The increasing prevalence of multidrug-resistant (MDR) bacteria has reduced the effectiveness of standard antibiotics, prompting renewed interest in bacteriophage (phage) therapy as an alternative or adjunctive treatment. Phage therapy offers high specificity, self-amplification at infection sites, and minimal disruption to the gut microbiota. However, clinical implementation is challenging, due to the risk of phage resistance and uncertainties regarding optimal dosing and immune interactions.
Previously, we demonstrated that a two-phage cocktail exhibited low immunogenicity in mice and, when combined with meropenem, significantly improved clearance of ventilator-associated Pseudomonas aeruginosa pneumonia, reduced inflammation, and disrupted biofilms more effectively than either treatment alone. In the present study, we investigated the interplay between this phage cocktail and innate immune defenses using a murine respiratory infection model and human in vitro assays.
Our findings reveal that the therapeutic efficacy of phage treatment is critically dependent on the presence of neutrophils, which act synergistically with phages to achieve effective bacterial clearance, particularly when bacterial burden exceeds a defined threshold. Alveolar macrophages, however, do not significantly contribute to infection resolution in vivo.
Since neutrophils play a key-role in supporting phage-mediated Pseudomonas clearance, the efficacy of phage therapy is closely linked to the hosts immune competence - an important consideration when treating immunocompromised patients.
Copyright © 2025 Weissfuss, Hoffmann, Behrendt, Bürkle, Twamley, Korf, Ahrens, Rohde, Zobel, Debarbieux, Ricard, Witzenrath and Nouailles.

Powassan virus (POWV) is a tick-borne flavivirus that causes neurotropic disease in humans. POWV causes fatal encephalitis and meningitis in 10% of human cases and long-term neurological sequelae in 50% of surviving patients. While innate antiviral responses have been extensively studied in mosquito-borne flavivirus infections, they remain less well characterized in the context of tick-borne flaviviruses. In this study, we investigated the role of interferon α/β receptor in the pathogenesis of POWV infection in vivo. Herein, we showed that unlike wild-type (WT) mice, interferon α/β receptor-deficient (Ifnar-/- ) mice were highly susceptible to POWV and rapidly succumbed to infection. Low inoculum dosage resulted in 100% mortality rate in Ifnar-/- mice early after infection. Higher levels of viremia accompanied by increased serum levels of proinflammatory cytokines and chemokines were observed in Ifnar-/- mice. Further, we detected significantly higher virus levels in the peripheral tissues including spleen, liver and kidney in Ifnar-/- mice compared to WT mice. Subsequent analyses revealed marked pathology and elevated inflammatory responses in the peripheral organs of Ifnar-/- mice. Additionally, Ifnar-/- mice showed a stunted immune response in the spleen with significantly decreased numbers of B cells, monocytes, and neutrophils. While WT mice exhibited increased splenic accumulation of Ly6C+ cells, this recruitment was markedly impaired in Ifnar-/- mice. Notably, viral load quantification and immunofluorescence analysis showed no significant difference in brain viral load between WT and Ifnar-/- mice; however, Ifnar-/- mice displayed elevated inflammatory response in the brain. These data suggest that the rapid mortality observed in Ifnar-/- mice is due to uncontrolled virus dissemination and excessive inflammation in the periphery rather than brain infection. Collectively, our data reveal that the type-I interferon response restricts viral tropism and pathogenesis of POWV in mice.
Copyright © 2025 Elsharkawy, Pathak, Dim and Kumar.

Microglial replacement is emerging as a promising concept for treating age-related disorders, but effects on epigenetic age remain unclear. Here, we examined DNA methylation dynamics in microglia from young and old mice and evaluated how ischemic stroke and microglial depletion/repopulation (D/R) influence their epigenetic landscape. Using epigenetic clocks, we confirmed that old microglia display an aged DNA methylation profile, consistent with functional decline. Both stroke and microglial D/R induced an acceleration of epigenetic age, likely reflecting proliferative stress associated with these conditions. However, genome-wide methylation profiling using DNA methylation arrays revealed that microglial repopulation also reversed a large fraction of age-associated DNA methylation changes, particularly within pathways related to immune activation and inflammatory responses. These findings suggest that microglial D/R, though linked to epigenetic age acceleration, leads to the widespread reversal of aging-associated DNA methylation changes, which may help explain the beneficial outcomes observed after microglial replacement. Overall, our results highlight the complexity of interpreting epigenetic age measures and underscore the potential of microglial replacement strategies for brain rejuvenation.

Acute liver injury often progresses to liver failure, with immune responses playing a critical role in regulating the inflammatory process. In this study, we aim to investigate the effects of iron on CD11c+ myeloid cells during acetaminophen-induced liver injury. Iron overload caused by F-box and leucine-rich repeat protein 5 (FBXL5) deficiency in CD11c+ cells exacerbates liver damage. CD11c+ myeloid cell-specific FBXL5-deficient mice exhibit higher serum transaminase levels, liver injury, and mortality than the controls. These phenotypes are associated with enhanced neutrophil infiltration and expression of interleukin (IL)-6, a pro-inflammatory cytokine. Mechanistically, iron overload in FBXL5-deficient cells increases IL-6 production by facilitating the recruitment of nuclear factor-κB to the Il-6 promoter. In vivo, IL-6 neutralization mitigates liver injury, confirming its role in disease progression. Our findings highlight the role of iron in immune responses and suggest that targeting iron may represent a potential therapeutic strategy for liver injury.
© 2025. The Author(s).

Traumatic brain injury (TBI) is an environmental risk factor for dementia and long-term neurological deficits, posing a significant public health challenge. TBI-induced neuroinflammation involves both brain-resident microglia and peripheral monocyte-derived macrophages (MDMs). Previous research has shown that MDMs contribute to the development of long-term memory deficits, yet their long-term behavior following brain infiltration remains unclear. To address this, our study uses two complementary fate-mapping mouse lines, CCR2-creERT2 and Ms4a3-cre, for precise and lasting tracking of MDMs in vivo. Here we show that MDMs persist in the brain for at least 8 months post-TBI in both male and female mice. MDMs retain phagocytic activity for at least 30 days post-TBI, remain transcriptionally distinct from microglia, and display a gene expression profile associated with aging and disease. Moreover, we identify a core transcriptomic signature of MDMs shared across various mouse models and brain perturbations, which is also enriched in the brain myeloid cells of male subjects with TBI and Alzheimer's disease patients. These findings enhance our understanding of MDMs' dynamics after TBI and inform future targeted myeloid-based therapies.
© 2025. The Author(s).