The proteomic landscape of microglia in health and disease.

Microglia are the resident immune cells of the central nervous system (CNS) and as such play crucial roles in regulating brain homeostasis. Their presence in neurodegenerative diseases is known, with neurodegeneration-associated risk genes heavily expressed in microglia, highlighting their importance in contributing to disease pathogenesis. Transcriptomics studies have uncovered the heterogeneous landscape of microglia in health and disease, identifying important disease-associated signatures such as DAM, and insight into both the regional and temporal diversity of microglia phenotypes. Quantitative mass spectrometry methods are ever increasing in the field of neurodegeneration, utilised as ways to identify disease biomarkers and to gain deeper understanding of disease pathology. Proteins are the main mechanistic indicators of cellular function, yet discordance between transcript and proteomic findings has highlighted the need for in-depth proteomic phenotypic and functional analysis to fully understand disease kinetics at the cellular and molecular level. This review details the current progress of using proteomics to define microglia biology, the relationship between gene and protein expression in microglia, and the future of proteomics and emerging methods aiming to resolve heterogeneous cell landscapes.

Reducing the Antigen Prevalence Target Threshold for Stopping and Restarting Mass Drug Administration for Lymphatic Filariasis Elimination: A Model-Based Cost-effectiveness Simulation in Tanzania, India and Haiti.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) aims to reduce and maintain infection levels through mass drug administration (MDA), but there is evidence of ongoing transmission after MDA in areas where Culex mosquitoes are the main transmission vector, suggesting that a more stringent criterion is required for MDA decision making in these settings. METHODS: We use a transmission model to investigate how a lower prevalence threshold (<1% antigenemia [Ag] prevalence compared with <2% Ag prevalence) for MDA decision making would affect the probability of local elimination, health outcomes, the number of MDA rounds, including restarts, and program costs associated with MDA and surveys across different scenarios. To determine the cost-effectiveness of switching to a lower threshold, we simulated 65% and 80% MDA coverage of the total population for different willingness to pay per disability-adjusted life-year averted for India ($446.07), Tanzania ($389.83), and Haiti ($219.84). RESULTS: Our results suggest that with a lower Ag threshold, there is a small proportion of simulations where extra rounds are required to reach the target, but this also reduces the need to restart MDA later in the program. For 80% coverage, the lower threshold is cost-effective across all baseline prevalences for India, Tanzania, and Haiti. For 65% MDA coverage, the lower threshold is not cost-effective due to additional MDA rounds, although it increases the probability of local elimination. Valuing the benefits of elimination to align with the GPELF goals, we find that a willingness to pay per capita government expenditure of approximately $1000-$4000 for 1% increase in the probability of local elimination would be required to make a lower threshold cost-effective. CONCLUSIONS: Lower Ag thresholds for stopping MDAs generally mean a higher probability of local elimination, reducing long-term costs and health impacts. However, they may also lead to an increased number of MDA rounds required to reach the lower threshold and, therefore, increased short-term costs. Collectively, our analyses highlight that lower target Ag thresholds have the potential to assist programs in achieving lymphatic filariasis goals.

Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.

Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-ß pathology.

Microglia are central players in Alzheimer's disease pathology but analyzing microglial states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine cytokine response microglia or CRM response to oligomeric Aß oligomers. Genetic deletion of TREM2 or APOE as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other Alzheimer's disease risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in a multipronged response to Alzheimer's disease-related pathology, which should be taken into account in translational studies.

An analytically tractable, age-structured model of the impact of vector control on mosquito-transmitted infections.

Vector control is a vital tool utilised by malaria control and elimination programmes worldwide, and as such it is important that we can accurately quantify the expected public health impact of these methods. There are very few previous models that consider vector-control-induced changes in the age-structure of the vector population and the resulting impact on transmission. We analytically derive the steady-state solution of a novel age-structured deterministic compartmental model describing the mosquito feeding cycle, with mosquito age represented discretely by parity-the number of cycles (or successful bloodmeals) completed. Our key model output comprises an explicit, analytically tractable solution that can be used to directly quantify key transmission statistics, such as the effective reproductive ratio under control, Rc, and investigate the age-structured impact of vector control. Application of this model reinforces current knowledge that adult-acting interventions, such as indoor residual spraying of insecticides (IRS) or long-lasting insecticidal nets (LLINs), can be highly effective at reducing transmission, due to the dual effects of repelling and killing mosquitoes. We also demonstrate how larval measures can be implemented in addition to adult-acting measures to reduce Rc and mitigate the impact of waning insecticidal efficacy, as well as how mid-ranges of LLIN coverage are likely to experience the largest effect of reduced net integrity on transmission. We conclude that whilst well-maintained adult-acting vector control measures are substantially more effective than larval-based interventions, incorporating larval control in existing LLIN or IRS programmes could substantially reduce transmission and help mitigate any waning effects of adult-acting measures.

Contribution of the veterinary profession to the Australian animal health surveillance system and opportunities for future contributions.

Animal health surveillance is crucial for early detection of emergency animal diseases and effective responses. However, surveillance systems are complex and rely on the contributions of many animal health stakeholders. Veterinarians are key stakeholders in this system, given their role and skills in investigating, diagnosing, and reporting notifiable diseases. This study investigated the contribution of the veterinary workforce to the Australian animal health surveillance system and opportunities for future involvement. To achieve the aims of the study, an online cross-sectional survey among the veterinary profession was conducted. Descriptive statistics and regression analyses were used to provide an overview and investigate drivers of attitudes and practices of veterinarians in relation to animal health surveillance. A total of 311 usable responses were obtained, with 191 being from veterinarians who worked in private practice in the previous 12 months. Among private practitioners, 58.6% worked with companion animals, 34.0% were mixed practice veterinarians and 7.3% were equine veterinarians. Over half (56.6%) of all participants considered themselves active participants in the local animal disease management system. The level of confidence in understanding the reporting system and knowing and identifying signs of endemic and exotic diseases was moderate among those working in private practice, with companion animal veterinarians reporting the lowest levels of confidence (p < 0.05). Approximately 40% of veterinarians had taken samples for diagnosis for notifiable diseases in the last year, with just over 20% reporting a notifiable disease. Awareness of and participation in training and surveillance programs for animal diseases by veterinarians was low, with those working in private practice having lower levels of both awareness and participation for most programs. In relation to potential future contribution to the surveillance system, over half of participants reported being interested and available to undertake surveillance work on behalf of the government, with those in mixed practice reporting higher levels of interest (69.6%) compared to those in companion (49.5%) and equine practice (30.8%). However, key challenges identified were related to perceived conflict of interest, and tensions between client needs and government agenda, followed by profitability and suitability of the business. This study provides evidence of a significant existing contribution by the veterinary profession to the surveillance system, and the capacity and willingness to increase this contribution. However, there are gaps in awareness, confidence and participation, as well as financial and veterinary-client relationship challenges that should be considered in any future planning to strengthen the Australian surveillance system.

How correlations between treatment access and surveillance inclusion impact neglected tropical disease monitoring and evaluation-A simulated study.

Neglected tropical diseases (NTDs) largely impact marginalised communities living in tropical and subtropical regions. Mass drug administration is the leading intervention method for five NTDs; however, it is known that there is lack of access to treatment for some populations and demographic groups. It is also likely that those individuals without access to treatment are excluded from surveillance. It is important to consider the impacts of this on the overall success, and monitoring and evaluation (M&E) of intervention programmes. We use a detailed individual-based model of the infection dynamics of lymphatic filariasis to investigate the impact of excluded, untreated, and therefore unobserved groups on the true versus observed infection dynamics and subsequent intervention success. We simulate surveillance in four groups-the whole population eligible to receive treatment, the whole eligible population with access to treatment, the TAS focus of six- and seven-year-olds, and finally in >20-year-olds. We show that the surveillance group under observation has a significant impact on perceived dynamics. Exclusion to treatment and surveillance negatively impacts the probability of reaching public health goals, though in populations that do reach these goals there are no signals to indicate excluded groups. Increasingly restricted surveillance groups over-estimate the efficacy of MDA. The presence of non-treated groups cannot be inferred when surveillance is only occurring in the group receiving treatment.

A modelling analysis of a new multi-stage pathway for classifying achievement of public health milestones for leprosy.

Several countries have come close to eliminating leprosy, but leprosy cases continue to be detected at low levels. Due to the long, highly variable delay from infection to detection, the relationship between observed cases and transmission is uncertain. The World Health Organization's new technical guidance provides a path for countries to reach elimination. We use a simple probabilistic model to simulate the stochastic dynamics of detected cases as transmission declines, and evaluate progress through the new public health milestones. In simulations where transmission is halted, 5 years of zero incidence in autochthonous children, combined with 3 years of zero incidence in all ages is a flawed indicator that transmission has halted (54% correctly classified). A further 10 years of only occasional sporadic cases is associated with a high probability of having interrupted transmission (99%). If, however, transmission continues at extremely low levels, it is possible that cases could be misidentified as historic cases from the tail of the incubation period distribution, although misleadingly achieving all three milestones is unlikely (less than 1% probability across a 15-year period of ongoing low-level transmission). These results demonstrate the feasibility and challenges of a phased progression of milestones towards interruption of transmission, allowing assessment of programme status. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.

microRNA-132 regulates gene expression programs involved in microglial homeostasis.

microRNA-132 (miR-132), a known neuronal regulator, is one of the most robustly downregulated microRNAs (miRNAs) in the brain of Alzheimer's disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathologies, and also restores adult hippocampal neurogenesis and memory deficits. However, the functional pleiotropy of miRNAs requires in-depth analysis of the effects of miR-132 supplementation before it can be moved forward for AD therapy. We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics, and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus. We find that miR-132 modulation significantly affects the transition of microglia from a disease-associated to a homeostatic cell state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells.

Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent ISR in C9ORF72 FTD/ALS.

GGGGCC (G4C2) hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat is bidirectionally transcribed and confers gain of toxicity. However, the underlying toxic species is debated, and it is not clear whether antisense CCCCGG (C4G2) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9ORF72 antisense C4G2 repeat expanded RNAs trigger the activation of the PKR/eIF2α-dependent integrated stress response independent of dipeptide repeat proteins that are produced through repeat-associated non-AUG-initiated translation, leading to global translation inhibition and stress granule formation. Reducing PKR levels with either siRNA or morpholinos mitigates integrated stress response and toxicity caused by the antisense C4G2 RNAs in cell lines, primary neurons, and zebrafish. Increased phosphorylation of PKR/eIF2α is also observed in the frontal cortex of C9ORF72 FTD/ALS patients. Finally, only antisense C4G2, but not sense G4C2, repeat expanded RNAs robustly activate the PKR/eIF2α pathway and induce aberrant stress granule formation. These results provide a mechanism by which antisense C4G2 repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9ORF72 repeat expansions.

Associations of Socioeconomic Status With Disease Progression in African Americans With Early Rheumatoid Arthritis.

OBJECTIVE: In prior cross-sectional analyses of African American patients with rheumatoid arthritis (RA), measures of socioeconomic status (SES) were associated with clinical joint damage and poorer patient-reported outcome scores. The purpose of this study was to determine whether SES measures are associated with disease progression in a cohort of African American patients with early RA (<2 years duration). METHODS: We analyzed baseline SES and change in 60-month clinical radiographs and patient-reported outcomes data (n = 101 and 177, respectively) in individuals with early RA. SES measures were educational attainment, occupation, homeownership, household income, and block group poverty. Outcomes were based on radiographs (total erosion and joint space narrowing [JSN] scores on hands and feet) and patient-reported outcomes (pain, fatigue, disability, and learned helplessness). We used logistic regression with mixed effects accounting for study site to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Both low education and occupation status were associated with worsening pain (adjusted OR 5.86 [95% CI 3.05-11.3] and adjusted OR 2.55 [95% CI 1.54-4.21], respectively). Patients without a high-school diploma were more likely to have worsened reports of learned helplessness (OR 1.92 [95% CI 1.37-2.67]). Community measures of SES were also significantly associated with patient-reported outcomes score changes. Patients living in areas of block group poverty ≥20% were twice as likely to experience increased disability scores over 60 months of disease duration (OR 1.95 [95% CI 1.17-3.25]). We found no association between SES measures and erosion or JSN score progression. CONCLUSION: Low educational attainment and nonprofessional occupation status were associated with increased worsening of patient-reported outcomes. However, there were no corresponding increases in radiographically assessed erosion or JSN score progression.

Evaluating and mitigating the potential indirect effect of COVID-19 on control programmes for seven neglected tropical diseases: a modelling study.

BACKGROUND: In line with movement restrictions and physical distancing essential for the control of the COVID-19 pandemic, WHO recommended postponement of all neglected tropical disease (NTD) control activities that involve community-based surveys, active case finding, and mass drug administration in April, 2020. Following revised guidance later in 2020, and after interruptions to NTD programmes of varying lengths, NTD programmes gradually restarted in the context of an ongoing pandemic. However, ongoing challenges and service gaps have been reported. This study aimed to evaluate the potential effect of the programmatic interruptions and strategies to mitigate this effect. METHODS: For seven NTDs, namely soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis, trachoma, visceral leishmaniasis, and human African trypanosomiasis, we used mathematical transmission models to simulate the effect of programme interruptions on the dynamics of each of these diseases in different endemic settings. We also explored the potential benefit of implementing mitigation strategies, primarily in terms of minimising the delays to control targets. FINDINGS: We show that the effect of the COVID-19-induced interruption in terms of delay to achieving elimination goals might in some cases be much longer than the duration of the interruption. For schistosomiasis, onchocerciasis, trachoma, and visceral leishmaniasis, a mean delay of 2-3 years for a 1-year interruption is predicted in areas of highest prevalence. We also show that these delays can largely be mitigated by measures such as additional mass drug administration or enhanced case-finding. INTERPRETATION: The COVID-19 pandemic has brought infectious disease control to the forefront of global consciousness. It is essential that the NTDs, so long neglected in terms of research and financial support, are not overlooked, and remain a priority in health service planning and funding. FUNDING: Bill & Melinda Gates Foundation, Medical Research Council, and the UK Foreign, Commonwealth & Development Office.

Australian veterinarians' perspectives on the contribution of the veterinary workforce to the Australian animal health surveillance system.

This study investigated the involvement of private veterinarians in surveillance activities and the veterinary workforce's contribution to the Australian animal health surveillance system. The perception that there is overall a decreased engagement by veterinarians in surveillance outcomes at a time when there is increased need for bolstering of surveillance systems was investigated. Three key questions were considered: (1) What is the current contribution of private veterinarians to the Australian surveillance system? (2) What is the veterinary professions capacity to assume a more prominent role in surveillance? (3) What is the interest and ability of the veterinary profession in Australia to undertake this surveillance role now and into the future? Semi-structured telephone interviews were conducted with 17 private veterinarians with data analyzed qualitatively to identify key themes. Results demonstrate that private veterinarians are aware of their responsibilities and are engaged in surveillance activities at both formal and informal levels. The key challenges associated with current and future contributions were related to workload, remuneration, conflicts of interest and clarity over how responsibility for surveillance is shared amongst those involved in the system. The study has demonstrated that even amongst an engaged population, barriers do need to be addressed if private veterinarians are to be tasked with increasing their involvement in animal health surveillance activities.

Bacterial Metabolism and Transport Genes Are Associated with the Preference of Drosophila melanogaster for Dietary Yeast.

Many animal traits are influenced by their associated microorganisms ("microbiota"). To expand our understanding of the relationship between microbial genotype and host phenotype, we report an analysis of the influence of the microbiota on the dietary preference of the fruit fly Drosophila melanogaster. First, we confirmed through experiments on flies reared bacteria-free ("axenic") or in monoassociation with two different strains of bacteria that the microbiota significantly influences fruit fly dietary preference across a range of ratios of dietary yeast:dietary glucose. Then, focusing on microbiota-dependent changes in fly dietary preference for yeast (DPY), we performed a metagenome-wide association (MGWA) study to define microbial species specificity for this trait and to predict bacterial genes that influence it. In a subsequent mutant analysis, we confirmed that disrupting a subset of the MGWA-predicted genes influences fly DPY, including for genes involved in thiamine biosynthesis and glucose transport. Follow-up tests revealed that the bacterial influence on fly DPY did not depend on bacterial modification of the glucose or protein content of the fly diet, suggesting that the bacteria mediate their effects independent of the fly diet or through more specific dietary changes than broad ratios of protein and glucose. Together, these findings provide additional insight into bacterial determinants of host nutrition and behavior by revealing specific genetic disruptions that influence D. melanogaster DPY. IMPORTANCE Associated microorganisms ("microbiota") impact the physiology and behavior of their hosts, and defining the mechanisms underlying these interactions is a major gap in the field of host-microbe interactions. This study expands our understanding of how the microbiota can influence dietary preference for yeast (DPY) of a model host, Drosophila melanogaster. First, we show that fly preferences for a range of different dietary yeast:dietary glucose ratios vary significantly with the identity of the microbes that colonize the fruit flies. We then performed a metagenome-wide association study to identify candidate bacterial genes that contributed to some of these bacterial influences. We confirmed that disrupting some of the predicted genes, including genes involved in glucose transport and thiamine biosynthesis, resulted in changes to fly DPY and show that the influence of two of these genes is not through changes in dietary ratios of protein to glucose. Together, these efforts expand our understanding of the bacterial genetic influences on a feeding behavior of a model animal host.

Central Retinal Vein Occlusion Associated with Fibromuscular Dysplasia: A Case Report.

In this report, we detail a rare presentation of central retinal vein occlusion (CRVO) in a patient with fibromuscular dysplasia (FMD). A 45-year-old woman with a 12-year history of FMD presented to the ophthalmology clinic with symptoms and exam findings consistent with CRVO. Dilated fundus examination revealed disc edema, diffuse flame, and dot-blot hemorrhages, and tortuous, engorged retinal veins. The patient was diagnosed with CRVO, and she was treated with monthly anti-VEGF monoclonal antibody followed by a VEGF inhibitor. At her most recent follow-up, her macular edema was resolved and her visual acuity had markedly improved. FMD has been shown to rarely present with retinal manifestations, especially in patients with hypertension. This appears to be first case report to document CRVO in the context of known FMD. We suggest that CRVO be considered as a potential complication for young patients with FMD.

Targeting cellular senescence as a novel treatment for osteoarthritis.

Cellular senescence is associated with normal development and wound healing, but has also been implicated in the pathogenesis of numerous aging-related diseases including osteoarthritis (OA). Treatment strategies for OA are being developed that target senescent cells and the paracrine and autocrine secretions of the senescence-associated secretory phenotype (SASP). The field of potential therapies continues to expand as new mechanistic targets of cell senescence and the SASP are identified. Ongoing pre-clinical and clinical studies of drugs targeting cellular senescence yield significant promise, but have yet to demonstrate long-term efficacy. Therapeutic targeting of senescence is challenged by the diverse phenotypes of senescent cells, which can vary depending on age, species, tissue source, and type of physiologic stressor. Accordingly, there remains considerable demand for more studies to further develop and assess senotherapeutics as disease-modifying treatments for OA.

Mitochondrial Translocator Protein (TSPO) Expression in the Brain After Whole Body Gamma Irradiation.

The brain's early response to low dose ionizing radiation, as may be encountered during diagnostic procedures and space exploration, is not yet fully characterized. In the brain parenchyma, the mitochondrial translocator protein (TSPO) is constitutively expressed at low levels by endothelial cells, and can therefore be used to assess the integrity of the brain's vasculature. At the same time, the inducible expression of TSPO in activated microglia, the brain's intrinsic immune cells, is a regularly observed early indicator of subtle or incipient brain pathology. Here, we explored the use of TSPO as a biomarker of brain tissue injury following whole body irradiation. Post-radiation responses were measured in C57BL/6 wild type (Tspo +/+) and TSPO knockout (Tspo -/-) mice 48 h after single whole body gamma irradiations with low doses 0, 0.01, and 0.1 Gy and a high dose of 2 Gy. Additionally, post-radiation responses of primary microglial cell cultures were measured at 1, 4, 24, and 48 h at an irradiation dose range of 0 Gy-2 Gy. TSPO mRNA and protein expression in the brain showed a decreased trend after 0.01 Gy relative to sham-irradiated controls, but remained unchanged after higher doses. Immunohistochemistry confirmed subtle decreases in TSPO expression after 0.01 Gy in vascular endothelial cells of the hippocampal region and in ependymal cells, with no detectable changes following higher doses. Cytokine concentrations in plasma after whole body irradiation showed differential changes in IL-6 and IL-10 with some variations between Tspo-/- and Tspo +/+ animals. The in vitro measurements of TSPO in primary microglial cell cultures showed a significant reduction 1 h after low dose irradiation (0.01 Gy). In summary, acute low and high doses of gamma irradiation up to 2 Gy reduced TSPO expression in the brain's vascular compartment without de novo induction of TSPO expression in parenchymal microglia, while TSPO expression in directly irradiated, isolated, and thus highly activated microglia, too, was reduced after low dose irradiation. The potential link between TSPO, its role in mitochondrial energy metabolism and the selective radiation sensitivity, notably of cells with constitutive TSPO expression such as vascular endothelial cells, merits further exploration.

Contact tracing is an imperfect tool for controlling COVID-19 transmission and relies on population adherence.

Emerging evidence suggests that contact tracing has had limited success in the UK in reducing the R number across the COVID-19 pandemic. We investigate potential pitfalls and areas for improvement by extending an existing branching process contact tracing model, adding diagnostic testing and refining parameter estimates. Our results demonstrate that reporting and adherence are the most important predictors of programme impact but tracing coverage and speed plus diagnostic sensitivity also play an important role. We conclude that well-implemented contact tracing could bring small but potentially important benefits to controlling and preventing outbreaks, providing up to a 15% reduction in R. We reaffirm that contact tracing is not currently appropriate as the sole control measure.

Conservation of Earth's biodiversity is embedded in Indigenous fire stewardship.

Increasingly, severe wildfires have led to declines in biodiversity across all of Earth's vegetated biomes [D. B. McWethy et al., Nat. Sustain. 2, 797-804 (2019)]. Unfortunately, the displacement of Indigenous peoples and place-based societies that rely on and routinely practice fire stewardship has resulted in significant declines in biodiversity and the functional roles of people in shaping pyrodiverse systems [R. Bliege Bird et al., Proc. Natl. Acad. Sci. U.S.A. 117, 12904-12914 (2020)]. With the aim of assessing the impacts of Indigenous fire stewardship on biodiversity and species function across Earth's major terrestrial biomes, we conducted a review of relevant primary data papers published from 1900 to present. We examined how the frequency, seasonality, and severity of human-ignited fires can improve or reduce reported metrics of biodiversity and habitat heterogeneity as well as changes to species composition across a range of taxa and spatial and temporal scales. A total of 79% of applicable studies reported increases in biodiversity as a result of fire stewardship, and 63% concluded that habitat heterogeneity was increased by the use of fire. All studies reported that fire stewardship occurred outside of the window of uncontrollable fire activity, and plants (woody and nonwoody vegetation) were the most intensively studied life forms. Three studies reported declines in biodiversity associated with increases in the use of high-severity fire as a result of the disruption of Indigenous-controlled fire regimes with the onset of colonization. Supporting Indigenous-led fire stewardship can assist with reviving important cultural practices while protecting human communities from increasingly severe wildfires, enhancing biodiversity, and increasing ecosystem heterogeneity.