Current understanding and knowledge gaps regarding wildlife as reservoirs of antimicrobial resistance.

Antimicrobial resistance (AMR) is a serious health issue shared across all One Health domains. Wildlife species represent a key intersection of the animal and environmental domains. They are a relevant but understudied reservoir and route of spread for AMR throughout the environment. Most wildlife AMR research thus far has focused on avian species, terrestrial mammals, and a selection of aquatic and marine species. Pathogens often identified in terrestrial wildlife include enteric zoonotic organisms such as Eschericia coli and Salmonella spp, in addition to nonenterics such as Staphylococci. Resistances have been commonly identified to antimicrobials important in veterinary and human medicine, including ß-lactams, tetracyclines, aminoglycosides, and macrolides. Our emerging understanding of the dynamics of AMR distribution across life on Earth provides further opportunities for us to assess the risk it poses to veterinary and human health. Future work will require prioritizing which wildlife most exacerbates and indicates AMR in domestic animals. However, decreasing prices and increasing ease for metagenomic sequencing allows for synergies with expanding wildlife viral disease surveillance. Improved understanding of how wildlife impacts veterinary and human healthcare may increase opportunities for related research funding and global equity in such research. The companion Currents in One Health article by Vezeau and Kahn, JAVMA, June 2024, addresses in further detail the routes of spread of AMR across different animal populations and actions that can be taken to mitigate AMR with special consideration for wildlife sources.

Spread and mitigation of antimicrobial resistance at the wildlife-urban and wildlife-livestock interfaces.

Antimicrobial resistance (AMR) is a health issue common to all One Health domains. Scientific understanding of what drives AMR and how it spreads is continually expanding. One such dimension of this expanding base of knowledge is the role wildlife populations play as reservoirs and spreaders of AMR. Indirect and direct sharing of resistant pathogens between wildlife and domestic animals occurs in a variety of ways across both the natural and built environment. Though AMR is found across much of the Earth's biome naturally, elevated levels in wildlife are largely attributed to the use of antimicrobials in human and veterinary medicine, along with other uses of antimicrobials in human industry. On the basis of current research, wildlife species appear to be net recipients of AMR overall. However, wildlife can carry and spread AMR across individual ecosystems and to other ecosystems via water, soil, arthropod vectors, and several other routes of conveyance. In addition to creating potential health issues for wildlife animals themselves, this potentially poses risks for both companion and production animals. This is especially due to urban/suburban and rural wildlife, respectively. If health practitioners and other stakeholders are adequately aware, measures can be taken to reduce risks across each interface discussed. The companion Currents in One Health article by Vezeau and Kahn, AJVR, June 2024, addresses in further detail the many wildlife reservoirs of AMR that are currently identified, as well as directions for further research.

STAT3 protects hematopoietic stem cells by preventing activation of a deleterious autocrine type-I interferon response.

Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, and interferon (IFN) pathways in Stat3-deficient HSPCs. Stat3-deficient LSKs accumulated γH2AX and showed increased expression of DNA sensors and type-I IFN (IFN-I), while treatment with A151-ODN inhibited expression of IFN-I and IFN-responsive genes. Further, the blockade of IFN-I receptor signaling suppressed aberrant cell cycling, STAT1 activation, and nuclear p53 accumulation. Collectively, our results show that STAT3 inhibits a deleterious autocrine IFN response in HSCs to maintain long-term HSC function. These data signify the importance of ensuring therapeutic STAT3 inhibitors are targeted specifically to diseased cells to avoid off-target loss of healthy HSPCs.

Who coined the term "One Health"? Cooperation amid the siloization.

This short communication is an effort to describe and elucidate the trajectory of the modern historical concept of "One Health." It is dedicated to the many integrated approaches of health closely related to One Health, while also recognizing the contribution and origination of One Health perspectives/notions from those that have led the way and spearheaded this movement while considering Indigenous cultures across the world. The effects of synergies of those involved in building these integrative approaches are potentially bigger and better lasting than the sum of the individual players. It is only through collaboration, cooperation and diplomacy that we can achieve impactful transformation to benefit health. In this commentary, we aim to appropriately and accurately describe how the current use of "One Health" came to be and who were the main players.

Automated detection of progressive speech changes in early Alzheimer's disease.

Speech and language changes occur in Alzheimer's disease (AD), but few studies have characterized their longitudinal course. We analyzed open-ended speech samples from a prodromal-to-mild AD cohort to develop a novel composite score to characterize progressive speech changes. Participant speech from the Clinical Dementia Rating (CDR) interview was analyzed to compute metrics reflecting speech and language characteristics. We determined the aspects of speech and language that exhibited significant longitudinal change over 18 months. Nine acoustic and linguistic measures were combined to create a novel composite score. The speech composite exhibited significant correlations with primary and secondary clinical endpoints and a similar effect size for detecting longitudinal change. Our results demonstrate the feasibility of using automated speech processing to characterize longitudinal change in early AD. Speech-based composite scores could be used to monitor change and detect response to treatment in future research. HIGHLIGHTS: Longitudinal speech samples were analyzed to characterize speech changes in early AD.Acoustic and linguistic measures showed significant change over 18 months.A novel speech composite score was computed to characterize longitudinal change.The speech composite correlated with primary and secondary trial endpoints.Automated speech analysis could facilitate remote, high frequency monitoring in AD.

STAT3 protects HSCs from intrinsic interferon signaling and loss of long-term blood-forming activity.

STAT3 function in hematopoietic stem and progenitor cells (HSPCs) has been difficult to discern as Stat3 deficiency in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. To address this, we established mixed bone marrow (BM) chimeric mice with CreER-mediated Stat3 deletion in 20% of the hematopoietic compartment. Stat3-deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM in contrast to Stat3-sufficient (CreER) controls. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells revealed altered transcriptional responses in Stat3-deficient hematopoietic stem cells (HSCs) and multipotent progenitors, including intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation, Stat3-deficient Lin-ckit+Sca1+ cells accumulated γH2AX over time. Following secondary BM transplantation, Stat3-deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs.

Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4-mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

STAT3 Inhibits Autocrine IFN Signaling in Type I Conventional Dendritic Cells.

Type I conventional dendritic cells (cDC1s) are an essential Ag-presenting population required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli regulate cDC1 function remain unclear. We previously demonstrated that the cytokine-responsive transcriptional regulator STAT3 inhibits polyinosinic:polycytidylic acid [poly(I:C)]-induced cDC1 maturation and cDC1-mediated antitumor immunity in murine breast cancer, indicating an intrinsic, suppressive role for STAT3 in cDC1s. To probe transcriptional mechanisms regulating cDC1 function, we generated novel RNA sequencing datasets representing poly(I:C)-, IL-10-, and STAT3-mediated gene expression responses in murine cDC1s. Bioinformatics analyses indicated that poly(I:C) stimulates multiple inflammatory pathways independent of STAT3, while IL-10-activated STAT3 uniquely inhibits the poly(I:C)-induced type I IFN (IFN-I) transcriptional response. We validated this mechanism using purified cDC1s deficient for STAT3 or IFN signaling. Our data reveal IL-10-activated STAT3 suppresses production of IFN-ß and IFN-γ, accrual of tyrosine phosphorylated STAT1, and IFN-stimulated gene expression in cDC1s after poly(I:C) exposure. Moreover, we found that maturation of cDC1s in response to poly(I:C) is dependent on the IFN-I receptor, but not the type II IFN receptor, or IFN-λ. Taken together, we elucidate an essential role for STAT3 in restraining autocrine IFN-I signaling in cDC1s elicited by poly(I:C) stimulation, and we provide novel RNA sequencing datasets that will aid in further delineating inflammatory and anti-inflammatory mechanisms in cDC1s.

Immune landscape of a genetically engineered murine model of glioma compared with human glioma.

Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that were predominantly myeloid cells (e.g., monocytes, macrophages, and microglia), with minor populations of T, B, and NK cells. When comparing spontaneous and implanted mouse samples, we found more neutrophils and T and NK cells in the implanted model. Neutrophils and T and NK cells were increased in abundance in samples derived from human high-grade glioma compared with those derived from low-grade glioma. Overall, our data demonstrate that our implanted and spontaneous QPP models recapitulate the immunosuppressive myeloid-dominant nature of the tumor microenvironment of human gliomas. Our model provides a suitable tool for investigating the complex immune compartment of gliomas.

Regulation and function of Id2 in plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-I) producing cells that promote anti-viral immune responses and contribute to autoimmunity. Development of pDCs requires the transcriptional regulator E2-2 and is opposed by inhibitor of DNA binding 2 (Id2). Prior work indicates Id2 is induced in pDCs upon maturation and may affect pDC IFN-I production via suppression of E2-2, suggesting an important yet uncharacterized role in this lineage. We found TLR7 agonists stimulate Id2 mRNA and protein expression in pDCs. We further show that transcriptional activation of Id2 is dependent on the E2 ubiquitin-conjugating enzyme Ubc13, but independent of IFN-I signaling in response to TLR7 agonist stimulation. Nonetheless, conditional Id2 depletion in pDCs indicates Id2 is dispensable for TLR7 agonist-induced maturation and inhibition of E2-2 expression. Thus, we identify new mechanisms of Id2 regulation by Ubc13, which may be relevant for understanding Id2 gene regulation in other contexts, while ruling out major roles for Id2 in pDC responses to TLR7 agonists.

Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.

Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti­programmed cell death 1 (anti­PD-1)­based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ­positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.

From the Approach to the Concept: One Health in Latin America-Experiences and Perspectives in Brazil, Chile, and Colombia.

Professionals throughout the world have been working to assess the interdisciplinary interaction and interdependence between health and wellbeing in a constantly changing environment. The One Health concept was developed to encourage sustainable collaborative partnerships and to promote optimal health for people, animals, plants, the environment, and the whole planet. The dissemination of scientific discoveries and policies, by working directly with diverse communities, has been one of the main goals for Global One Health. The One Health concept has also been referred or related to as "One Medicine, One Medicine-One Health, One World-One Health, EcoHealth," and Planetary Health," depending on each fundamental view and approach. In Latin America, despite the concept still being discussed among health professionals and educators, several One Health initiatives have been used daily for more than decades. One Health action has been applied especially in rural and underserved urban areas where low socioeconomic status, lack of health professionals, and scarcity of medical resources may require professionals to work together. Local communities from diverse social and economic statuses, including indigenous populations have been working with institutions and social organizations for many years, accomplishing results through grassroots movements. These "bottom-up" socio-community approaches have also been tools for the prevention and control of diseases, such practice has preceded the One Health concepts in Latin American countries. It is strongly believed that collaborative, multidisciplinary, political, and economic initiatives with prosocial focus may become investments toward obtaining significant results in the face of global, economic and health challenges; working for a healthier world with inclusivity, equity, and equality. In this study, it is briefly presented how the One Health approach has been initiated and developed in Latin America, highlighting the events and actions taken in Brazil, Chile, and Colombia.

Developing a one health approach by using a multi-dimensional matrix.

The One Health concept that human, animal, plant, environmental, and ecosystem health are linked provides a framework for examining and addressing complex health challenges. This framework can be represented as a multi-dimensional matrix that can be used as a tool to identify upstream drivers of disease potential in a concise, systematic, and comprehensive way. The matrix can involve up to four dimensions depending on users' needs. This paper describes and illustrates how the matrix tool might be used to facilitate systems thinking, enabling the development of effective and equitable public policies. The multidimensional One Health matrix tool will be used to examine, as an example, global human and animal fecal wastes. The fecal wastes are analyzed at the microbial and population levels over a timeframe of years. Political, social, and economic factors are part of the matrix and will be examined as well. The One Health matrix tool illustrates how foodborne illnesses, food insecurity, antimicrobial resistance, and climate change are inter-related. Understanding these inter-relationships is essential to develop the public policies needed to achieve many of the United Nations' Sustainable Development Goals.

Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rß). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.

Complexities in understanding antimicrobial resistance across domesticated animal, human, and environmental systems.

Antimicrobial resistance (AMR) is a significant threat to both human and animal health. The spread of AMR bacteria and genes across systems can occur through a myriad of pathways, both related and unrelated to agriculture, including via wastewater, soils, manure applications, direct exchange between humans and animals, and food exposure. Tracing origins and drivers of AMR bacteria and genes is challenging due to the array of contexts and the complexity of interactions overlapping health practice, microbiology, genetics, applied science and engineering, as well as social and human factors. Critically assessing the diverse and sometimes contradictory AMR literature is a valuable step in identifying tractable mitigation options to stem AMR spread. In this article we review research on the nonfoodborne spread of AMR, with a focus on domesticated animals and the environment and possible exposures to humans. Attention is especially placed on delineating possible sources and causes of AMR bacterial phenotypes, including underpinning the genetics important to human and animal health.

Critically important antibiotics: criteria and approaches for measuring and reducing their use in food animal agriculture.

Globally, increasing acquired antimicrobial resistance among pathogenic bacteria presents an urgent challenge to human and animal health. As a result, significant efforts, such as the One Health Initiative, are underway to curtail and optimize the use of critically important antimicrobials for human medicine in all applications, including food animal production. This review discusses the rationale behind multiple and competing "critically important antimicrobial" lists and their contexts as created by international, regional, and national organizations; identifies discrepancies among these lists; and describes issues surrounding risk management recommendations that have been made by regulatory organizations on the use of antibiotics in food animal production. A more harmonized approach to defining criticality in its various contexts (e.g., for human versus animal health, enteric diseases versus other systemic infections, and direct versus indirect selection of resistance) is needed in order to identify shared contextual features, aid in their translation into risk management, and identify the best ways to maintain the health of food animals, all while keeping in mind the wider risks of antimicrobial resistance, environmental impacts, and animal welfare considerations.

From farm management to bacteriophage therapy: strategies to reduce antibiotic use in animal agriculture.

To reduce the use of antibiotics in animal agriculture, a number of effective or commercially viable alternatives have been implemented by food animal producers or are under development. Perhaps the most well-established strategies are flock and herd management practices to mitigate disease introduction and spread, and, subsequently, reduce the need for antibiotic use. While vaccines in food animal production have been used to prevent both bacterial and viral diseases, but historically, most vaccines have targeted viral diseases. Though vaccines against viral diseases can help reduce the need for antibiotic use by controlling the spread of secondary bacterial infections, more recent vaccines under development specifically target bacteria. New developments in selecting and potentially tailoring bacteriophages provide a promising avenue for controlling pathogenic bacteria without the need for traditional small-molecule antibiotics. In this article we discuss these established and emerging strategies, which are anticipated to reduce the reliance on antibiotics in food animal production and should reduce the prevalence and transmission to humans of antimicrobial resistant bacteria from these systems.