides insights into the development and function of CD4+ T cells during protozoan parasitic infections and identifies key immunoregulatory molecules.

Nanotechnology-Based Strategies in Parasitic Disease Management: From Prevention to Diagnosis and Treatment.

Parasitic infections are a major global health issue causing significant mortality and morbidity. Despite substantial advances in the diagnostics and treatment of these diseases, the currently available options fall far short of expectations. From diagnosis and treatment to prevention and control, nanotechnology-based techniques show promise as an alternative approach. Nanoparticles can be designed with specific properties to target parasites and deliver antiparasitic medications and vaccines. Nanoparticles such as liposomes, nanosuspensions, polymer-based nanoparticles, and solid lipid nanoparticles have been shown to overcome limitations such as limited bioavailability, poor cellular permeability, nonspecific distribution, and rapid drug elimination from the body. These nanoparticles also serve as nanobiosensors for the early detection and treatment of these diseases. This review aims to summarize the potential applications of nanoparticles in the prevention, diagnosis, and treatment of parasitic diseases such as leishmaniasis, malaria, and trypanosomiasis. It also discusses the advantages and disadvantages of these applications and their market values and highlights the need for further research in this field.

Field-friendly anti-PGL-I serosurvey in children to monitor Mycobacterium leprae transmission in Bihar, India.

Background: It has been amply described that levels of IgM antibodies against Mycobacterium leprae (M. leprae) phenolic glycolipid I (PGL-I) correlate strongly with the bacterial load in an infected individual. These findings have generated the concept of using seropositivity for antibodies against M. leprae PGL-I as an indicator of the proportion of the population that has been infected. Although anti-PGL-I IgM levels provide information on whether an individual has ever been infected, their presence cannot discriminate between recent and past infections. Since infection in (young) children by definition indicates recent transmission, we piloted the feasibility of assessment of anti-PGL-I IgM seroprevalence among children in a leprosy endemic area in India as a proxy for recent M. leprae transmission. Material and methods: A serosurvey for anti-PGL-I IgM antibodies among children in highly leprosy endemic villages in Bihar, India, was performed, applying the quantitative anti-PGL-I UCP-LFA cassette combined with low-invasive, small-volume fingerstick blood (FSB). Results: Local staff obtained FSB of 1,857 children (age 3-11 years) living in 12 leprosy endemic villages in Bihar; of these, 215 children (11.58%) were seropositive for anti-PGL-I IgM. Conclusion: The anti-PGL-I seroprevalence level of 11.58% among children corresponds with the seroprevalence levels described in studies in other leprosy endemic areas over the past decades where no prophylactic interventions have taken place. The anti-PGL-I UCP-LFA was found to be a low-complexity tool that could be practically combined with serosurveys and was well-accepted by both healthcare staff and the population. On route to leprosy elimination, quantitative anti-PGL-I serology in young children holds promise as a strategy to monitor recent M. leprae transmission in an area.

Marker assisted early generation identification of root knot disease resistant orange tomato segregants with multiple desirable alleles.

Enhanced bioavailability of cis-isomers of lycopene, accumulated in orange-fruited tangerine mutant has broadened the scope of nutritional enrichment in tomato. At the same time, advancements in the field of marker assisted selection (MAS) have made the stacking of multiple desirable alleles through molecular breeding to develop superior tomato genotypes possible. Here we report seedling stage MAS from 146 F2 plants, to identify 3 superior performing, root knot disease resistant orange-fruited segregants. In the selected segregants, fruit weight ranged from 39.2 to 54.6 g, pericarp thickness ranged from 4.56 to 6.05 mm and total soluble solid content ranged from 3.65 to 4.87° Brix. Presence of parental diversity allowed identification of the other desirable alleles of the genes governing late blight and mosaic disease resistance, growth habit (determinate and indeterminate) as well as fruit elongation and firmness. Resistance to root knot disease of the selected 3 segregants was also validated through a unique method employing in vitro rooted stem cuttings subjected to artificial inoculation, where the resistant parent and the selected segregants developed no galls in comparison to ~ 24 galls developed in the susceptible parent. The selected segregants form the base for development of multiple disease resistant, nutritionally enriched orange-fruited determinate/indeterminate tomato lines with superior fruit quality. The study also highlights the utility of early generation MAS for detailed characterization of segregants, through which multiple desirable alleles can be precisely targeted and fixed to develop superior tomato genotypes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-023-01361-1.

Advancements and Challenges in Developing Malaria Vaccines: Targeting Multiple Stages of the Parasite Life Cycle.

Malaria, caused by Plasmodium species, remains a major global health concern, causing millions of deaths annually. While the introduction of the RTS,S vaccine has shown promise, there is a pressing need for more effective vaccines due to the emergence of drug-resistant parasites and insecticide-resistant vectors. However, the complex life cycle and genetic diversity of the parasite, technical obstacles, limited funding, and the impact of the 2019 pandemic have hindered progress in malaria vaccine development. This review focuses on advancements in malaria vaccine development, particularly the ongoing clinical trials targeting antigens from different stages of the Plasmodium life cycle. Additionally, we discuss the rationale, strategies, and challenges associated with vaccine design, aiming to enhance the immune response and protective efficacy of vaccine candidates. A cost-effective and multistage vaccine could hold the key to controlling and eradicating malaria.

Post kala-azar dermal leishmaniasis in the Indian sub-continent: challenges and strategies for elimination.

Visceral leishmaniasis (VL) is a severe and often fatal form of leishmaniasis caused by Leishmania donovani in the Indian sub-continent. Post Kala-azar Dermal Leishmaniasis (PKDL) is a late cutaneous manifestation of VL, typically occurring after apparent cure of VL, but sometimes even without a prior history of VL in India. PKDL serves as a significant yet neglected reservoir of infection and plays a crucial role in the transmission of the disease, posing a serious threat to the VL elimination program in the Indian sub-continent. Therefore, the eradication of PKDL should be a priority within the current VL elimination program aimed at achieving a goal of less than 1 case per 10,000 in the population at the district or sub-district levels of VL endemic areas. To accomplish this, a comprehensive understanding of the pathogenesis of PKDL is essential, as well as developing strategies for disease management. This review provides an overview of the current status of diagnosis and treatment options for PKDL, highlighting our current knowledge of the immune responses underlying disease development and progression. Additionally, the review discusses the impact of PKDL on elimination programs and propose strategies to overcome this challenge and achieve the goal of elimination. By addressing the diagnostic and therapeutic gaps, optimizing surveillance and control measures, and implementing effective intervention strategies, it is possible to mitigate the burden of PKDL and facilitate the successful elimination of VL in the Indian sub-continent.

Reactivity vs. selectivity of quinone methides: synthesis of pharmaceutically important molecules, toxicity and biological applications.

Quinone methides (QMs) are considered to be highly reactive intermediates because of their aromatization both in chemical and biological systems. Being highly accessible, quinone methides (QMs) have been widely exploited and their concurrent use has been manifested for the synthesis of tertiary and quaternary carbon centers of bioactives, drugs and drug-like molecules. In this feature article, the synthetic routes, structure-reactivity relationships and synthetic applications of quinone methides are discussed. Formation of the intermediates during bioactivation of different chemical entities and possible chemical manifestations leading to their toxicity in biological systems are also covered.

Emerging role of γδ T cells in protozoan infection and their potential clinical application.

γδ T cells are thymus derived heterogeneous and unconventional T- lymphocyte expressing TCR γ (V γ9) and TCRδ (Vδ2) chain and play an important role in connecting innate and adaptive armaments of immune response. These cells can recognize wide ranges of antigens even without involvement of major histocompatibility complex and exert their biological functions by cytotoxicity or activating various types of immune cells. In recent past, γδ T cells have emerged as an important player during protozoa infection and rapidly expand after exposure with them. They have also been widely studied in vaccine induced immune response against many bacterial and protozoan infections with improved clinical outcome. In this review, we will discuss the various roles of γδ T cells in immunity against malaria and leishmaniasis, the two important protozoan diseases causing significant mortality and morbidity throughout the world.

Amphiregulin in cellular physiology, health, and disease: Potential use as a biomarker and therapeutic target.

Amphiregulin (AREG), which acts as one of the ligands for epidermal receptor growth factor receptor (EGFR), plays a crucial role in tissue repair, inflammation, and immunity. AREG is synthesized as membrane-anchored pre-protein, and is excreted after proteolytic cleavage, and serves as an autocrine or paracrine factor. After engagement with the EGFR, AREG triggers a cascade of signaling events required for many cellular physiological processes including metabolism, cell cycle, and proliferation. Under different inflammatory and pathogenic conditions, AREG is expressed by various activated immune cells that orchestrate both tolerance and host resistance mechanisms. Several factors including xenobiotics, cytokines, and inflammatory lipids have been shown to trigger AREG gene expression and release. In this review, we discuss the structure, function, and regulation of AREG, its role in tissue repair, inflammation, and homeostasis as well as the potential of AREG as a biomarker and therapeutic target.