Division of Infectious Diseases, Research Labs

Abstract

Vaccination with rVSV-ZEBOV is highly effective against Ebola virus, but protection against Bundibugyo virus (BDBV) is unproven. We evaluated the relative population impact and dose efficiency of a partially cross-protective hypothetical vaccine under operationally realistic constraints during a BDBV outbreak.We developed a stochastic transmission model on a clustered household-community contact network with empirically realistic local structure, calibrated to 2026 DR Congo BDBV outbreak data. Time-varying effective reproduction numbers were estimated using a Bayesian renewal model. We evaluated case detection, isolation, contact tracing, reactive ring vaccination (Ring 1: direct contacts of the index case; Ring 2: contacts of contacts), and community vaccination (20-80% coverage). Base-case vaccine effectiveness was 45% and included post-exposure protection against disease and mortality. Primary outcomes were mortality and incidence reductions, total doses, and dose efficiency (doses per death averted) over 90 days, evaluated in a probabilistic sensitivity analysis with 10 000 matched stochastic replicates per strategy.Compared with base operations alone (30% detection, 30% tracing), enhanced operations alone (70% detection, 80% tracing) reduced expected mortality by 81·6% (95% uncertainty interval 73·1-87·7). Reactive Ring 2 vaccination under base operations reduced mortality by 24·6% (18·0-29·6), requiring 35·1 doses per death averted. Added to enhanced operations, Ring 2 vaccination reduced mortality by 83·6% overall (76·4-89·0), an incremental benefit of 10·5% (6·2-15·6) beyond enhanced operations alone. Community vaccination at 20%, 40%, 60%, and 80% coverage reduced mortality by 44·7% (34·8-52·5), 67·4% (56·2-74·3), 79·8% (70·4-85·3), and 86·6% (79·2-90·4), respectively, requiring 53·8-111·4 doses per death averted.Strengthened case finding, contact tracing, and isolation averted most deaths even without vaccination. Once these operations were strong, reactive ring vaccination added a modest further benefit, whereas rapid community vaccination produced the largest reductions in simulated scenarios but required substantially more doses. A partially protective BDBV vaccine's population-level value will depend principally on rapid, broad delivery.Canadian Institutes of Health Research.For the French translation of the abstract see Supplementary Materials section.

View details for DOI 10.1016/S1473-3099(26)00464-0

View details for PubMedID 42685736

Abstract

Tuberculosis control efforts have traditionally targeted symptomatic individuals; however, the role of asymptomatic cases in sustaining transmission is increasingly recognised. We aimed to quantify the contribution of asymptomatic tuberculosis to recent transmission using genomic and epidemiological data from a high-transmission setting.We conducted a retrospective genomic epidemiology study of Mycobacterium tuberculosis isolates collected in Mato Grosso do Sul, Brazil, between Aug 25, 2008, and March 19, 2024. Available isolates underwent whole-genome sequencing. Demographic, clinical, incarceration history, and laboratory metadata were obtained from surveillance records. From Jan 1, 2017, to March 19, 2024, active case finding was conducted in the state's three largest prisons (all male-only facilities), during which sputum samples were collected from individuals irrespective of symptoms and tested using GeneXpert and culture. Comparisons of transmission between individuals with and without symptoms were restricted to individuals who were incarcerated and were identified through active case finding and for whom high-quality, M tuberculosis lineage 4 genomes were available. Metrics of recent transmission included phylogenetic clustering, time-scaled haplotype density (THD), local branching index (LBI), and transmission probabilities inferred using Bayesian Reconstruction and Evolutionary Analysis of Transmission Histories.4448 tuberculosis cases were notified in Mato Grosso do Sul in 2008-24. After excluding cases for which M tuberculosis isolates were not available or had low sequencing quality, who had contaminated cultures or mixed infection, or who were infected with non-lineage 4 M tuberculosis, we included 2362 lineage 4 M tuberculosis isolates with high-quality genome sequences. 1849 (78·3%) of 2362 isolates were part of a genomic cluster. Among 2362 individuals with tuberculosis, 1137 (48·1%) were incarcerated at diagnosis. Of these individuals, 505 were identified through active case finding in three male-only prisons. The median age was 30 years (IQR 25-37); 304 (60·2%) had mixed ethnicity, 90 (17·8%) were White, 56 (11·1%) were Black, 13 (2·6%) were Indigenous, and six (1·2%) were Asian. 277 (54·9%) had symptomatic disease and 228 (45·1%) had asymptomatic tuberculosis. There were no significant differences between symptomatic and asymptomatic individuals in phylogenetic clustering (213 [76·9%] of 277 vs 195 [85·5%] of 228; p=0·37), THD (median 0·39 [IQR 0·06-0·62] vs 0·50 [0·09-0·65]; p=0·12), or LBI (0·00863 [0·00810-0·00988] vs 0·00871 [0·00829-0·01020]; p=0·088). Bayesian transmission trees showed no significant difference in the number of secondary infections inferred from symptomatic compared with asymptomatic individuals (p=0·56). These findings were consistent across genomic clusters and robust to model assumptions.We identified no differences in transmission between individuals who were symptomatic and those who were asymptomatic using multiple genomic measures. In this high-transmission setting, where systematic screening is implemented, our findings indicate that asymptomatic tuberculosis substantially contributes to tuberculosis transmission at the population level. These results suggest that symptom-based case detection alone is likely to be insufficient to interrupt transmission and highlight the importance of expanded screening strategies in high-risk populations.US National Institutes of Health and the Brazilian National Research Council (CNPq).

View details for DOI 10.1016/j.lanmic.2026.101407

View details for PubMedID 42276094

View details for DOI 10.1001/jama.2026.3719

View details for PubMedID 41989771

Abstract

Mycobacterium tuberculosis complex (MTBC) species evolve slowly, so isolates from individuals linked in transmission often have identical or nearly identical genomes, making it difficult to reconstruct transmission chains. Finding additional sources of shared MTBC variation could help overcome this problem. Previous studies have reported MTBC diversity within infected individuals; however, whether within-host variation improves transmission inferences remains unclear. Here, we aimed to quantify within-host MTBC variation and assess whether such information improves transmission inferences.We conducted a retrospective genomic epidemiology study in which we reanalysed publicly available sequence data from household transmission studies published in PubMed from database inception until Jan 31, 2024, for which both genomic and epidemiological contact data were available, using household membership as a proxy for transmission linkage. We quantified minority variants (ie, positions with two or more alleles each supported by at least five-fold coverage and with a minor allele frequency of 1% or more) outside of PE and PPE genes, within individual samples and shared across samples. We used receiver operator characteristic (ROC) curves to compare the performance of a general linear model for household membership that included shared minority variants and one that included only fixed genetic differences.We identified three MTBC household transmission studies with publicly available whole-genome sequencing data and epidemiological linkages: a household transmission study in Vitória, Brazil (Colangeli et al), a retrospective population-based study of paediatric tuberculosis in British Columbia, Canada (Guthrie et al), and a retrospective population-based study in Oxfordshire, England (Walker et al). We found moderate levels of minority variation present in MTBC sequence data from cultured isolates that varied significantly across studies: mean 168·6 minority variants (95% CI 151·4-185·9) for the Colangeli et al dataset, 5·8 (1·5-10·2) for Guthrie et al (p<0·0001, Wilcoxon rank sum test, vs Colangeli et al), and 7·1 (2·4-11·9) for Walker et al (p<0·0001, Wilcoxon rank sum test, vs Colangeli et al). Isolates from household pairs shared more minority variants than did randomly selected pairs of isolates: mean 97·7 shared minority variants (79·1-116·3) versus 9·8 (8·6-11·0) in Colangeli et al, 0·8 (0·1-1·5) versus 0·2 (0·1-0·2) in Guthrie et al, and 0·7 (0·1-1·3) versus 0·2 (0·2-0·2) in Walker et al (all p<0·0001, Wilcoxon rank sum test). Shared within-host variation was significantly associated with household membership (odds ratio 1·51 [95% CI 1·30-1·71], p<0·0001), for one standard deviation increase in shared minority variants. Models that included shared within-host variation versus models without within-host variation improved the accuracy of predicting household membership in all three studies: area under the ROC curve 0·95 versus 0·92 for the Colangeli et al study, 0·99 versus 0·95 for the Guthrie et al study, and 0·93 versus 0·91 for the Walker et al study.Within-host MTBC variation persists through culture of sputum and could enhance the resolution of transmission inferences. The substantial differences in minority variation recovered across studies highlight the need to optimise approaches to recover and incorporate within-host variation into automated phylogenetic and transmission inference.National Institutes of Health.

View details for DOI 10.1016/j.lanmic.2024.06.003

View details for PubMedID 39615498

Abstract

At this stage in the COVID-19 pandemic, most infections are "breakthrough" infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.

View details for DOI 10.1126/scitranslmed.adq1086

View details for PubMedID 39879318

Abstract

Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor-β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced TGFB1 expression. Females who developed LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced ETS1 expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that ETS1 alterations may drive aberrantly elevated T helper cell 2-like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.

View details for DOI 10.1126/scitranslmed.adr1032

View details for PubMedID 39536117

Abstract

Inference of cell-cell communication from single-cell RNA sequencing data is a powerful technique to uncover intercellular communication pathways, yet existing methods perform this analysis at the level of the cell type or cluster, discarding single-cell-level information. Here we present Scriabin, a flexible and scalable framework for comparative analysis of cell-cell communication at single-cell resolution that is performed without cell aggregation or downsampling. We use multiple published atlas-scale datasets, genetic perturbation screens and direct experimental validation to show that Scriabin accurately recovers expected cell-cell communication edges and identifies communication networks that can be obscured by agglomerative methods. Additionally, we use spatial transcriptomic data to show that Scriabin can uncover spatial features of interaction from dissociated data alone. Finally, we demonstrate applications to longitudinal datasets to follow communication pathways operating between timepoints. Our approach represents a broadly applicable strategy to reveal the full structure of niche-phenotype relationships in health and disease.

View details for DOI 10.1038/s41587-023-01782-z

View details for PubMedID 37169965

View details for PubMedCentralID 8104132

Abstract

Natural killer (NK) cells are cytotoxic effector cells that target and lyse virally infected cells; many viruses therefore encode mechanisms to escape such NK cell killing. Here, we interrogate the ability of SARS-CoV-2 to modulate NK cell recognition and lysis of infected cells. We find that NK cells exhibit poor cytotoxic responses against SARS-CoV-2-infected targets, preferentially killing uninfected bystander cells. We demonstrate that this escape is driven by downregulation of ligands for the activating receptor NKG2D (NKG2D-L). Indeed, early in viral infection, prior to NKG2D-L downregulation, NK cells are able to target and kill infected cells; however, this ability is lost as viral proteins are expressed. Finally, we find that SARS-CoV-2 non-structural protein 1 (Nsp1) mediates downregulation of NKG2D-L and that Nsp1 alone is sufficient to confer resistance to NK cell killing. Collectively, our work demonstrates that SARS-CoV-2 evades direct NK cell cytotoxicity and describes a mechanism by which this occurs.

View details for DOI 10.1016/j.celrep.2022.111892

View details for PubMedID 36543165

Abstract

Bacteriophage (phage) therapy is a promising therapeutic modality for multidrug-resistant bacterial infections, but its application is mainly limited to personalized therapy due to the narrow host range of individual phages. While phage cocktails targeting all possible bacterial receptors could theoretically confer broad coverage, the extensive diversity of bacteria and the complexity of phage-phage interactions render this approach challenging. Here, using screening protocols for identifying "complementarity groups" of phages using non-redundant receptors, we generate effective, broad-range phage cocktails that prevent the emergence of bacterial resistance. We also discover characteristic interactions between phage complementarity groups and particular antibiotic classes, facilitating the prediction of phage-antibiotic as well as phage-phage interactions. Using this strategy, we create three phage-antibiotic cocktails, each demonstrating efficacy against ≥96% of 153 Pseudomonas aeruginosa clinical isolates, including biofilm cultures, and demonstrate comparable efficacy in an in vivo wound infection model. We similarly develop effective Staphylococcus aureus phage-antibiotic cocktails and demonstrate their utility of combined cocktails against polymicrobial (mixed P. aeruginosa/S. aureus) cultures, highlighting the broad applicability of this approach. These studies establish a blueprint for the development of effective, broad-spectrum phage-antibiotic cocktails, paving the way for off-the-shelf phage-based therapeutics to combat multidrug-resistant bacterial infections.

View details for DOI 10.1038/s41467-024-53994-9

View details for PubMedID 39609398

View details for PubMedCentralID 11153159

Abstract

Bacteriophages, viruses that infect bacteria, have great specificity for their bacterial hosts at the strain and species level. However, the relationship between the phageome and associated bacterial population dynamics is unclear. Here we generated a computational pipeline to identify sequences associated with bacteriophages and their bacterial hosts in cell-free DNA from plasma samples. Analysis of two independent cohorts, including a Stanford Cohort of 61 septic patients and 10 controls and the SeqStudy cohort of 224 septic patients and 167 controls, reveals a circulating phageome in the plasma of all sampled individuals. Moreover, infection is associated with overrepresentation of pathogen-specific phages, allowing for identification of bacterial pathogens. We find that information on phage diversity enables identification of the bacteria that produced these phages, including pathovariant strains of Escherichia coli. Phage sequences can likewise be used to distinguish between closely related bacterial species such as Staphylococcus aureus, a frequent pathogen, and coagulase-negative Staphylococcus, a frequent contaminant. Phage cell-free DNA may have utility in studying bacterial infections.

View details for DOI 10.1038/s41564-023-01406-x

View details for PubMedID 37308590

View details for PubMedCentralID 5594678

Abstract

Chronic wounds infected by Pseudomonas aeruginosa (Pa) are characterized by disease progression and increased mortality. We reveal Pf, a bacteriophage produced by Pa that delays healing of chronically infected wounds in human subjects and animal models of disease. Interestingly, impairment of wound closure by Pf is independent of its effects on Pa pathogenesis. Rather, Pf impedes keratinocyte migration, which is essential for wound healing, through direct inhibition of CXCL1 signaling. In support of these findings, a prospective cohort study of 36 human patients with chronic Pa wound infections reveals that wounds infected with Pf-positive strains of Pa are more likely to progress in size compared with wounds infected with Pf-negative strains. Together, these data implicate Pf phage in the delayed wound healing associated with Pa infection through direct manipulation of mammalian cells. These findings suggest Pf may have potential as a biomarker and therapeutic target in chronic wounds.

View details for DOI 10.1016/j.xcrm.2022.100656

View details for PubMedID 35732145

View details for DOI 10.1126/scitranslmed.aau9748

View details for Web of Science ID 000465116400003

Abstract

Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)- and TIR domain-containing adapter-inducing interferon-β (TRIF)-dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.

View details for PubMedID 30923196

Abstract

Placental malaria disproportionately affects primigravid women and is a leading cause of morbidity in endemic settings. IgG specific to VAR2CSA, a placenta-binding Plasmodium falciparum protein, accumulates with successive pregnancies, but protective mechanisms remain incompletely understood. We investigated whether natural killer antibody-dependent cellular activation (NK-ADCA) was acquired in a gravidity-dependent manner and associated with improved birth outcomes.We characterised second trimester NK-ADCA and VAR2CSA-specific antibody features among pregnant women in Eastern Uganda (NCT04336189). NK-ADCA (n = 53) against VAR2CSA-expressing P. falciparum-infected erythrocytes was assessed using primary NK cells with autologous or pooled donor plasma with characterised IgG Fc-fucosylation profiles. VAR2CSA-specific IgG abundance and Fc-fucosylation (n = 71) were quantified by ELISA and mass spectrometry. Responses were compared across gravidity and associations with placental malaria and birth weight determined.NK-ADCA increased significantly with gravidity (median 31.0% in multigravida [n = 20] vs. 11.7 in primigravid [n = 18], p = 0.0014) and correlated with reduced placental malaria severity (rs = -0.28, p = 0.043) and higher birth weight (rs = 0.52, p = 1 × 10-4). NK cell phenotypes did not differ across gravidities; instead, gravidity-dependent NK-ADCA was associated with VAR2CSA-specific IgG abundance (rs = 0.50, p = 0.00014) and reduced Fc-fucosylation (rs = -0.69, p = 1.2 × 10-8). Depletion of VAR2CSA-specific antibodies reduced NK-ADCA in multigravid but not primigravid plasma. A CD56neg adaptive-like NK subset (CD85j+FcεRIγ-NKG2C-) mediated most NK-ADCA and was preferentially activated by Fc-afucosylated antibodies.Gravidity-dependent protection against placental malaria was associated with enhanced NK-ADCA driven by accumulation of Fc-afucosylated VAR2CSA-specific antibodies, identifying NK-ADCA as a potentially important component of protective immunity to placental malaria.This work was supported by the National Institutes of Health, the Blavatnik Family Foundation, the Stanford University Office of the Vice Provost for Graduate Education, the Stanford Maternal and Child Health Research Institute, and the Danish Research Council for Development Research.

View details for DOI 10.1016/j.ebiom.2026.106446

View details for PubMedID 42660020

Abstract

Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells capable of long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical knowledge gap, we first performed scRNA-seq on gated cell populations and validated CXCR6+ CD127- as new phenotypic markers to enrich for bona-fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127- Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFNγ during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFNγ, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127- Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.

View details for DOI 10.1172/JCI200628

View details for PubMedID 42084919

Abstract

Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin-piperaquine (IPTp-DP) is more effective than sulfadoxine-pyrimethamine (IPTp-SP) at reducing the burden of malaria in pregnancy in settings with high SP resistance. Paradoxically, IPTp-DP has been associated with lower birth weights compared with IPTp-SP. Whether the impacts of IPTp-DP extend after birth is unknown.We conducted a double-blind randomized controlled trial to compare malaria burden and growth among infants born to mothers who were randomized to monthly IPTp-SP, IPTp-DP, or IPTp-DP+SP. Infants were followed to 12 months of age by passive and active surveillance. The primary outcome was clinical malaria incidence; secondary outcomes included parasite prevalence by microscopy or quantitative PCR, and infant growth outcomes.Among 871 infants enrolled, there were 667 episodes of clinical malaria. Compared to infants whose mothers received IPTp-SP, malaria incidence was similar in infants whose mothers received IPTp-DP (incidence rate ratio [IRR] 1.04, 95% confidence interval (CI) 0.78-1.38) or IPTp-DP+SP (IRR=0.93, 95% CI 0.68-1.26). Overall parasite prevalence at monthly visits was 21.8%. Parasite prevalence was also similar between groups. The prevalence of wasting at birth was higher in infants whose mothers received IPTp-DP+SP (PR= 2.30, 95% CI 1.07, 4.97) or IPTp-DP (RR= 2.25, 95% CI 1.03, 4.94) than those that received IPTp-SP, but differences between groups resolved by 3-6 months of age.There were no significant differences in infant outcomes between the three IPTp arms apart from a transiently increased risk of wasting among infants born to mothers who received DP-containing IPTp regimens.

View details for DOI 10.1093/cid/ciag253

View details for PubMedID 42007686

Abstract

Vaccine effectiveness against malaria is dramatically reduced in malaria-exposed compared to malaria-naïve populations, potentially due to altered immune responses in secondary lymphoid organs following repeated infection. Newly developed human tonsil and spleen organoids, which replicate key features of B and T cell immunity, provide an exciting opportunity to overcome challenges of other models and to improve our understanding of innate-adaptive interactions in lymphoid tissue. The objectives of this study were to use these organoids to investigate the impact of malaria parasites on 1) cells within lymphoid tissues and 2) responses to a heterologous antigen. When we exposed organoids from malaria-naïve donors to Plasmodium falciparum-infected red blood cells (iRBC), we observed that iRBC exposure did not disrupt organoid formation and significantly increased Vδ2 + γδ T cell frequencies in both tonsil and spleen organoids at multiple timepoints. Single-cell RNA/TCR sequencing revealed that iRBC-responsive Vδ2 + T cells in organoids were clonally expanded and exhibited activated, cytotoxic phenotypes with upregulated expression of granzymes, interferon-stimulated genes, and antigen presentation machinery. TCR repertoire analysis demonstrated that malaria exposure drove clonal expansion of cytotoxic Vδ2 + T cells, contrasting with the diverse, smaller clones observed in control conditions. To validate these findings, we analyzed tonsils from Ugandan children with asymptomatic parasitemia and found expanded Vδ2 + T cells with enhanced cytotoxic potential compared to uninfected controls. When we tested whether malaria pre-exposure affected subsequent recall responses to influenza vaccine, malaria pre-exposure or γδ T cell depletion did not significantly alter cellular frequencies or influenza-specific antibody responses in most donors, though modest reductions were observed in some individuals. This work demonstrates the utility of human lymphoid organoids for studying malaria-host interactions and provides novel insights into Vδ2 + T cell biology, including evidence for clonal expansion and cytotoxic differentiation in response to malaria parasites within secondary lymphoid tissues.

View details for DOI 10.1371/journal.ppat.1013565

View details for PubMedID 41961880

Abstract

Few studies have tracked human CD4+ T cell clones through repeated infections. We used longitudinal single-cell RNA and T cell receptor (TCR) tracking to study the functional stability and memory potential of CD4+ T cell clonotypes during repeated Plasmodium falciparum (Pf) infections in Ugandan children and adults. Nearly all clonotypes displayed a strong preference for one of seven CD4+ subsets. This phenomenon of "clonal fidelity" was influenced by clonal expansion, linking T cell polarization and proliferation in vivo. Using clone tracking, we characterized subset-specific activation trajectories and identified antigen-specific clones. Type 1 regulatory T (TR1) cells accounted for nearly 90% of Pf-specific CD4+ T cells in blood. Tracking these clones longitudinally for hundreds of days, we observed malaria-induced expansion of TR1 effectors, long-term persistence of TR1 memory cells, and high-fidelity recall responses after reinfection. This work establishes clonal fidelity as a natural phenomenon and demonstrates the stable, long-term memory potential of TR1 cells.

View details for DOI 10.1126/sciimmunol.ads2957

View details for PubMedID 40279404

Abstract

Measles and other vaccine-preventable diseases are re-emerging worldwide in locations where they were once eliminated. Targeted policy interventions in the locations at greatest risk may be an effective strategy to curb this public health threat.

View details for DOI 10.1371/journal.pmed.1005175

View details for PubMedID 42461903

View details for DOI 10.1001/jama.2025.24407

View details for PubMedID 41533386

View details for PubMedCentralID PMC12805488

View details for DOI 10.1001/jamapediatrics.2025.3561

View details for PubMedID 41021249

Abstract

Schistosomiasis is a neglected disease caused by parasitic flatworms of the genus Schistosoma and affects more than 150 million people worldwide. Praziquantel, the drug used in public health control programmes, has minimal activity against juvenile schistosomes (within 6 weeks of infection) and imperfect cure rates. We aimed to model the population-level impact of hypothetical novel drug candidates, targeting both juvenile and adult schistosomes with various efficacies, across a range of baseline epidemiological settings.In this modelling study, we used a stochastic, individual-based mechanistic model of Schistosoma mansoni infection and simulated mass drug administration control programmes in diverse epidemiological environments. These programmes involved the administration, over a 5-year period at 75% coverage, of praziquantel (single-dose or two-dose regimens) or hypothetical novel drugs with various assumed efficacies against adult and juvenile schistosome parasites: novel drug A, with equivalent efficacy to praziquantel against adult schistosomes plus perfect (100%) efficacy against juvenile schistosomes; novel drug B, with higher efficacy than praziquantel against adult schistosomes and no activity against juveniles; and novel drug C, with higher efficacy than praziquantel against adult schistosomes plus perfect efficacy against juveniles. The outcomes were median observed S mansoni infection prevalence and infection intensity over time in simulated populations.In a simulated high-endemicity setting (baseline prevalence of S mansoni infection of 53%), modelled prevalence after a single treatment was 20·8% (uncertainty interval 15·8-23·6) for single-dose praziquantel, 17·8% (15·2-19·8) for two-dose praziquantel, 18·4% (13·4-21·4) for novel drug A, 16·0% (15·0-16·8) for novel drug B, and 13·4% (12·6-14·0) for novel drug C; at year 5, modelled prevalence was 14·6% (12·2-16·4) for single-dose praziquantel, 13·6% (11·6-14·6) for two-dose praziquantel, 11·8% (9·4-13·4) for novel drug A, 12·6% (11·6-13·4) for novel drug B, and 9·6% (9·0-10·4) for novel drug C. In a simulated low-endemicity setting (baseline prevalence 15%), modelled prevalence after a single treatment was 4·8% (3·6-5·8) for single-dose praziquantel, 4·2% (3·6-5·0) for two-dose praziquantel, 4·6% (3·2-5·4) for novel drug A, 4·0% (3·4-4·6) for novel drug B, and 3·6% (3·2-4·2) for novel drug C; at year 5, modelled prevalence was 3·0% (2·2-3·6) for single-dose praziquantel, 2·8% (2·2-3·4) for two-dose praziquantel, 2·6% (1·8-3·2) for novel drug A, 2·7% (2·2-3·2) for novel drug B, and 2·2% (1·8-2·6) for novel drug C.This study provides policy-relevant data that could help to guide the development and selection of novel drugs for schistosomiasis. Novel anthelmintic drugs that can kill both adult and juvenile schistosomes with higher efficacy than praziquantel could have some public health gains in control programmes for schistosomiasis, especially in high-burden settings. Novel drugs with increased efficacy against adult schistosomes are likely to have an initial and larger impact on disease control, whereas targeting juveniles could moderately improve longer-term control outcomes.US National Institutes of Health.

View details for DOI 10.1016/j.lanmic.2024.101065

View details for PubMedID 40412412

Abstract

Widespread childhood vaccination has eliminated many infectious diseases in the US. However, vaccination rates are declining, and there are ongoing policy debates to reduce the childhood vaccine schedule, which may risk reemergence of previously eliminated infectious diseases.To estimate the number of cases and complications in the US under scenarios of declining childhood vaccination for measles, rubella, poliomyelitis, and diphtheria.A simulation model was used to assess the importation and dynamic spread of vaccine-preventable infectious diseases across 50 US states and the District of Columbia. The model was parameterized with data on area-specific estimates for demography, population immunity, and infectious disease importation risk. The model evaluated scenarios with different vaccination rates over a 25-year period. Inputs for current childhood vaccination rates were based on 2004-2023 data.The primary outcomes were estimated cases of measles, rubella, poliomyelitis, and diphtheria in the US. The secondary outcomes were estimated rates of infection-related complications (postmeasles neurological sequelae, congenital rubella syndrome, paralytic poliomyelitis, hospitalization, and death) and the probability and timing for an infection to reestablish endemicity.At current state-level vaccination rates, the simulation model predicts measles may reestablish endemicity (83% of simulations; mean time of 20.9 years) with an estimated 851 300 cases (95% uncertainty interval [UI], 381 300 to 1.3 million cases) over 25 years. Under a scenario with a 10% decline in measles-mumps-rubella (MMR) vaccination, the model estimates 11.1 million (95% UI, 10.1-12.1 million) cases of measles over 25 years, whereas the model estimates only 5800 cases (95% UI, 3100-19 400 cases) with a 5% increase in MMR vaccination. Other vaccine-preventable diseases are unlikely to reestablish endemicity under current levels of vaccination. If routine childhood vaccination declined by 50%, the model predicts 51.2 million (95% UI, 49.7-52.5 million) cases of measles over a 25-year period, 9.9 million (95% UI, 6.4-13.0 million) cases of rubella, 4.3 million cases (95% UI, 4 cases to 21.5 million cases) of poliomyelitis, and 197 cases (95% UI, 1-1000 cases) of diphtheria. Under this scenario, the model predicts 51 200 cases (95% UI, 49 600-52 600 cases) with postmeasles neurological sequelae, 10 700 cases (95% UI, 6700-14 600 cases) of congenital rubella syndrome, 5400 cases (95% UI, 0-26 300 cases) of paralytic poliomyelitis, 10.3 million hospitalizations (95% UI, 9.9-10.5 million hospitalizations), and 159 200 deaths (95% UI, 151 200-164 700 deaths). In this scenario, measles became endemic at 4.9 years (95% UI, 4.3-5.6 years) and rubella became endemic at 18.1 years (95% UI, 17.0-19.6 years), whereas poliovirus returned to endemic levels in about half of simulations (56%) at an estimated 19.6 years (95% UI, 14.0-24.7 years). There was large variation across the US population.Based on estimates from this modeling study, declining childhood vaccination rates will increase the frequency and size of outbreaks of previously eliminated vaccine-preventable infections, eventually leading to their return to endemic levels. The timing and critical threshold for returning to endemicity will differ substantially by disease, with measles likely to be the first to return to endemic levels and may occur even under current vaccination levels without improved vaccine coverage and public health response. These findings support the need to continue routine childhood vaccination at high coverage to prevent resurgence of vaccine-preventable infectious diseases in the US.

View details for DOI 10.1001/jama.2025.6495

View details for PubMedID 40272967

Abstract

Systematic evidence indicating the effect of antimicrobial selection pressure on resistance remains scarce. We aimed to estimate the effect of prescription behaviour of key antimicrobial classes on antimicrobial resistance (AMR) in patients across US Veterans Affairs medical centres (VAMCs).In this multicentre, retrospective, cohort study, we identified all hospital-onset isolates (cultures that were collected on or after 3 days of admission) of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa from 138 US VAMCs between Feb 1, 2007, and Dec 31, 2021, using routine antimicrobial susceptibility and prescription data from Veterans Affairs administrative records. Facility-year periods with more than 30% missing susceptibility testing results were excluded. The study population comprised individuals admitted to acute care wards, and analyses were restricted to inpatient settings. The primary outcomes were the associations between facility-level prescription and resistance data and the temporal trends in pathogen-specific AMR profiles and prescription. AMR profiles were defined as pathogen-specific susceptibility patterns to clinically relevant antimicrobial panels. AMR profile incidence was quantified as the number of isolates per AMR profile category (susceptible, single-class resistant, or multidrug resistant) per 1000 admissions; facility-level prescription rate was defined as inpatient days of therapy per 1000 patient-days. The temporal trends were modelled using generalised estimating equations to estimate average annual percentage changes (AAPC). Multilevel multinomial logistic regression-related recent facility-level antimicrobial exposure (days of therapy per 100 patient-days in the preceding 14 days) to the relative odds of each AMR profile compared with the broadly susceptible profile. We adjusted models for calendar year, community-level AMR incidence, and facility-level characteristics (including census region, facility complexity, and facility rurality) to address potential confounding. To assess robustness, we performed sensitivity analyses by varying the exposure window, incorporating alternative model specifications, and using multiple imputation for missing antimicrobial susceptibility data under different assumptions.We analysed 84 657 (51·6%) of 164 047 hospital-onset isolates across four pathogens-namely, S aureus (n=17 722), E coli (n=25 777), K pneumoniae (n=22 908), and P aeruginosa (n=19 299). Among 68 910 participants, 96·4% (66 430) were male and 69·8% (48 119) were classified as White, 23·4% (16 092) as Black or African American, and 8·7% (7414) as Hispanic or Latino. The median age was 70 years (IQR 62-79). Hospital-onset incidence declined for infections by all pathogens, except for those caused by third-generation or fourth-generation cephalosporin-resistant E coli. Antimicrobial prescription rates remained stable or decreased, except for third-generation or fourth-generation cephalosporin prescription rate, which increased during 2007-19 (AAPC 3·1% [95% CI 2·1 to -4·1]; p<0·0001). Fluoroquinolone exposure was consistently associated with resistance development in all pathogens. In S aureus, each unit increase in fluoroquinolone exposure was associated with 4·6% (1·5-7·7; p=0·0033) of increased relative odds of fluoroquinolone-resistant, macrolide-susceptible, meticillin-resistant S aureus. Anti-staphylococcal β-lactam prescription behaviour was not linked to the prevalence of meticillin-resistant S aureus. Third-generation or fourth-generation cephalosporin exposure increased the relative odds of third-generation or fourth-generation cephalosporin-resistant and β-lactam-β-lactamase-resistant E coli by 4·8% (2·1-7·5; p=0·00040) and K pneumoniae by 4·0% (1·9-6·2; p=0·00020. Carbapenem exposure increased the relative odds of carbapenem-resistant, fluoroquinolone-susceptible, and β-lactam-β-lactamase inhibitor-susceptible P aeruginosa by 15·7% (9·4-22·4%; p<0·0001). Community-level AMR prevalence was associated with increased relative odds of corresponding hospital-onset resistance profiles across most pathogen-profile combinations. Sensitivity analyses using alternative exposure windows, model specifications, and multiple imputation for missing susceptibility data yielded consistent results.Consistent associations between fluoroquinolone prescription and resistance patterns across multiple pathogens reinforce stewardship rationale for restricting fluoroquinolone use, whereas emerging co-resistance of fluoroquinolones with that of third-generation or fourth-generation cephalosporins in E coli highlights the need to monitor multidrug resistance patterns as prescription behaviours shift. Effective stewardship requires coordinated strategies across antimicrobial classes, informed by pathogen-specific selection dynamics. By analysing AMR profiles across multiple pathogens and linking individual-level clinical isolates with facility-level antimicrobial prescription patterns, this study moves beyond single-pathogen, single-antimicrobial approaches to assess how antimicrobial use shapes resistance patterns.US Centers for Disease Control and Prevention, the Agency for Healthcare Research and Quality, and the Department of Veterans Affairs.

View details for DOI 10.1016/j.lanmic.2026.101445

View details for PubMedID 42537681

Abstract

Seasonal trends in infectious diseases are shaped by climatic and social factors, with many respiratory viruses peaking in winter. However, the seasonality of COVID-19 remains in dispute, with significant waves of cases across the United States occurring in both winter and summer. Using wavelet analysis of COVID-19 cases during the pandemic period, we find that the periodicity of epidemic COVID-19 varies markedly across the U.S. and correlates with winter temperatures, indicating seasonal forcing. However, seasonal forcing alone cannot explain the pattern of multiple waves per year that has been so characteristic of COVID-19. Using a modified SIRS model that allows specification of the tempo of waning immunity, we show that specific forms of non-durable immunity can sufficiently explain the sub-annual waves characteristic of the COVID-19 epidemic.

View details for DOI 10.1371/journal.ppat.1014169

View details for PubMedID 42044189

View details for DOI 10.1038/s41893-026-01879-8

View details for Web of Science ID 001809830100001

Abstract

A previous cluster-randomized controlled trial in Bangladesh found that individual or combined water, handwashing, sanitation, and nutrition interventions during pregnancy and after birth improved developmental outcomes of children at 1 and 2 years of age. In this study, we aimed to determine if these intervention effects were sustained for children at school age.Clusters of pregnant women were enrolled between May 31, 2012 and July 7, 2013 and block-randomized into chlorinated drinking water (W); improved sanitation (S); handwashing with soap (H); combined WSH; nutrition counseling and provision of lipid-based supplements (N); combined WSH + N, or a double-sized passive control arm (C) with no intervention visits (N = 5,551). The primary outcomes of the main trial after the 2-year intervention were 7-day diarrhea prevalence and length-for-age z-score, measured in 4,584 children of enrolled pregnant women. We conducted a post hoc, follow-up of all initially enrolled mothers and their children 5 years after intervention completion, when children were 7 years old. Primary outcomes were child cognition assessed using the Wechsler Pre and Primary Scale of Intelligence (WPPSI-IV), along with assessments of fine motor abilities, behavior, school achievement, and executive function; secondary outcomes were maternal mental health and stimulation in the home environment. We conducted intention-to-treat analyses using generalized linear models to calculate unadjusted and adjusted comparisons between each arm and the control group, accounting for block-level clustering. Between September 2019 and February 2021, we re-enrolled 4,175 households from all 720 original clusters, with the full set of child development assessments conducted on 3,833 children across 718 clusters. Children in the WSH + N, N, and S arms had improved cognitive scores on one or more domains compared to the control arm, with adjusted effect sizes between 0.10 (95%CI: 0.00, 0.20) and 0.15 (0.03, 0.27). Children in the W, H, N, WSH, and WSH + N arms demonstrated improved prosocial behaviors (adjusted effect sizes between 0.20 (0.07, 0.33) and 0.31 (0.16, 0.46)) and reduced difficult behaviors (adjusted effect sizes between -0.15 (-0.28, -0.01) and -0.31 (-0.45, -0.17)). No intervention effects were observed for fine motor, executive functioning, or school achievement outcomes. Maternal depressive symptoms were improved in the WSH + N, H, and N arms (adjusted effect sizes between -0.14 (-0.24, -0.03) and -0.21 (-0.31, -0.11)), and the stimulating home environment was improved in all intervention arms (adjusted effect sizes between 0.17 (0.01, 0.33) and 0.40 (0.25, 0.56)). Children whose families had higher wealth at baseline and those who were male tended to have larger effect sizes on the FSIQ. Data collection for this study was interrupted by a 6-month pause at the start of the COVID-19 pandemic. The main limitation of this study is loss to follow-up.At 7 years of age, we found small, sustained benefits of early water, sanitation, handwashing, and nutrition interventions on child cognitive and socioemotional outcomes, the stimulating home environment, and maternal mental health. Future work to determine the mechanisms underlying these intervention effects will further inform the design of early interventions to improve child health and development. Trial registration: Follow-up trial: ClinicalTrials.gov, NCT04443855. Original WASH-Benefits Bangladesh (WASH-B): ClinicalTrials.gov, NCT01590095.

View details for DOI 10.1371/journal.pmed.1004793

View details for PubMedID 41401135

View details for PubMedCentralID PMC12707674

Abstract

We present results from a randomized controlled trial in Bangladesh that introduced operational practices to improve energy efficiency and reduce emissions in 276 "zigzag" brick kilns. Of all intervention kilns, 65% adopted the improved practices. Treatment assignment reduced energy use by 10.5% (P-value <0.001) and decreased CO2 and PM2.5 emissions by 171 and 0.45 metric tons, respectively, per kiln per year. Valuing the CO2 reductions using a social cost of carbon of 185 USD per metric ton, we find that the social benefits outweigh costs by a factor of 65 to 1. The intervention, which required no new capital investment, also decreased fuel costs and increased brick quality. Our results demonstrate the potential for privately profitable, as well as publicly beneficial, improvements to address environmental problems in informal industries.

View details for DOI 10.1126/science.adr7394

View details for PubMedID 40339018

View details for DOI 10.1056/NEJMsb2515372

View details for PubMedID 41812202

Abstract

Wastewater surveillance for infectious agents has proved useful in identifying the circulation of viruses within populations. We investigated the presence and concentration of human immunodeficiency virus (HIV)-1 total nucleic acids (including both viral RNA and proviral DNA) in wastewater solids. We retrospectively measured HIV-1 nucleic acids in two samples per week for 26 months at two wastewater treatment plants serving populations with different prevalences of HIV infections in San Francisco and Santa Clara County, California, USA. We detected HIV nucleic acids in a majority of samples with concentrations ranging from non-detect to 3.9 × 105 cp/g (N = 459 samples total). Concentrations of HIV-1 were significantly higher in samples from the wastewater treatment plant serving a population with a higher prevalence of people living with HIV than in the plant serving a population with a lower prevalence. The HIV-1 nucleic acids amplified were primarily DNA and thus represented proviral DNA shedding into wastewater. Additionally, we found that HIV-1 nucleic acid concentrations in wastewater solids were orders of magnitude higher than those in liquid wastewater indicating that the HIV-1 target preferentially sorbs to solids. Whether concentrations of HIV-1 in wastewater solids can be used to identify the number of incident cases remains unknown. Additional work on HIV-1 shedding from individuals with viremia and people living with HIV is needed to translate wastewater measurements into quantitative information on infections. Additional work may also be needed to document non-human sources of HIV-1 nucleic acids in wastewater.Human immunodeficiency virus (HIV)-1 has infected nearly 100 million people since it emerged in the 1980s. Antiretroviral therapy prevents transmission of HIV and also allows infected individuals to live healthy lives with normal life expectancy. Consequently, identifying unrecognized cases of HIV is of paramount importance. Since wastewater represents a composite biological sample from a community, it may provide valuable information on HIV-1 prevalence that can be used to inform HIV testing and outreach.

View details for DOI 10.1128/aem.01477-24

View details for PubMedID 39526804

Abstract

Respiratory syncytial virus (RSV) is a leading cause of respiratory illness and hospitalization, but clinical surveillance detects only a minority of cases. Wastewater surveillance could determine the onset and extent of RSV circulation in the absence of sensitive case detection, but to date, studies of RSV in wastewater are few. We measured RSV RNA concentrations in wastewater solids from 176 sites during the 2022-2023 RSV season and compared those to publicly available RSV infection positivity and hospitalization rates. Concentrations ranged from undetectable to 107 copies per gram. RSV RNA concentration aggregated at state and national levels correlated with infection positivity and hospitalization rates. RSV season onset was determined using both wastewater and clinical positivity rates using independent algorithms for 14 states where both data were available at the start of the RSV season. In 4 of 14 states, wastewater and clinical surveillance identified RSV season onset during the same week; in 3 states, wastewater onset preceded clinical onset, and in 7 states, wastewater onset occurred after clinical onset. Wastewater concentrations generally peaked in the same week as hospitalization rates but after case positivity rates peaked. Differences in onset and peaks in wastewater versus clinical data may reflect inherent differences in the surveillance approaches.

View details for DOI 10.1021/acsestwater.3c00725

View details for PubMedID 38633368

View details for PubMedCentralID PMC11019535

Abstract

BACKGROUND: Standard pediatric growth curves cannot be used to impute missing height or weight measurements in individual children. The Michaelis-Menten equation, used for characterizing substrate-enzyme saturation curves, has been shown to model growth in many organisms including nonhuman vertebrates. We investigated whether this equation could be used to interpolate missing growth data in children in the first three years of life and compared this interpolation to several common interpolation methods and pediatric growth models.METHODS: We developed a modified Michaelis-Menten equation and compared expected to actual growth, first in a local birth cohort (N=97) then in a large, outpatient, pediatric sample (N=14,695).RESULTS: The modified Michaelis-Menten equation showed excellent fit for both infant weight (median RMSE: boys: 0.22kg [IQR:0.19; 90%<0.43]; girls: 0.20kg [IQR:0.17; 90%<0.39]) and height (median RMSE: boys: 0.93cm [IQR:0.53; 90%<1.0]; girls: 0.91cm [IQR:0.50;90%<1.0]). Growth data were modeled accurately with as few as four values from routine well-baby visits in year 1 and seven values in years 1-3; birth weight or length was essential for best fit. Interpolation with this equation had comparable (for weight) or lower (for height) mean RMSE compared to the best performing alternative models.CONCLUSIONS: A modified Michaelis-Menten equation accurately describes growth in healthy babies aged 0-36months, allowing interpolation of missing weight and height values in individual longitudinal measurement series. The growth pattern in healthy babies in resource-rich environments mirrors an enzymatic saturation curve.

View details for DOI 10.1186/s12874-024-02145-1

View details for PubMedID 38302887

View details for DOI 10.31478/202310a

View details for PubMedID 38784640

View details for PubMedCentralID PMC11114596

Abstract

Metabolic profiling of respiratory samples from individuals infected and uninfected with respiratory viral infections may identify biomarker signatures that complement routine clinical diagnostic testing and offer unique insights into pathophysiology. We used liquid chromatography quadrupole time-of-flight mass spectrometry to generate untargeted metabolomic profiles and identified top biomarker signatures differentiating severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) positive from negative samples via machine learning. We then adapted these signatures to liquid chromatography-tandem mass spectrometry for targeted profiling and assessed classification performance, including samples positive for other respiratory viruses and negative for viral testing. A total of 1,226 samples were tested, including 521 positive samples for SARS-CoV-2, 97 for influenza A, 96 for respiratory syncytial virus (RSV), 211 for other respiratory viruses, and 301 negative samples. The top-performing model was the Light Gradient Boosting Model, which showed an area under the receiver operating characteristic curve (AUC) of 0.99 (95% confidence interval [CI], 0.99-1.00), sensitivity of 0.96 (95% CI, 0.91-0.99), and specificity of 0.95 (95% CI, 0.90-0.97). A separate machine learning analysis investigating the performance by viral subtype showed high performance for the identification of influenza A virus with an AUC of 0.97 (95% CI, 0.94-0.99) and RSV with an AUC of 0.99 (95% CI, 0.97-1.00). The two features with the highest ranking were identified as 3-oxo-heneicosanoic acid and 2-(4-hydroxyphenyl) ethanol. These findings extend our understanding of the metabolic impact of respiratory viral infections and support the potential of metabolomics to complement routine clinical diagnostic methods.IMPORTANCEMolecular testing has greatly improved how viruses are diagnosed; however, gaps remain, including limited sensitivity directly from specimens and inability to differentiate active from resolved infection. In this study, we investigated the use of a distinct diagnostic approach, mass spectrometry for detection of metabolites (small molecules) combined with machine learning analysis, for the diagnosis of SARS-CoV-2 and other respiratory viruses. We demonstrated strong performance of this approach directly from upper respiratory swab samples to differentiate SARS-CoV-2-infected versus uninfected individuals. Extension of this approach to influenza and RSV maintained a high level of performance. This research suggests that mass spectrometry-based infectious disease diagnostic testing has clinical potential and that these metabolomic features may reveal novel host-pathogen interactions and therapeutic targets. Applying a similar approach to prospective, multisite cohorts of patients with other infectious diseases carries potential to extend our understanding of the metabolic pathways involved in the host response to infection.

View details for DOI 10.1128/jcm.02042-24

View details for PubMedID 41065362

Abstract

The routine clinical diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely restricted to real-time reverse transcription quantitative PCR (RT-qPCR), and tests that detect SARS-CoV-2 nucleocapsid antigen. Given the diagnostic delay and suboptimal sensitivity associated with these respective methods, alternative diagnostic strategies are needed for acute infection.We studied the use of a clinically validated liquid chromatography triple quadrupole method (LC/MS-MS) for detection of amino acids from plasma specimens. We applied machine learning models to distinguish between SARS-CoV-2-positive and negative samples and analyzed amino acid feature importance.A total of 200 samples were tested, including 70 from individuals with COVID-19, and 130 from negative controls. The top performing model overall allowed discrimination between SARS-CoV-2-positive and negative control samples with an area under the receiver operating characteristic curve (AUC) of 0.96 (95%CI 0.91, 1.00), overall sensitivity of 0.99 (95%CI 0.92, 1.00), and specificity of 0.92 (95%CI 0.85, 0.95).This approach holds potential as an alternative to existing methods for the rapid and accurate diagnosis of acute SARS-CoV-2 infection.

View details for DOI 10.3389/fmicb.2022.1059289

View details for PubMedID 37063449

View details for PubMedCentralID PMC10092816

View details for DOI 10.1056/NEJMc2107799

View details for PubMedID 34233096

Abstract

The emergence of SARS-CoV-2 variants t 23 hat reduce antibody neutralization and vaccine efficacy is of significant global concern..

View details for DOI 10.1128/JCM.00741-21

View details for PubMedID 33952596

View details for DOI 10.1001/jama.2020.5445

View details for PubMedID 32250394

Abstract

To evaluate the impact of discontinuing contact precautions for vancomycin-resistant enterococci (VRE) on strain and plasmid transmission using long-read whole-genome sequencing (WGS).Before-after trial of adults with Enterococcus bloodstream infections pre-(Jan-Oct 2021) and post-(Oct-Dec 2021 and Jan-Oct 2023) discontinuation of contact precautions for VRE infections.Quaternary referral and transplant academic medical center.Hospitalized adults (≥18 yr) with E. faecalis or E. faecium bacteremia.Classical epidemiology identified potential transmissions via shared unit exposure within a 14-day window. Blood culture isolates underwent long-read WGS to assess strain and vanA plasmid relatedness. Clonal transmission was defined as <20 single-nucleotide polymorphisms. Plasmid similarity was assessed with Mash distance.Among 288 isolates from 202 patients, there was no significant difference in possible epidemiologic transmissions pre-versus postdiscontinuation (9.5% vs 8.1%; P = .679). Genomic analysis identified four clonal transmission events, two of which occurred postdiscontinuation. Among 70 vanA plasmids from 54 patients, 38 highly related plasmids formed a low-diversity cluster. The proportion of cluster plasmids was not significantly different between periods (47% vs 60%; P = .267). Postdiscontinuation, vanA-positive E. faecium ST117 was more prevalent (22/44 vs 53/75; P = .024).Discontinuation of contact precautions for VRE was not associated with increased transmission of enterococci or vanA plasmids in bloodstream infections. Transmission patterns remained largely stable, though the postdiscontinuation period showed increased prevalence of the dominant E. faecium ST117. These findings suggest limited impact of contact precautions on VRE transmission.

View details for DOI 10.1017/ash.2026.10392

View details for PubMedID 42130491

View details for PubMedCentralID PMC13162067

Abstract

We used a large language model integrated in the electronic health record to evaluate unnecessary central lines. It had a 16% sensitivity and 99% specificity for detecting unnecessary lines. Although it missed many unnecessary lines, the high specificity suggests potential as a tool where human review is not feasible.

View details for DOI 10.1017/ice.2026.10462

View details for PubMedID 42037194

Abstract

Bacterial pathogens adapt rapidly to clinical and within-host selective pressures1. Insertion sequences (IS) are transposable elements that can contribute to pathogenic adaptation2, but their activity and consequences in contemporary clinical populations are not well characterized. Here, combining large-scale genomic surveys with long-read sequencing of clinical isolates and longitudinal gut metagenomes, we quantify pathogen IS dynamics from global patterns to within-host evolution. Across 19,485 publicly available high-contiguity ESKAPEE pathogen genomes, Enterococcus faecium genomes are the most IS dense, dominated by replicative ISL3 family elements, which have proliferated in clinical lineages over the past 30 years. We find extensive chromosomal structural variation, largely involving ISL3, within a new single-hospital collection of bloodstream isolates. Long-read metagenomic sequencing of 28 longitudinal stool samples from 12 haematopoietic cell transplantation (HCT) recipients demonstrates within-host IS dynamics and their regulatory consequences. In one patient, an ISL3 insertion upstream of a folate transporter formed a strong promoter, increasing transcription and improving relative fitness under folate limitation. Enhanced folate scavenging may enable E. faecium to thrive in the setting of microbiome collapse, which is common in HCT and other critically ill patients3. Together, these results show that a recent ISL3 expansion is driving rapid evolution in healthcare-associated E. faecium, with consequences for its metabolic fitness that may help explain its increasing clinical burden. Several other pathogens also show elevated IS loads in our survey, which suggests that IS expansion-mediated evolution might be more broadly relevant.

View details for DOI 10.1038/s41586-026-10373-2

View details for PubMedID 42020750

View details for PubMedCentralID 7190074

Abstract

Our study evaluated a large language model (gpt-4o-mini) for surgical site infection (SSI) adjudication, achieving 100% sensitivity but 69.4% specificity. While reducing the manual screening workload by 66%, the agent generated many false positives, underscoring the need for refined models to improve specificity without compromising accuracy.

View details for DOI 10.1017/ice.2026.10432

View details for PubMedID 41972262

Abstract

AIM: To evaluate the feasibility and performance of wastewater-based healthcare epidemiology for monitoring respiratory viruses and antimicrobial resistance genes.METHODS: We conducted a pilot study at an 800-bed academic quaternary care hospital in Northern California. Composite wastewater samples were collected weekly over three timepoints (June-July 2024) from the main hospital outflow. Droplet digital PCR was performed to quantify nucleic acids from respiratory viruses (SARS-CoV-2, influenza A, RSV) and ARGs (mecA, vanA, KPC, NDM, OXA-48, VIM). Viral levels were compared with hospital testing data and community wastewater trends. Antimicrobial resistance genes were compared with contemporaneous clinical cultures.FINDINGS: Sampling was logistically feasible but constrained by equipment size and placement limitations. Viral nucleic acid levels in hospital wastewater broadly reflected hospital testing results and community wastewater trends. By contrast, ARG levels showed limited alignment with clinical culture data. mecA levels were low despite an elevated number of MRSA cultures, while vanA and carbapenemase genes were abundant, including during weeks with no corresponding clinical cases.CONCLUSIONS: Wastewater-based healthcare epidemiology captured trends in hospital respiratory virus testing but showed limited concordance with culture-based detection of resistant bacteria. While not suited for case detection of resistant pathogens, it may serve as a system-level tool to assess the hospital resistome, antimicrobial pressures, and potential environmental transmission risks.

View details for DOI 10.1016/j.jhin.2026.03.007

View details for PubMedID 41864437

Abstract

Broadly neutralizing antibodies (bnAbs) against HIV-1 are promising components of long-acting antiretroviral treatment (ART) due to their prolonged activity and potential for recruiting additional immune effector functions. Their use is most advanced in virologically suppressed people living with HIV-1 switching from a standard daily ART regimen to a long-acting regimen comprising one or two bnAbs combined with one of the currently approved long-acting small-molecule inhibitors: cabotegravir or lenacapavir. Implementation of bnAb-based therapies, however, requires accurate assessment of viral susceptibility. Although phenotypic assays provide the most direct and reliable measures of bnAb activity, their limited scalability has prompted interest in genotypic approaches. Here we summarize evidence linking HIV-1 Env sequence characteristics to reduced bnAb susceptibility, including in vivo selection data in animal models and human studies, and in vitro selection and susceptibility data. Although genotypic analysis of HIV-1 Env may reliably identify resistance in some viruses, more research is required before genotypic methods can reliably predict susceptibility in clinical settings.

View details for DOI 10.1038/s43856-026-01680-w

View details for PubMedID 42209804

Abstract

Antimicrobial resistance poses a significant threat to the sustainability of effective treatments against the three most prevalent infectious diseases: malaria, human immunodeficiency virus (HIV) infection and tuberculosis. Therefore, there is an urgent need to develop novel drugs and treatment protocols capable of reducing the emergence of resistance and combating it when it does occur. In this Review, we present an overview of the status and underlying molecular mechanisms of drug resistance in these three diseases. We also discuss current strategies to address resistance during the research and development of next-generation therapies. These strategies vary depending on the infectious agent and the array of resistance mechanisms involved. Furthermore, we explore the potential for cross-fertilization of knowledge and technology among these diseases to create innovative approaches for minimizing drug resistance and advancing the discovery and development of new anti-infective treatments. In conclusion, we advocate for the implementation of well-defined strategies to effectively mitigate and manage resistance in all interventions against infectious diseases.

View details for DOI 10.1038/s41573-024-00933-4

View details for PubMedID 38750260

View details for PubMedCentralID 9490302

Abstract

Dolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART.We performed a PubMed search using the term "Dolutegravir", last updated 18 December 2023, to estimate the prevalence of VF with emergent INSTI DRMs in people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART.Of 2131 retrieved records, 43 clinical trials, 39 cohorts, and 6 cross-sectional studies provided data across 6 clinical scenarios based on ART history, virological status, and co-administered ARVs: (1) ART-naïve PLWH receiving DTG plus two NRTIs; (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on a previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The median proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.5% for scenario 3 and 3.4% for scenario 6. In the remaining four trial scenarios, VF prevalence with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, whereas cross-sectional studies yielded prevalence data lacking denominator details.In clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess VF prevalence with emergent INSTI DRMs in PLWH receiving DTG in real-world settings.

View details for DOI 10.3390/v16030399

View details for PubMedID 38543764

View details for PubMedCentralID PMC10975848

Abstract

Author summary Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.

View details for DOI 10.1371/journal.pmed.1004293

View details for PubMedID 37738247

Abstract

Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) rarely leads to virological failure (VF) and drug resistance in integrase strand transfer inhibitor (INSTI)-naïve persons living with HIV (PLWH). As a result, limited data are available on INSTI-associated drug resistance mutations (DRMs) selected by DTG-containing ART regimens. Methods: We reviewed studies published through July 2023 to identify those reporting emergent major INSTI-associated DRMs in INSTI-naïve PLWH receiving DTG and those containing in vitro DTG susceptibility results using a standardized assay. Results: We identified 36 publications reporting 99 PLWH in whom major nonpolymorphic INSTI-associated DRMs developed on a DTG-containing regimen and 21 publications containing 269 in vitro DTG susceptibility results. DTG-selected DRMs clustered into four largely non-overlapping mutational pathways characterized by mutations at four signature positions: R263K, G118R, N155H, and Q148H/R/K. Eighty-two (82.8%) viruses contained just one signature DRM, including R263K (n = 40), G118R (n = 24), N155H (n = 9), and Q148H/R/K (n = 9). Nine (9.1%) contained ≥1 signature DRM, and eight (8.1%) contained just other DRMs. R263K and G118R were negatively associated with one another and with N155H and Q148H/K/R. R263K alone conferred a median 2.0-fold (IQR: 1.8-2.2) reduction in DTG susceptibility. G118R alone conferred a median 18.8-fold (IQR:14.2-23.4) reduction in DTG susceptibility. N155H alone conferred a median 1.4-fold (IQR: 1.2-1.6) reduction in DTG susceptibility. Q148H/R/K alone conferred a median 0.8-fold (IQR: 0.7-1.1) reduction in DTG susceptibility. Considerably higher levels of reduced susceptibility often occurred when signature DRMs occurred with additional INSTI-associated DRMs. Conclusions: Among INSTI-naïve PLWH with VF and treatment emergent INSTI-associated DRMs, most developed one of four signature DRMs, most commonly R263K or G118R. G118R was associated with a much greater reduction in DTG susceptibility than R263K.

View details for DOI 10.3390/v15091932

View details for PubMedID 37766338

View details for PubMedCentralID PMC10536831