Sociodemographic representation in randomized controlled trials for anxiety-related disorders in the U.S.: A systematic review (1993-2023).

Cognitive behavioral therapies have been identified as evidence-based treatments for anxiety-related disorders. However, data supporting the effectiveness of these treatments have been largely collected from participants with majoritized identities, potentially limiting the extent to which they can be considered "evidence-based" for clients from minoritized groups. The current review examined sociodemographic representation and quality of sociodemographic reporting in randomized controlled trials for anxiety-related disorders in the U.S. between 1993 and 2023. We conducted a systematic literature review of U.S.-based randomized controlled trials of cognitive behavioral therapies for anxiety-related disorders, extracted data on sociodemographic variables, and rated quality of reporting. Data from 55 eligible studies (N = 4492) indicated that white and female identities were overrepresented relative to the U.S. population, with variables like disability status, sexual orientation, and religious identification consistently ignored. In addition, quality of reporting was generally poor (mean = 3.6 out of 10), with many studies failing to account for demographic variables in their analyses or description of study limitations. Publication year, sample size, and NIH funding status did not significantly predict gender representation (% women), ethnoracial representation (% white), or quality of reporting. These findings underscore the importance of critically evaluating to whom "evidence-based" treatments apply and increasing diversity of clinical samples, to ensure that evidence-based treatments are inclusive. Recommendations for future research, clinical implications, and limitations are discussed.

Probing ligand conformation and net dimensionality in a series of tetraphenylethene-based metal-organic frameworks.

Tetraphenylethene-based ligands with lowered symmetry are promising building blocks for the construction of novel luminescent metal-organic frameworks (MOFs). However, few examples have been reported, and predicting the ligand conformation and the dimensionality of the resulting MOF remains challenging. In order to uncover how synthetic conditions and accessible ligand conformations may affect the resulting MOF structure, four new MOF structures were synthesized under solvothermal conditions using the meta-coordinated tetraphenylethene-based ligand m-ETTC and paddlewheel SBUs composed of Co(II), Cu(II), and Zn(II). WSU-10 (WSU = Washington State University) is formed with either Zn or Cu comprising stacked psuedo-2D layers. The dimensionality of WSU-10 can be intentionally increased through the addition of pyrazine as a pillar ligand into the synthesis, forming the 3D structure WSU-11. The third structure, WSU-20, is formed by the combination of Zn or Co with m-ETTC and is intrinsically 3D without the use of a pillar ligand; interestingly, this is the result of a distortion in the paddlewheel SBU. Finally, Cu was also found to form a new structure (WSU-12), which displays an m-ETTC conformation unique from that found in the other isolated MOFs. Structural features are compared across the series and a mechanistic relationship between WSU-10 and -20 is proposed, providing insight into the factors that can encourage the generation of frameworks with increased dimensionality.

Achieving Clearance of Drug-Resistant Bacterial Infection and Rapid Cutaneous Wound Regeneration Using an ROS-Balancing-Engineered Heterojunction.

Intractable infected microenvironments caused by drug-resistant bacteria stalls the normal course of wound healing. Sono-piezodynamic therapy (SPT) is harnessed to combat pathogenic bacteria, but the superabundant reactive oxygen species (ROS) generated during SPT inevitably provoke severe inflammatory response, hindering tissue regeneration. Consequently, an intelligent nanocatalytic membrane composed of poly(lactic-co-glycolic acid) (PLGA) and black phosphorus /V2C MXene bio-heterojunctions (2D2-bioHJs) is devised. Under ultrasonication, 2D2-bioHJs effectively eliminate drug-resistant bacteria by disrupting metabolism and electron transport chain (ETC). When ultrasonication ceases, they enable the elimination of SPT-generated ROS. The 2D2-bioHJs act as a "lever" that effectively achieves a balance between ROS generation and annihilation, delivering both antibacterial and anti-inflammatory properties to the engineered membrane. More importantly, in vivo assays corroborate that the nanocatalytic membranes transform the stalled chronic wound environment into a regenerative one by eradicating the bacterial population, dampening the NF-κB inflammatory pathway and promoting angiogenesis. As envisaged, this work demonstrates a novel tactic to arm membranes with programmed antibacterial and anti-inflammatory effects to remedy refractory infected wounds from drug-fast bacteria.

Uranyl uptake into metal-organic frameworks: a detailed X-ray structural analysis.

Metal-organic frameworks (MOF) are a subclass of porous framework materials that have been used for a wide variety of applications in sensing, catalysis, and remediation. Among these myriad applications is their remarkable ability to capture substances in a variety of environments ranging from benign to extreme. Among the most common and problematic substances found throughout the world's oceans and water supplies is [UO2]2+, a common mobile ion of uranium, which is found both naturally and as a result of anthropogenic activities, leading to problematic environmental contamination. While some MOFs possess high capability for the uptake of [UO2]2+, many more of the thousands of MOFs and their modifications that have been produced over the years have yet to be studied for their ability to uptake [UO2]2+. However, studying the thousands of MOFs and their modifications presents an incredibly difficult task. As such, a way to narrow down the numbers seems imperative. Herein, we evaluate the binding behaviors as well as identify the specific binding sites of [UO2]2+ incorporated into six different Zr MOFs to elucidate specific features that improve [UO2]2+ uptake. In doing so, we also present a method for the determination and verification of these binding sites by Anomalous wide-angle X-ray scattering, X-ray fluorescence, and X-ray absorption spectroscopy. This research not only presents a way for future research into the uptake of [UO2]2+ into MOFs to be conducted but also a means to evaluate MOFs more generally for the uptake of other compounds to be applied for environmental remediation and improvement of ecosystems globally.

Recent progress in electrode materials for micro-supercapacitors.

Micro-supercapacitors (MSCs) stand out in the field of micro energy storage devices due to their high power density, long cycle life, and environmental friendliness. The key to improving the electrochemical performance of MSCs is the selection of appropriate electrode materials. To date, both the composition and structure of electrode materials in MSCs have become a hot research topic, and it is urgent to compose a review to highlight the most important research achievements, major challenges, opportunities, and encouraging perspectives in this field. In this review, research background of MSCs is first reviewed followed by their working principles, structural classifications, and physiochemical and electrochemical characterization techniques. Next, various materials and preparation methods are summarized, and the relationship between the MSC performance and structure and composition of materials are discussed in depth. Finally, this review provides a comprehensive suggestion on accelerating the development of electrode materials to facilitate the commercialization of MSCs.

Predictors of non-offending caregiver support in cases of child sexual abuse.

BACKGROUND: In cases of child sexual abuse (CSA), a supportive non-offending caregiver (NOC) is important for the child's overall well-being and adjustment. NOC support is also predictive of CSA cases moving forward to prosecution. Limited research has studied CSA case factors in relation to NOC supportive behaviors across numerous support dimensions. OBJECTIVE: We investigated what case details predicted four different dimensions of caregiver support. PARTICIPANTS AND SETTINGS: In this secondary analysis, a sample of 500 CSA cases from four prosecutors' offices in one New England state from 2009 to 2013 were randomly selected and reviewed. METHOD: This study used regression analysis to test 13 case characteristics (e.g., disclosure of abuse, NOC's relationship to perpetrator) as predictors of NOC support dimensions: belief of victim, support of prosecution, protection of victim, and whether a child protective services neglect report was filed against the caregiver. RESULTS: When the perpetrator was their romantic partner, the NOC was less likely to protect and believe the child victim, yet more likely to support prosecution. NOCs were more likely to demonstrate belief when the child disclosed to them first. CONCLUSION: Our findings reveal the importance of the key case factors that are predictive of NOC support. This is the first study to examine these many case factors in relation to these four dimensions of support. Knowledge of these predictors can play an important role in better understanding the complexity of NOC support predictors and facilitating interventions designed to enhance such support.

Engineered Bio-Heterojunction Confers Extra- and Intracellular Bacterial Ferroptosis and Hunger-Triggered Cell Protection for Diabetic Wound Repair.

Nanomaterial-mediated ferroptosis has garnered considerable interest in the antibacterial field, as it invokes the disequilibrium of ion homeostasis and boosts lipid peroxidation in extra- and intracellular bacteria. However, current ferroptosis-associated antibacterial strategies indiscriminately pose damage to healthy cells, ultimately compromising their biocompatibility. To address this daunting issue, this work has designed a precise ferroptosis bio-heterojunction (F-bio-HJ) consisting of Fe2 O3 , Ti3 C2 -MXene, and glucose oxidase (GOx) to induce extra-intracellular bacteria-targeted ferroptosis for infected diabetic cutaneous regeneration. Fe2 O3 /Ti3 C2 -MXene@GOx (FMG) catalytically generates a considerable amount of ROS which assaults the membrane of extracellular bacteria, facilitating the permeation of synchronously generated Fe2+ /Fe3+ into bacteria under near-infrared (NIR) irradiation, causing planktonic bacterial death via ferroptosis, Fe2+ overload, and lipid peroxidation. Additionally, FMG facilitates intracellular bacterial ferroptosis by transporting Fe2+ into intracellular bacteria via inward ferroportin (FPN). With GOx consuming glucose, FMG creates hunger protection which helps macrophages escape cell ferroptosis by activating the adenosine 5'-monophosphate (AMP) activated protein kinase (AMPK) pathway. In vivo results authenticate that FMG boosts diabetic infectious cutaneous regeneration without triggering ferroptosis in normal cells. As envisaged, the proposed tactic provides a promising approach to combat intractable infections by precisely terminating extra-intracellular infection via steerable ferroptosis, thereby markedly elevating the biocompatibility of therapeutic ferroptosis-mediated strategies.

MXene-Decorated Nanofibrous Membrane with Programmed Antibacterial and Anti-Inflammatory Effects via Steering NF-κB Pathway for Infectious Cutaneous Regeneration.

Although antibiotic is still the main choice for antibacteria both in hospital and community, phototherapy has become a possibly one of the alternative approaches in the treatment of microbe-associated infections nowadays because of its considerable potential in effective eradication of pathogenic bacteria. However, overwhelming reactive oxygen species (ROS) generated from phototherapy inevitably provoke an inflammatory response, complicating the healing process. To address this outstanding issue, a MXene-decorated nanofibrious is devised that not only yield localized heat but also elevate ROS levels under near-infrared laser exposure ascribed to the synergistic photothermal/photodynamic effect, for potent bacterial inactivation. After being further loaded with aspirin, the nanofibrous membranes exhibit benign cytocompatibility, boosting cell growth and suppressing the (nuclear factor kappa-B ( NF-κB) signaling pathways through RNA sequencing analysis, indicating an excellent anti-inflammatory effect. Interestingly, in vivo investigations also corroborate that the nanofibrous membranes accelerate infectious cutaneous regeneration by efficiently killing pathogenic bacteria, promoting collagen deposition, boosting angiogenesis, and dampening inflammatory reaction via steering NF-κB pathway. As envisaged, this work furnishes a decorated nanofibrous membrane with programmed antibacterial and anti-inflammatory effects for remedy of refractory bacteria-invaded wound regeneration.

Unleashing the Potential of MXene-Based Flexible Materials for High-Performance Energy Storage Devices.

Since the initial discovery of Ti3 C2 a decade ago, there has been a significant surge of interest in 2D MXenes and MXene-based composites. This can be attributed to the remarkable intrinsic properties exhibited by MXenes, including metallic conductivity, abundant functional groups, unique layered microstructure, and the ability to control interlayer spacing. These properties contribute to the exceptional electrical and mechanical performance of MXenes, rendering them highly suitable for implementation as candidate materials in flexible and wearable energy storage devices. Recently, a substantial number of novel research has been dedicated to exploring MXene-based flexible materials with diverse functionalities and specifically designed structures, aiming to enhance the efficiency of energy storage systems. In this review, a comprehensive overview of the synthesis and fabrication strategies employed in the development of these diverse MXene-based materials is provided. Furthermore, an in-depth analysis of the energy storage applications exhibited by these innovative flexible materials, encompassing supercapacitors, Li-ion batteries, Li-S batteries, and other potential avenues, is conducted. In addition to presenting the current state of the field, the challenges encountered in the implementation of MXene-based flexible materials are also highlighted and insights are provided into future research directions and prospects.

Discernment of Children's True and False Memory Reports: Police Officers and Laypersons.

Adults' ability to accurately evaluate children's statements can have far-reaching consequences within the legal system. This study examined the evaluations of police officers ("experts") and laypersons ("nonexperts") when presented with videotaped interviews of children aged 3 and 5 years who provided either true or false reports or denials. Participants were drawn from several counties in the eastern United States. Children's interview statements fell within four statement types: accurate reports, false reports, accurate denials, and false denials. Both groups of participants displayed overbelief in false denials. Several control variables predicted accuracy, including children's age and children's race. A significant interaction emerged: Experts (vs. nonexperts) had greater odds of being accurate when judging false reports (vs. false denials). These findings highlight the challenges adults face when distinguishing between various types of children's statements. The results have important implications for legal contexts, emphasizing that fact finders need to be mindful of the risks associated with both overaccepting false denials and accepting false reports.

Enhanced Iodine Capture Using a Postsynthetically Modified Thione-Silver Zeolitic Imidazole Framework.

Efficient management of radionuclides that are released from various processes in the nuclear fuel cycle is of significant importance. Among these nuclides, radioactive iodine (mainly 129I and 131I) is a major concern due to the risk it poses to the environment and to human health; thus, the development of materials that can capture and safely store radioactive iodine is crucial. Herein, a novel silver-thione-functionalized zeolitic imidazole framework (ZIF) was synthesized via postsynthetic modification and assessed for its iodine uptake capabilities alongside the parent ZIF-8 and intermediate materials. A solvent-assisted ligand exchange procedure was used to replace the 2-methylimidazole linkers in ZIF-8 with 2-mercaptoimidazole, forming intermediate compound ZIF-8 = S, which was reacted with AgNO3 to yield the ZIF-8 = S-Ag+ composite for iodine uptake. Despite possessing the lowest BET surface area of the derivatives, the Ag-functionalized material demonstrated superior I2 adsorption in terms of both maximum capacity (550 g I2/mol) and rapid kinetics (50% loading achieved in 5 h, saturation in 50 h) compared to that of our pristine ZIF-8, which reached 450 g I2/mol after 150 h and 50% loading in 25 h. This improvement is attributed to the presence of the Ag+ ions, which provide a strong chemical driving force to form a stable Ag-I species. The results of this study contribute to a broader understanding of the strategies that can be employed to engineer adsorbents with robust iodine uptake behavior.

Engineered Bio-Heterojunction with Infection-Primed H2 S Liberation for Boosted Angiogenesis and Infectious Cutaneous Regeneration.

Photodynamic therapy (PDT) acts as a powerful weapon against infectious diseases for its enormous antimicrobial activity that quickly elicits storms of reactive oxygen species (ROS). Nevertheless, redundant ROS during treatment inevitably bring detriments in revascularization. To address this dilemma, an innovative P-N bio-heterojunction (bio-HJ) material consisting of p-type copper sulfide (p-CuS), n-type bismuth sulfide (n-Bi2 S3 ), and lactate oxidase (LOx) for effective treatment of recalcitrant infectious wounds by promoting angiogenesis is devised. LOx exhausts lactic acid accumulated in infection environment and converts it to hydrogen peroxide (H2 O2 ), which subsequently yields bactericidal hydroxyl radicals (·OH) via Fenton-like reactions. Ultimately, the P-N bio-HJs exert synergistic photothermal, photodynamic, and chemodynamic effects for rapid bacterial annihilation. Moreover, in vitro and RNA-seq analyses reveal that the crafted bio-HJs dramatically expedite the proliferation of L929 cells and promote angiogenesis by up-regulating angiogenic gene expression in hypoxia-inducible factor-1 (HIF-1) signaling pathway, which may ascribe to the evolution of H2 S in response to the infection microenvironment. Critically, results of in vivo experiments have authenticated that the bio-HJs significantly boost healing rates of full-thickness wounds by slaughtering bacteria, elevating angiogenesis, and promoting cytothesis. As envisioned, this work furnishes a novel tactic for the effective treatment of bacteria-invaded wound using H2 S-liberating P-N bio-HJs.

Predictors of Prosecutorial Decisions in Reports of Child Sexual Abuse.

A retrospective examination of 500 child sexual abuse reports to prosecutor's offices analyzed case progress and predictors of attrition, including details about alleged perpetrator(s), victim(s), their families, and other case characteristics. Less than one in five cases proceeded to prosecution. For the full sample, we describe all outcomes and differentiate prosecutors' decisions to (a) intake/close, (b) investigate/close, or (c) prosecute; these stages comprise a 3-level dependent variable. Because it is important to understand which variables are associated with progress to each stage, we examined unique predictors of the decision to "investigate," and to "prosecute." Our multivariate analyses examine 325 cases with a perpetrator aged 16 and older. Caregiver support and perpetrator age were significant predictors across all outcome variables, while other factors were barriers to the "prosecute" decision only. Results highlight the complexities of case characteristics that are important at different stages of prosecutorial decision-making and inform future interventions.

Pathways to Registered Nursing: Influences of Health-Related Work Experience and Education Financing.

A larger and more diverse registered nurse (RN) workforce in the U.S. is needed to meet growing demand and address social determinants of health and improve health equity. To improve understanding of pathways and barriers to becoming an RN, this study examined prior health care employment and financial assistance factors associated with completion of pre-licensure RN education programs, by initial entry degree (associate degree or bachelor of science in nursing) and across racial and ethnic groups, using the 2018 National Sample Survey of Registered Nurses. The study found higher percentages of associate degree-entry RNs held a health-related job prior to completing their initial RN program than did bachelor's degree entrants. Employer support for education financing as well as reliance on loans and scholarships increased among RNs graduating in 2000 and later, and reliance on self-financing was reported less frequently. Hispanic associate degree-entry RNs reported education financing from only federal loans more frequently compared with White RNs, and higher percentages of Black, multiracial, and "some other race" baccalaureate degree entry RNs accessed federal loans compared with White baccalaureate degree-entry RNs. These findings indicate diversifying the RN workforce should remain a priority to increase representation by underrepresented racial and ethnic groups. Equitable pathways into the RN profession will be facilitated and expedited through policies that overcome financial and social barriers that enable individuals from population groups underrepresented in the nursing workforce to identify with the RN role and route to the profession.

Mapping the effects of physical and chemical reduction parameters on local atomic distributions within bimetallic nanoparticles.

Bimetallic nanoparticles prove advantageous over their monometallic counterparts due to the tunable, hybrid properties that result from combining different atomic species in a controlled way. The favorable optical and catalytic properties resulting from AgAu nanoparticle formation have been widely attributed to the existence of Ag-Au bonds, the maximization of which assumes the formation of a homogeneous alloy. Despite the importance of atomic scale structure in these systems, synthetic studies are typically not paired with structural characterization at the atomic scale. Herein, a comprehensive synthetic exploration of physical and chemical reduction parameters of resulting nanoparticle products is complemented with thorough X-ray characterization to probe how these parameters affect atomic scale alloy distributions within AgAu nanoparticles. Presented evidence shows Ag is substantially underincorporated into nanoparticle constructs compared with solution Ag : Au ratios regardless of precursor : reductant ratio or volume of reductant added. Both Ag and Au exhibit significant local clustering, with Ag distributed preferentially towards the nanoparticle surface. Most significantly, the results of this investigation suggest that reduction parameters alone can affect the local alloy distributions and homogeneity within bimetallic nanoparticles, even when the ratio of metallic precursors remains constant. Overall, this investigation presents the ability to control alloy distributions using kinetics and provides new considerations for optimizing synthetic methods to produce functional bimetallic nanoparticles.

Deprivation Has Inconsistent Effects on Delay Discounting: A Review.

Delay discounting, the tendency for outcomes to be devalued as they are more temporally remote, has implications as a target for behavioral interventions. Because of these implications, it is important to understand how different states individuals may face, such as deprivation, influence the degree of delay discounting. Both dual systems models and state-trait views of delay discounting assume that deprivation may result in steeper delay discounting. Despite early inconsistencies and mixed results, researchers have sometimes asserted that deprivation increases delay discounting, with few qualifications. The aim of this review was to determine what empirical effect, if any, deprivation has on delay discounting. We considered many kinds of deprivation, such as deprivation from sleep, drugs, and food in humans and non-human animals. For 23 studies, we analyzed the effect of deprivation on delay discounting by computing effect sizes for the difference between delay discounting in a control, or baseline, condition and delay discounting in a deprived state. We discuss these 23 studies and other relevant studies found in our search in a narrative review. Overall, we found mixed effects of deprivation on delay discounting. The effect may depend on what type of deprivation participants faced. Effect sizes for deprivation types ranged from small for sleep deprivation (Hedge's gs between -0.21 and 0.07) to large for opiate deprivation (Hedge's gs between 0.42 and 1.72). We discuss possible reasons why the effect of deprivation on delay discounting may depend on deprivation type, including the use of imagined manipulations and deprivation intensity. The inconsistency in results across studies, even when comparing within the same type of deprivation, indicates that more experiments are needed to reach a consensus on the effects of deprivation on delay discounting. A basic understanding of how states affect delay discounting may inform translational efforts.

The Effects of Feeding Antibiotic on the Intestinal Microbiota of Weanling Pigs.

This study investigated the use of carbadox in the diet of nursery pigs. Ten pens of weanling piglets were assigned to 2 treatments: one containing carbadox and another without it. From days 21 to 35 of age, the first group of piglets was fed carbadox at 55 mg/kg of diet; followed by 27.5 mg/kg from days 36 to 49; and 0 mg/kg from days 50 to 63. The second group of pigs was fed a control diet without carbadox from days 21 to 63 of age. On days 35, 49, and 63, fecal samples were collected directly from the rectum of 2 piglets in each pen, and the samples were subjected to microbial DNA sequencing and metagenomic functional analysis using the 16S rRNA gene. Feed conversion from days 21 to 63 was improved (P = 0.04) in the group of piglets fed carbadox. Faith's phylogenetic diversity was similar (P = 0.89) for both groups of piglets on day 35, but it was diminished (P = 0.01) in the carbadox-fed group on day 49; however, following the complete removal of carbadox from their diets, this microbial diversity index was once again found to be similar (P = 0.27) in both groups on day 63. Likewise, abundances of Slackia, Peptococcus, Catenibacterium, Coprococcus, and Blautia were all similar between the two groups (P ≥ 0.40) on day 35, but were smaller in the carbadox group (P ≤ 0.05) on day 49; however, on day 63, abundances of all these genera were once again similar (P ≥ 0.29). Metabolic pathways involved in cellular growth, death, and genetic information processing (translation) were found to be similarly expressed in the microbiota of piglets from both groups on day 35 (P ≥ 0.52), but decreased in the carbadox group on day 49 (P ≤ 0.05), and were similar again in both groups on day 63 (P ≥ 0.51). These results revealed that feeding carbadox to piglets during the first 4 weeks after weaning significantly affected their fecal microbiotas; however, 2 weeks after the removal of carbadox, those changes tended to disappear, indicating that the shifts were carbadox-dependent.

Disrupting Bordetella Immunosuppression Reveals a Role for Eosinophils in Coordinating the Adaptive Immune Response in the Respiratory Tract.

Recent findings revealed pivotal roles for eosinophils in protection against parasitic and viral infections, as well as modulation of adaptive immune responses in the gastric mucosa. However, the known effects of eosinophils within the respiratory tract remain predominantly pathological, associated with allergy and asthma. Simulating natural respiratory infections in mice, we examined how efficient and well-adapted pathogens can block eosinophil functions that contribute to the immune response. Bordetella bronchiseptica, a natural pathogen of the mouse, uses the sigma factor btrS to regulate expression of mechanisms that interfere with eosinophil recruitment and function. When btrS is disrupted, immunomodulators are dysregulated, and eosinophils are recruited to the lungs, suggesting they may contribute to much more efficient generation of adaptive immunity induced by this mutant. Eosinophil-deficient mice failed to produce pro-inflammatory cytokines, to recruit lymphocytes, to organize lymphoid aggregates that resemble Bronchus Associated Lymphoid Tissue (BALT), to generate an effective antibody response, and to clear bacterial infection from the respiratory tract. Importantly, the failure of eosinophil-deficient mice to produce these lymphoid aggregates indicates that eosinophils can mediate the generation of an effective lymphoid response in the lungs. These data demonstrate that efficient respiratory pathogens can block eosinophil recruitment, to inhibit the generation of robust adaptive immune responses. They also suggest that some post-infection sequelae involving eosinophils, such as allergy and asthma, might be a consequence of bacterial mechanisms that manipulate their accumulation and/or function within the respiratory tract.

Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections.

Well-adapted pathogens have evolved to survive the many challenges of a robust immune response. Defending against all host antimicrobials simultaneously would be exceedingly difficult, if not impossible, so many co-evolved organisms utilize immunomodulatory tools to subvert, distract, and/or evade the host immune response. Bordetella spp. present many examples of the diversity of immunomodulators and an exceptional experimental system in which to study them. Recent advances in this experimental system suggest strategies for interventions that tweak immunity to disrupt bacterial immunomodulation, engaging more effective host immunity to better prevent and treat infections. Here we review advances in the understanding of respiratory pathogens, with special focus on Bordetella spp., and prospects for the use of immune-stimulatory interventions in the prevention and treatment of infection.

Enhancement of immune response against Bordetella spp. by disrupting immunomodulation.

Well-adapted pathogens must evade clearance by the host immune system and the study of how they do this has revealed myriad complex strategies and mechanisms. Classical bordetellae are very closely related subspecies that are known to modulate adaptive immunity in a variety of ways, permitting them to either persist for life or repeatedly infect the same host. Exploring the hypothesis that exposure to immune cells would cause bordetellae to induce expression of important immunomodulatory mechanisms, we identified a putative regulator of an immunomodulatory pathway. The deletion of btrS in B. bronchiseptica did not affect colonization or initial growth in the respiratory tract of mice, its natural host, but did increase activation of the inflammasome pathway, and recruitment of inflammatory cells. The mutant lacking btrS recruited many more B and T cells into the lungs, where they rapidly formed highly organized and distinctive Bronchial Associated Lymphoid Tissue (BALT) not induced by any wild type Bordetella species, and a much more rapid and strong antibody response than observed with any of these species. Immunity induced by the mutant was measurably more robust in all respiratory organs, providing completely sterilizing immunity that protected against challenge infections for many months. Moreover, the mutant induced sterilizing immunity against infection with other classical bordetellae, including B. pertussis and B. parapertussis, something the current vaccines do not provide. These findings reveal profound immunomodulation by bordetellae and demonstrate that by disrupting it much more robust protective immunity can be generated, providing a pathway to greatly improve vaccines and preventive treatments against these important pathogens.