bims-traimu 2026-05-24 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–05–24
fourteen papers selected by
Yantong Wan, Southern Medical University

Early clearance of Mycobacterium tuberculosis among Indonesian household contacts is not associated with circulating beta-glucan present at the time of exposure.
BCG Vaccination Modulates Long-Term TNF-α and sCD40L in COVID-19: An Exploratory Longitudinal Study.
High Mobility Group Protein B1 Promotes Interferon Regulatory Factor 1 SUMOylation to Prime Trained Immunity of Circulating Monocytes and Aggravate the Progressive Synovial Inflammation in Knee Osteoarthritis.
Monocyte exhaustion associated with systemic lupus erythematosus.
Inflammation-driven mitochondrial dysfunction and ROS accumulation orchestrate pulmonary fibrotic remodeling in sepsis.
Mapping the holonomic signaling network that drives pathological changes in endotoxic shock.
Differential regulation of monocyte exhaustion by distinct TLR agonists and underlying mechanisms.
Rethinking the origins and functions of adaptive immunity.
Soluble uric acid suppresses neutrophil-mediated host defense in sepsis.
Kinetic control of macrophage death by PTM-turnover crosstalk in infection and inflammation.
Past viral infections can shape inter-individual variability in anti-viral TLR responses.
A Novel Two-Hit Murine Model of Viral Primed Sepsis-Associated Acute Kidney Injury.
Stress History Establishes a Transient Tolerant State That Shapes Antibiotic Survival Upon Resuscitation.
Manganese enhances macrophage bactericidal activity in mice with Staphylococcus aureus osteomyelitis via Sirt3-mitophagy axis.

Tuberculosis (Edinb). 2026 May 13. pii: S1472-9792(26)00052-1. [Epub ahead of print]159 102782

Early clearance of Mycobacterium tuberculosis among Indonesian household contacts is not associated with circulating beta-glucan present at the time of exposure.

Todia P Setiabudiawan, Lika Apriani, Marlou Tehupeiory-Kooreman, Jochem B Buil, Ayesha J Verrall, Andrei Sarlea, Mihai G Netea, Bachti Alisjahbana, Philip C Hill, Reinout van Crevel.

  A significant proportion of individuals heavily exposed to infectious tuberculosis patients do not acquire Mycobacterium tuberculosis (Mtb) infection, as detected by an interferon gamma release assay (IGRA). Trained immunity may contribute to this host resistance to Mtb infection, also termed early clearance. From a prospective tuberculosis household study in Indonesia we selected 80 heavily exposed IGRA-negative household contacts, of whom 40 converted their baseline-negative IGRA to positive after three months (IGRA converters) and 40 remained IGRA-negative (early clearers). From all individuals we measured circulating β-D-glucan and used their serum for induction of trained immunity in vitro, using peripheral blood mononuclear cells from healthy unexposed Dutch donors, that were stimulated with unrelated stimuli six days after exposure to serum from household contacts. β-D-glucan concentrations and positivity did not correlate with early clearance, nor with serum-induced in-vitro trained immunity as measured by heterologous cytokine responses. These findings suggest that early clearance is unlikely to be maintained by circulating β-D-glucan or other serum factors present at exposure to Mtb, and may instead depend on cell-intrinsic or local host processes not captured by serum-based assays.

Keywords:  BCG vaccination; Beta-glucan; Early clearance; IGRA; Trained immunity; Tuberculosis

DOI:  https://doi.org/10.1016/j.tube.2026.102782
Int J Gen Med. 2026 ;19 600024

BCG Vaccination Modulates Long-Term TNF-α and sCD40L in COVID-19: An Exploratory Longitudinal Study.

Caroline Fávero, Gabriela Barbosa, Vanessa Pellegrini, Dayane Melo, Shahrokh F Shariat, Lívia Bitencourt Pascoal, Leonardo O Reis.

   Background: Bacillus Calmette-Guérin (BCG) vaccination exerts non-specific immunomodulatory effects through trained immunity, potentially modulating inflammatory responses in COVID-19. Tumor necrosis factor-alpha (TNF-α) and soluble CD40 ligand (sCD40L) are key inflammatory and pro-thrombotic mediators implicated in COVID-19 pathogenesis.
Methods: A randomized, placebo-controlled trial was conducted involving young, healthy adults with mild COVID-19 (BATTLE trial). Intradermal BCG vaccination or placebo was administered during the acute phase of infection. Plasma TNF-α and sCD40L levels were measured at days 7 and 45, and at 6 months post-intervention in a subset of participants, total n=13; BCG n=7; placebo n=6. The sCD40L/TNF-α ratio was calculated to explore the balance between adaptive immune activation and systemic inflammation.
Results: At day 7, BCG-vaccinated individuals exhibited higher TNF-α (p=0.01) and sCD40L (p=0.018) levels compared with the placebo group. In the placebo group, TNF-α showed a transient decline by day 45 (p=0.040), whereas sCD40L remained stable throughout follow-up (all p>0.05). In contrast, BCG recipients demonstrated a sustained reduction in both mediators from day 45 to 6 months (TNF-α: p=0.0012 at day 45 and p=0.0017 at 6 months; sCD40L: p=0.024 at day 45 and p=0.05 at 6 months). The sCD40L/TNF-α ratio increased transiently at day 45 in the BCG group (p=0.035), suggesting a temporary predominance of adaptive immune activation.
Conclusion: BCG vaccination induced a distinct and durable modulation of TNF-α and sCD40L in mild COVID-19, consistent with the concept of trained immunity. This immune profile may support faster resolution of inflammation and potentially reduce the risk of inflammatory complications. Larger and more diverse controlled trials are needed to confirm these findings and clarify their clinical implications.

Keywords:  Bacillus Calmette–Guérin; COVID-19; TNF-alpha; cytokines; inflammation; sCD40L; trained immunity

DOI:  https://doi.org/10.2147/IJGM.S600024
Research (Wash D C). 2026 ;9 1243

High Mobility Group Protein B1 Promotes Interferon Regulatory Factor 1 SUMOylation to Prime Trained Immunity of Circulating Monocytes and Aggravate the Progressive Synovial Inflammation in Knee Osteoarthritis.

Lishi Jie, Jun Mao, Li Zhang, Houyu Fu, Xiaochen Li, Taiyang Liao, Yibao Wei, Deren Liu, Jiaojiao Du, Peng Wu, Songjiang Yin, Nongshan Zhang, Meng Cao, Peimin Wang.

Knee osteoarthritis (KOA) is clinically characterized by recurrent and progressively worsening episodes; however, its underlying pathological mechanisms remain incompletely understood. Phenotypic changes and the specific migration of circulating monocytes may be key factors contributing to the recurrence and progressive exacerbation of synovial inflammation in KOA. In this study, we report a specific subtype of circulating monocytes in KOA that highly express interleukin 1A (IL1A), IL1R1, tumor necrosis factor, CXCL12, CXCL3, CXCL2, CCL20, and G0S2. These monocytes exhibit a trained immune phenotype, and their CXCR4-dependent migration to the synovium exacerbates synovial inflammation. HMGB1 (high mobility group protein B1) primes the trained immunity of this subtype, resulting in increased chromatin accessibility, and the transcriptional storage of multiple proinflammatory factors enables them to exhibit a more positive inflammatory response when restimulated by HMGB1. In addition, we find that MyD88, downstream of HMGB1, recruits cytoplasmic interferon regulatory factor 1 to the nucleus and then stabilizes interferon regulatory factor 1 in chromatin through SUMOylation of tripartite motif containing 28 to exert transcriptional activity and epigenetic enhancement of proinflammatory factor expression. Finally, we found that KOA inflammation was effectively attenuated by blocking HMGB1. Taken together, this study reveals the mechanism by which trained immunity of circulating monocytes promotes the progression of synovial inflammation, supporting a future therapeutic approach in the management of KOA.

DOI: https://doi.org/10.34133/research.1243
Autoimmunity. 2026 Dec 31. 59(1): 2674057

Monocyte exhaustion associated with systemic lupus erythematosus.

Blake A Caldwell, Caitlin Armstrong, Md Shakhawat Hossain, Ran Lu, Ying Shen, Xin M Luo, Liwu Li.

  Monocytes are major contributors to systemic lupus erythematosus (SLE) pathogenesis, modulating B- and T-cell autoreactivity through inflammatory cytokine secretion and disrupted immune clearance. Under prolonged inflammatory pressure, monocytes develop a pathogenic "exhausted" immune memory state defined by paradoxical proinflammatory and immunosuppressive gene expression and diminished immune effector functions. To determine whether chronic inflammation in SLE elicits a similar monocyte exhaustion phenotype, we analyzed bone marrow and splenic reservoir monocytes from lupus-prone MRL and MRL/lpr (LPR) mice. Monocytes from LPR mice exhibit chronic immune exhaustion, including reduced chemokine receptor CX3CR1 cell surface levels, heightened sensitivity to endotoxin stress, and altered expression of T cell regulatory molecules PD-L1, CD200R, ICOS-L, and CD86. Exhaustion severity correlated with SLE progression, although the development of monocyte exhaustion preceded the onset of disease symptoms. These features were largely recapitulated in monocytes from patients with SLE, demonstrating that monocyte exhaustion is a generalizable feature of SLE pathogenesis.

Keywords:  Monocyte exhaustion; autoimmune disease; chronic inflammation; innate memory; lupus pathogenesis

DOI:  https://doi.org/10.1080/08916934.2026.2674057
Redox Biol. 2026 May 16. pii: S2213-2317(26)00223-5. [Epub ahead of print]94 104225

Inflammation-driven mitochondrial dysfunction and ROS accumulation orchestrate pulmonary fibrotic remodeling in sepsis.

Zhaoqian Zhong, Kan Wu, Junhao Wang, Guiming Chen, Haihua Luo, Guangqin Chen, Chang Sun, Danyan Guo, Leyi Li, Lei Li, Yong Jiang.

  Inflammation-induced pulmonary fibrosis is an irreversible and severe complication that leads to persistent decline in lung function and increased mortality; however, its early pathogenesis is still unclear. This study aimed to systematically elucidate the initiation mechanism of pulmonary fibrosis in the early stages of inflammation. By integrating multi-omics data and animal models, we found that lung exhibits stronger immune amplification and more severe mitochondrial dysfunction in comparison with other organs during inflammation, consequently fibrotic signaling is initiated in the acute phase. Mitochondria-related gene analysis identified six key genes (Bcl2l1, Gsr, Msrb3, AA467197, Stom, and Sod2) involved in the regulation of reactive oxygen species (ROS) metabolism, which were closely associated with clinical outcomes in sepsis. Temporal data and TNF-α/IL-1β intervention experiments revealed that these cytokines are persistently overexpressed in septic lungs, serving as critical drivers of ROS activation. In vitro assays further confirmed that ROS overload directly induces cellular damage and functional reprogramming of fibroblasts. Through bulk and single-cell transcriptomic analyses, we elucidated the alteration of intercellular communication between immune and parenchymal cells, and identified Col13a1+ fibroblasts as a key subpopulation with the capability to drive fibrotic remodeling. In conclusion, sustained TNF-α/IL-1β signaling in septic lungs exacerbates ROS accumulation, thereby driving aberrant fibroblast repair and initiating pulmonary fibrosis, in which Col13a1+ fibroblasts represent the major profibrotic subpopulation. Thus, the early inhibition of TNF-α/IL-1β expression, suppression of ROS accumulation, and regulation of Col13a1+ fibroblast activation may provide an effective therapeutic strategy for sepsis.

Keywords:  Mitochondrial disfunction; Multi-omics analysis; Pulmonary fibrosis; Reactive oxygen species; Sepsis

DOI:  https://doi.org/10.1016/j.redox.2026.104225
Cell Mol Immunol. 2026 May 22.

Mapping the holonomic signaling network that drives pathological changes in endotoxic shock.

Teng Teng, Xinhe Gao, Peipei Zhang, Ye-Hsuan Sun, Yifei Liu, Rui Zhao, Yilong Fu, Yiyuan Liu, Zhizhong Lin, Yingying Zhang, Jiahuai Han.

  Bacterial lipopolysaccharide (LPS) is among the most potent pathogen-associated molecular patterns (PAMPs). In animals, LPS can induce endotoxic shock, a widely used model of sepsis. Studies of this system have yielded important insights into innate immunity, including key immune sensors and signaling pathways. However, how inflammatory pathways are spatially coordinated across cell types and organs in vivo during endotoxic shock remains poorly understood. Here, we systematically analyzed LPS-induced lethality in mice to define the coordinated contributions of cell death pathways, inflammatory cytokines, and lipid mediators to endotoxic shock pathology. We found that caspase-11 signaling acts primarily in nonhematopoietic cells and drives tissue injury, whereas caspase-8 and RIPK3 function predominantly in hematopoietic cells and are both controlled by TRIF. Although proinflammatory cytokines are thought to promote cell death, it is surprising that cell death and/or components of death signaling are critical for initiating the cytokine storm because disruption of these cell death pathways markedly and preferentially reduces LPS-induced cytokine production in vivo. Combined deficiency of caspase-11, RIPK3, and caspase-8 fully protected mice from LPS-induced death, and additional cyclooxygenase inhibition eliminated remaining sickness behaviors such as reduced mobility. Together, these interventions rendered LPS-treated mice nearly indistinguishable from healthy controls. Overall, we delineate the core of the integrated signaling network that governs the pathological manifestations of LPS-induced endotoxic shock in mice.

Keywords:  cyclooxygenase; cytokines; endotoxic shock; lipopolysaccharide; programmed cell death

DOI:  https://doi.org/10.1038/s41423-026-01427-6
Cell Commun Signal. 2026 May 20.

Differential regulation of monocyte exhaustion by distinct TLR agonists and underlying mechanisms.

Jing Wang, Yajun Wu, Grace Lee, Babak Razani, Liwu Li.

  Monocyte exhaustion is a dysfunctional immune state marked by persistent inflammation and immune suppression, reflected in STAT1-mediated expression of pathogenic inflammatory mediator CD38 and immune suppressive PD-L1, as well as a suppression of Akt signaling and a reduction of immune-enhancing mediator CD86. While prolonged Toll-like receptor 4 (TLR4) stimulation induces monocyte exhaustion, the roles of other TLRs remain unclear. Here, we systematically evaluated the ability of TLR-2, TLR-3, TLR-7, and TLR-9 agonists to induce murine bone marrow-derived monocytes exhaustion in vitro. Although all tested agonists promoted exhaustion phenotypes to varying degrees, characterized by upregulation of STAT1 mediated expression of CD38 and PD-L1, only TLR-2 and TLR7 agonists drastically suppressed Akt and CD86. In contrast, TLR-3 or TLR-9 agonists preferentially sustained Akt activation and CD86 expression. Mechanistically, STAT1/STAT3 activation mediated by mTROC1 was common across TLR agonists responsible for elevated expression of CD38 and PD-L1. On the other hand, Akt signaling mediated by mTORC2 responsible for the expression of CD86 was preferentially suppressed by TLR-2 and TLR-7 agonists, but retained by TLR-3 and TLR-9 agonists. Deletion of Rictor, a key component of mTORC2, blocked the activation of Akt/CD86 triggered by TLR-3/9 agonists, and further elevated mTORC1 mediated activation of STAT1/3 as well as CD38 expression. Conversely, Fumagillin or Rapamycin treatment, which has been associated with reduced mTORC1 signaling activity, mitigated TLR-2/7-induced STAT1/STAT3 activation and CD38 expression. These findings reveal that monocyte exhaustion is a shared but differentially regulated outcome of distinct TLR pathways, with the mTOR axis potentially serving as a key therapeutic target for immune dysfunction.

Keywords:  Comparative analyses; Distinct TLR agonists; Mechanisms; Monocyte exhaustion dynamics

DOI:  https://doi.org/10.1186/s12964-026-02955-4
Trends Immunol. 2026 May 16. pii: S1471-4906(26)00101-8. [Epub ahead of print]

Rethinking the origins and functions of adaptive immunity.

Derick Okwan-Duodu, Erik A Sperling, Edgar G Engleman.

  The adaptive immune system (AIS) is traditionally viewed as a defensive vertebrate innovation forged by pathogen pressure. Yet many of its core features suggest it is a homeostatic, regulatory circuit, not simply a sophisticated means of antimicrobial warfare. The horizontal transfer of mitochondria--endogenous endosymbiotic organelles-is a conserved mechanism for maintaining tissue homeostasis through metabolic rescue but can alter a cell's identity and provoke immune responses. We propose that escalating multicellular complexity accommodated mitochondrial mobility-and the inevitable intrinsic immunological danger it presents-through a complementary supervisory system with buffering (tolerance), contextualization (specificity), memory, and eliminatory capacities. This perspective reframes the AIS as a constitutive danger management network, integrating tissue homeostasis, metabolic surveillance, immune tolerance, and immunological defense.

Keywords:  constitutive danger; horizontal mitochondria transfer; immunity; tissue homeostasis; tolerance

DOI:  https://doi.org/10.1016/j.it.2026.04.008
Nat Commun. 2026 05 19. pii: 4453. [Epub ahead of print]17(1):

Soluble uric acid suppresses neutrophil-mediated host defense in sepsis.

Qiubo Li, Juliane Anders, Kailey Flora, Louisa Ehreiser, Carolin Wendling, Fengjun Zhang, Liang Chang, Danyang Zhao, Li Li, Raimund Vogl, Oliver Soehnlein, Stefanie Steiger.

Neutrophils are essential for host defense and inflammation, yet their dysfunction is a hallmark of acquired immunodeficiency in kidney disease, contributing to increased susceptibility to infections such as peritonitis, sepsis, and pneumonia. We speculated that impaired renal clearance of the metabolite soluble uric acid (sUA) accounts for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-14 mg/dL) related or unrelated to kidney disease significantly exacerbates the inflammatory immune response in mice with endotoxemia and bacterial sepsis. Despite promoting hyperinflammation, HU simultaneously impairs host defense, an effect that is partially reversible by lowering UA levels with febuxostat. We validated these findings in vitro using neutrophils or serum from healthy individuals or hyperuricemic patients with chronic kidney disease. Depleting UA partially restores neutrophil function. Mechanistically, sUA promotes neutrophil activation and degranulation but impairs phagocytosis, leading to reduced NOX2 expression independent of intracellular MPO levels. This results in diminished ROS production and defective bacterial clearance in human neutrophils. In contrast, sUA has no impact on neutrophil extracellular trap formation following exposure to LPS or E.coli. Together, our findings identify HU as an immunometabolic regulator that amplifies hyperinflammation, while simultaneously impairing effective host defense, suggesting that targeting UA may help to overcome acquired immunodeficiency in kidney disease.

DOI: https://doi.org/10.1038/s41467-026-73090-4
Cell Chem Biol. 2026 May 18. pii: S2451-9456(26)00146-7. [Epub ahead of print]

Kinetic control of macrophage death by PTM-turnover crosstalk in infection and inflammation.

Sandhini Saha, Rohit Verma, Aleksandra Nita-Lazar.

  Macrophage fate decisions during infection are commonly framed as receptor-proximal transcriptional choices. We propose that the functional outcome results from a "kinetic race," a dynamic proteostatic competition among protein synthesis, post-translational modifications (PTMs), and degradation. Building on experimental evidence of infection-induced proteostasis, we outline a conceptual "turnover-first" framework. In this model, we hypothesize that the ubiquitin proteasome system (UPS), autophagy, and translational control create a master molecular timer that licenses or restrains pyroptosis, apoptosis, necroptosis, and PANoptosis. We detail how PTMs act as decision codes and present examples of how bacterial pathogens and viruses hijack this network, deploying specialized effectors to move death thresholds by host shutoff, ubiquitin/ISG15 editing, and autophagy evasion. We summarize the emerging chemical biology platforms allowing quantification of these "death competence codes" in real-time, and map drug-addressable nodes offering a systems level strategy to tune macrophage longevity and inflammatory output in sepsis and infectious disease.

Keywords:  PTMs; cell death; infection; inflammation; protein turnover

DOI:  https://doi.org/10.1016/j.chembiol.2026.04.011
bioRxiv. 2026 May 08. pii: 2025.09.15.675924. [Epub ahead of print]

Past viral infections can shape inter-individual variability in anti-viral TLR responses.

Chad Hogan, Zafiirah Baurhoo, Nathália Beller, Ifeoma Osakwe, Ernest Turro, Samira Asgari.

Viral infections can shape adaptive immunity, but whether they also influence innate immune responses later in life remains incompletely characterized. Here, we profiled serum from 12 healthy adults using VirScan, a high-throughput serological assay that infers prior viral exposures by mapping antiviral antibody reactivity across a broad range of viral epitopes. We paired this with ex vivo stimulation of TLR3 and TLR7/8 antiviral pathways and tested whether post-stimulation inflammatory responses are associated with prior viral exposures. At the antibody level, we observed consistent immunodominance at the protein level across individuals, alongside substantial variability at the epitope level. At the functional level, prior exposure to HSV-1, HSV-2, and norovirus was associated with differential production of CCL4, MCP-2, and TNF following TLR7/8 stimulation, respectively. This pilot study establishes a framework for integrating broad viral serology with functional immune profiling to investigate links between lifetime exposures and immune variability. Our results suggest that past viral infections, including acute infections, can contribute to variation in innate immune responses later in life. Larger studies will be required to validate these associations, establish causality, and determine the underlying mechanisms.

DOI: https://doi.org/10.1101/2025.09.15.675924
Am J Physiol Renal Physiol. 2026 May 20.

A Novel Two-Hit Murine Model of Viral Primed Sepsis-Associated Acute Kidney Injury.

James D Odum, Giacynta A Vollmer, Juheb Akhter, Karly Laprocina, Robert P Richter, Jillian R Richter, Anupam Agarwal, Subhashini Bolisetty.

  Viral priming refers to the host's recognition of viral components, triggering an antiviral response and upregulating pathogen recognition receptors. When followed closely by bacterial infection, this immune activation can provoke a hyperinflammatory response, increasing the risk for secondary hemophagocytic lymphohistiocytosis (sHLH), multiorgan failure, and death. We developed a novel murine two-hit model of viral-primed sepsis-associated acute kidney injury (SA-AKI) using polyinosinic-polycytidylic acid (poly(I:C)) for viral mimicry and lipopolysaccharide (LPS) for bacterial stimulation. Male 8-week-old C57BL/6J mice were primed with poly(I:C) (2.5 mg/kg, intraperitoneal (IP) injection) at 24 hours prior to low-dose LPS (0.5 mg/kg, IP) (time = 0 hours) and compared to vehicle-treated controls for up to 48 hours. Poly(I:C)+LPS mice exhibited a significant reduction in glomerular filtration rate at 4 hours post-LPS, and elevated serum creatinine and urinary kidney injury molecule-1 (KIM-1) at 48 hours, indicating sustained kidney injury. These mice also showed marked increases in plasma ferritin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) at 8 hours post-LPS versus non-primed LPS-treated mice, consistent with a hyperinflammatory state. Poly(I:C) alone induced a rapid type I interferon response, with elevated plasma IFNα, IFNβ, and renal Ifnb1 expression by 4 hours post-injection. This model effectively replicates viral-bacterial co-infection and provides a valuable platform to dissect the mechanisms linking viral priming to dysregulated immune responses and acute tubular injury in sepsis.

Keywords:  Acute Kidney Injury; Hyperferritinemia; Poly(I:C); Sepsis; Viral priming

DOI:  https://doi.org/10.1152/ajprenal.00342.2025
Adv Sci (Weinh). 2026 May 19. e21993

Stress History Establishes a Transient Tolerant State That Shapes Antibiotic Survival Upon Resuscitation.

Kieran Abbott, Georgeos Hardo, Ruizhe Li, Jack Bradley, Ashraf Zarkan, Somenath Bakshi.

  Antibiotic treatment failure, often driven by non-genetic mechanisms such as tolerance and persistence, remains a major global health challenge. β$\beta$ -lactams, the most widely prescribed antibiotic class, are particularly compromised by tolerance in dormant, non-growing cells; yet, how these drugs act on cells resuscitating from dormancy remains poorly understood. Here, we investigate the resuscitation phase at an unprecedented scale using Hi-DFA (High-throughput Dynamic Fate Analyser), a single-cell microfluidic platform integrating time-lapse imaging with machine-learning-based image analysis for dynamic cell-fate tracking. We identify a distinct survival strategy: a significant fraction of resuscitating cells transiently slow their growth, facilitating survival upon β$\beta$ -lactam exposure. This 'transiently tolerant' phenotype is considerably less frequent in unstressed, exponentially growing cells, indicating that prior starvation history predisposes cells to this state. Using simulated in vitro pharmacokinetic treatment profiles, we show that suboptimal dosing selectively enriches for this transient tolerance state. A population dynamics model built from this single-cell antibiotic-response data suggests that these transient-tolerant cells, not typical starvation-triggered persisters, may be the primary drivers of rapid population regrowth post-treatment under clinically relevant conditions. Together, our findings define a distinct class of antibiotic survival shaped by stress history and treatment profile, offering a quantitative framework for optimizing antibiotic dosing strategy.

Keywords:  antibiotic persistence; antibiotic pharmacokinetics; relapse dynamics; single‐cell analysis; transient tolerance

DOI:  https://doi.org/10.1002/advs.202521993
Nat Commun. 2026 May 22.

Manganese enhances macrophage bactericidal activity in mice with Staphylococcus aureus osteomyelitis via Sirt3-mitophagy axis.

Xin Guan, Bingsheng Yang, Bowen Bai, Naiqian Cui, Muqi Wang, Jianwen Su, Xiaohu Wu, Chenghua Zhang, Hui Dai, Peng Zhao, Bin Yu, Bowei Wang.

Staphylococcus aureus (S. aureus)-induced osteomyelitis remains challenging in clinical practice, wherein macrophages with impaired bactericidal function serve as reservoirs for intracellular bacterial survival, contributing to persistent and relapsing infections. Here, we show that exogenous manganese (Mn2+) enhances the bactericidal capacity of S. aureus-infected macrophages. By repressing the mitochondrial protein Sirt3, Mn2+ inhibits S. aureus-induced mitophagy via the PTEN-induced kinase 1/parkin pathway, thereby boosting the production of mitochondrial reactive oxygen species to eradicate intracellular bacteria. Pharmacological activation or genetic overexpression of Sirt3 abolishes these effects, identifying this axis as a key molecular target of Mn2+. Based on this, we further develop a biomimetic nanotherapeutic system for targeted Mn2+ delivery. In a mouse model of osteomyelitis, this nanosystem precisely represses Sirt3 in macrophages within the infected medullary cavity, markedly reduces bacterial burden, and effectively alleviates bone destruction. Our findings implicate an immunomodulatory mechanism by which Mn2+ enhances macrophage bactericidal activity and develops a potent Mn2+-based metalloimmunotherapeutical strategy for S. aureus-induced osteomyelitis.

DOI: https://doi.org/10.1038/s41467-026-73529-8