Promotion of Th17 Polarized Immunity via Co-Delivery of Mincle Agonist and Tuberculosis Antigen Using Silica Nanoparticles.

Adjuvants and immunomodulators that effectively drive a Th17-skewed immune response are not part of the standard vaccine toolkit. Vaccine adjuvants and delivery technologies that can induce Th17 or Th1/17 immunity and protection against bacterial pathogens, such as tuberculosis (TB), are urgently needed. Th17-polarized immune response can be induced using agonists that bind and activate C-type lectin receptors (CLRs) such as macrophage inducible C-type lectin (Mincle). A simple but effective strategy was developed for codelivering Mincle agonists with the recombinant Mycobacterium tuberculosis fusion antigen, M72, using tunable silica nanoparticles (SNP). Anionic bare SNP, hydrophobic phenyl-functionalized SNP (P-SNP), and cationic amine-functionalized SNP (A-SNP) of different sizes were coated with three synthetic Mincle agonists, UM-1024, UM-1052, and UM-1098, and evaluated for adjuvant activity in vitro and in vivo. The antigen and adjuvant were coadsorbed onto SNP via electrostatic and hydrophobic interactions, facilitating multivalent display and delivery to antigen presenting cells. The cationic A-SNP showed the highest coloading efficiency for the antigen and adjuvant. In addition, the UM-1098-adsorbed A-SNP formulation demonstrated slow-release kinetics in vitro, excellent stability over 12 months of storage, and strong IL-6 induction from human peripheral blood mononuclear cells. Co-adsorption of UM-1098 and M72 on A-SNP significantly improved antigen-specific humoral and Th17-polarized immune responses in vivo in BALB/c mice relative to the controls. Taken together, A-SNP is a promising platform for codelivery and proper presentation of adjuvants and antigens and provides the basis for their further development as a vaccine delivery platform for immunization against TB or other diseases for which Th17 immunity contributes to protection.

Potential Impact of a Diagnostic Test for Detecting Prepatent Guinea Worm Infections in Dogs.

Chad has seen a considerable reduction in cases of Guinea worm disease (or dracunculiasis) in domestic dogs in recent years. Tethering of dogs and application of Abate® larvicide to water sources appear to have contributed to this progress, but with 767 reported dog cases in 2021, accelerating elimination of the disease in Chad may require additional tools. We investigate the potential benefits of a hypothetical diagnostic test that could be capable of detecting prepatent infections in dogs. We adapt an agent-based simulation model for forecasting the impact of interventions on guinea worm disease in dogs to examine the interaction of multiple test factors including test accuracy, when the test can detect infection, dog selection, and dog-owner compliance with tethering recommendations. We find that a diagnostic test could be successful if used in conjunction with existing interventions, and elimination can be achieved within 2 years with 80% or higher test sensitivity, 90% or higher specificity, systematic testing of each dog twice per year, and more than 90% long-term tethering compliance when a dog tests positive or a worm is emerging. Because of the long incubation period of Guinea worm disease (10-14 months) and the fact that no treatment exists, the benefits of the test rely on the testing rollout and response of dog owners. If the test could estimate the timing of worm emergence, long-term tethering could be eliminated and infected dogs could be tethered only when the worms are expected, minimizing the related resources (human and financial) to support the intervention.

The effects of COVID-19 risk, gender, and self-compassion on the workplace cyberbullying and job satisfaction of university faculty.

The purpose of this study is to examine workplace cyberbullying (WPCB) in higher education. Specifically, the study examines the relationship between WPCB and several important factors such as self-compassion, job satisfaction, and gender. The cross-sectional study administered a survey to a convenience sample of 179 faculty members. The regression model showed that self-compassion was positively related to job satisfaction, whereas WPCB was negatively related to job satisfaction after controlling for covariates. The path analysis model results showed that gender and COVID-19 risk of severe illness were related to WPCB. Additionally, self-compassion mediated the inverse relationship between WPCB and job satisfaction.

Advancing Health Security and Disease Eradication Through Peace and Health: A Mali Case Study.

Conflict and violence constitute threats to public health. As levels of conflict increase within and between countries, it is important to explore how conflict resolution initiatives can be adapted to meet the health needs of communities, and how addressing the health needs of communities can assist in conflict resolution and contribute to health security. In conflict-affected central Mali, a Peace through Health Initiative, piloted between 2018 and 2022, used conflict resolution trainings, facilitated community meetings, and human and animal health interventions to negotiate "periods of tranquility" to achieve public health goals. Project activities resulted in improved health, improved livelihoods, reduced violence, improved trust among stakeholders, and greater inclusion of community members in peace and health decisionmaking. The Peace-Health Initiative generated several lessons learned related to 3 phases of peace-health programming: preintervention, program development, and implementation. These lessons can be applied to support expanded Peace through Health Initiatives within Mali, may be adaptable to other conflict-afflicted contexts, and should be considered in relation to the implementation of global health security.

Progress Toward Eradication of Dracunculiasis - Worldwide, January 2022-June 2023.

The effort to eradicate Dracunculus medinensis, the etiologic agent of dracunculiasis, or Guinea worm disease, commenced at CDC in 1980. In 1986, with an estimated 3.5 million cases worldwide in 20 African and Asian countries, the World Health Assembly called for dracunculiasis elimination. The Guinea Worm Eradication Program (GWEP) was established to help countries with endemic dracunculiasis reach this goal. GWEP is led by The Carter Center and supported by partners that include the World Health Organization, UNICEF, and CDC. In 2012, D. medinensis infections were unexpectedly confirmed in Chadian dogs, and since then, infections in dogs, cats, and baboons have posed a new challenge for GWEP, as have ongoing civil unrest and insecurity in some areas. By 2022, dracunculiasis was endemic in five countries (Angola, Chad, Ethiopia, Mali, and South Sudan), with only 13 human cases identified, the lowest yearly total ever reported. Animal infections, however, were not declining at the same rate: 686 animal infections were reported in 2022, including 606 (88%) in dogs in Chad. Despite these unanticipated challenges as well as the COVID-19 pandemic, countries appear close to reaching the eradication goal. GWEP will continue working with country programs to address animal infections, civil unrest, and insecurity, that challenge the eradication of Guinea worm.

Understanding How Cationic Polymers' Properties Inform Toxic or Immunogenic Responses via Parametric Analysis.

Cationic polymers are widely used materials in diverse biotechnologies. Subtle variations in these polymers' properties can change them from exceptional delivery agents to toxic inflammatory hazards. Conventional screening strategies optimize for function in a specific application rather than observing how underlying polymer-cell interactions emerge from polymers' properties. An alternative approach is to map basic underlying responses, such as immunogenicity or toxicity, as a function of basic physicochemical parameters to inform the design of materials for a breadth of applications. To demonstrate the potential of this approach, we synthesized 107 polymers varied in charge, hydrophobicity, and molecular weight. We then screened this library for cytotoxic behavior and immunogenic responses to map how these physicochemical properties inform polymer-cell interactions. We identify three compositional regions of interest and use confocal microscopy to uncover the mechanisms behind the observed responses. Finally, immunogenic activity is confirmed in vivo. Highly cationic polymers disrupted the cellular plasma membrane to induce a toxic phenotype, while high molecular weight, hydrophobic polymers were uptaken by active transport to induce NLRP3 inflammasome activation, an immunogenic phenotype. Tertiary amine- and triethylene glycol-containing polymers did not invoke immunogenic or toxic responses. The framework described herein allows for the systematic characterization of new cationic materials with different physicochemical properties for applications ranging from drug and gene delivery to antimicrobial coatings and tissue scaffolds.

Evaluating the Effectiveness of Potential Interventions for Guinea Worm Disease in Dogs in Chad Using Simulations.

Guinea worm (GW) disease (or dracunculiasis) is currently transmitted among dogs in Chad, which presents risks for the human population. We studied how interventions implemented at different levels might reduce the spread of GW disease (geographically and over time) and what levels of interventions might accelerate elimination. We built a multiple-water-source agent-based simulation model to analyze the disease transmission among dogs in Chad, as well as in geographic district clusters, and validated it using local infection data. We considered two interventions: 1) tethering, where infected dogs are kept on a leash during periods of infectivity, and 2) Abate®, under which the water source is treated to reduce infectivity. Our results showed that elimination (0 dog infections) is most likely achieved within 5 years with extremely high levels of tethering (95%) and Abate (90%), when intervention levels are uniform across district clusters. We used an optimization model to determine an improved strategy, with intervention levels which minimize the number of dogs newly infected in the 6th year, under limitations on intervention levels across clusters; the number of dogs infected after 5 years of intervention could be reduced by approximately 220 dogs with an optimized strategy. Finally, we presented strategies that consider fairness based on intervention resource levels and outcomes. Increased tethering and Abate resources above historical levels are needed to achieve the target of GW disease elimination; optimization methods can inform how best to target limited resources and reach elimination faster.

Development of Masitinib Derivatives with Enhanced Mpro Ligand Efficiency and Reduced Cytotoxicity.

Recently, a high-throughput screen of 1900 clinically used drugs identified masitinib, an orally bioavailable tyrosine kinase inhibitor, as a potential treatment for COVID-19. Masitinib acts as a broad-spectrum inhibitor for human coronaviruses, including SARS-CoV-2 and several of its variants. In this work, we rely on atomistic molecular dynamics simulations with advanced sampling methods to develop a deeper understanding of masitinib's mechanism of Mpro inhibition. To improve the inhibitory efficiency and to increase the ligand selectivity for the viral target, we determined the minimal portion of the molecule (fragment) that is responsible for most of the interactions that arise within the masitinib-Mpro complex. We found that masitinib forms highly stable and specific H-bond interactions with Mpro through its pyridine and aminothiazole rings. Importantly, the interaction with His163 is a key anchoring point of the inhibitor, and its perturbation leads to ligand unbinding within nanoseconds. Based on these observations, a small library of rationally designed masitinib derivatives (M1-M5) was proposed. Our results show increased inhibitory efficiency and highly reduced cytotoxicity for the M3 and M4 derivatives compared to masitinib.

Cell-targeted vaccines: implications for adaptive immunity.

Recent advancements in immunology and chemistry have facilitated advancements in targeted vaccine technology. Targeting specific cell types, tissue locations, or receptors can allow for modulation of the adaptive immune response to vaccines. This review provides an overview of cellular targets of vaccines, suggests methods of targeting and downstream effects on immune responses, and summarizes general trends in the literature. Understanding the relationships between vaccine targets and subsequent adaptive immune responses is critical for effective vaccine design. This knowledge could facilitate design of more effective, disease-specialized vaccines.