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Klebsiella pneumoniae , particularly hypervirulent strains (hv Kp ), poses a critical public health threat due to its capacity to cause severe, rapidly progressing infections such as pneumonia and sepsis, often leading to acute lung injury (ALI) and high mortality. Despite the recognized role of excessive inflammation and cytokine storms in hv Kp pathogenesis, the precise mechanisms linking immune hyperactivation to fatal tissue damage remain poorly defined. This study reveals that hv Kp infection triggers a coordinated form of inflammatory cell death, PANoptosis, in AMs, the frontline immune defenders in the lungs. We identify the transcription factor STAT1 as a central regulator of this process, driven by a synergistic cytokine milieu, especially involving IFN-γ. Our findings establish a direct mechanistic pathway from hv Kp -induced cytokine release to STAT1-mediated PANoptosis, macrophage depletion, and subsequent lung failure. This work not only advances the understanding of hv Kp virulence but also highlights host signaling pathways and specific cytokines as potential therapeutic targets to modulate immunopathology and improve outcomes in severe Klebsiella infections.

Pathogen interactions with the lungs are very dynamic processes. In biomedical research, it is paramount to model these processes in the laboratory as accurately as possible. Influenza A virus has been extensively studied in epithelial cell culture models, including advanced organoids and organ-on-a-chip systems. Here, we use ex vivo cultured precision cut lung slices (PCLS) and generate transcriptomic data to assess the global tissue resident host response to viral and bacterial challenges. Our data show (i) that murine PCLS faithfully reflect core responses to viral infection, while missing proinflammatory responses linked to infiltrating immune cells and (ii) that human PCLS show a highly diversified tissue resident immune response to viral infection due to previous exposures of the host to this pathogen. These responses are clearly distinct from antibacterial gene profiles. Our data advertise PCLS as a complex and realistic model to study tissue resident immune responses to microbes in a human system.

Aspergillus fumigatus is an environmental mold that causes invasive pulmonary disease in immunocompromised individuals. Owing to limited diagnostic tools, a narrow arsenal of effective treatments, and rising antifungal resistance, the World Health Organization (WHO) has designated A. fumigatus as a critical priority fungal pathogen, highlighting the urgent need for further research. Patients with compromised immunity often receive broad-spectrum antibiotics to prevent or treat opportunistic infections, leading to significant disruption of the resident commensal microbiota. This antibiotic-induced dysbiosis has been linked to Clostridium difficile colitis and to intestinal overgrowth of vancomycin-resistant Enterococcus and Candida parapsilosis , preceding bloodstream infection. However, the impact of antibiotic treatment on susceptibility to invasive pulmonary aspergillosis remains undefined. In this study, we found that oral treatment with ampicillin, but not neomycin or vancomycin, significantly increased mortality in mice following A. fumigatus infection. Neutrophils from the lungs of ampicillin-treated mice also showed markedly impaired fungal killing. These findings raise the possibility that preserving microbiome integrity during antibiotic treatment could enhance immune protection against invasive aspergillosis in at-risk patient groups.

Bacille Calmette Guerin (BCG) vaccination in genetically diverse outbred (DO) mice provides significant protection against Mycobacterium tuberculosis ( Mtb) challenge. This protection induced pathways associated with transforming growth factor B (TGF-β) receptor complex, genes associated with lung repair, and Toll-like receptor (TLR)-10 pathway. The enhanced protection observed in BCG-vaccinated mice correlated with improved formation of B-cell follicles and IL-17-producing CD4 + T-cell responses. CD4 + T-cell responses mediated the enhanced protection in the lungs of DO mice vaccinated with BCG + adjuvant, as depletion of CD4 + T-cell responses reversed the enhanced protection. The DO mouse model of tuberculosis vaccination is a highly relevant model to probe mechanisms of vaccine-induced protection and provide novel insights into lung pathways that mediate protection. The study also found that genes associated with lung repair, including TGF-β receptor complex pathways, were induced in BCG-vaccinated Mtb -infected DO mouse lungs. The study suggests that the activation of lung innate pathways in BCG vaccination through the use of mucosal Amph CpG delivery, CD40L activation, and IL-10 neutralization could significantly enhance protection upon Mtb challenge.

is an opportunistic respiratory commensal bacterium and leading cause of pneumonia, meningitis, and sepsis, resulting in over a million deaths annually, particularly in children aged under 5. The rapid spread of macrolide-resistant strains led the WHO to designate as a priority pathogen that urgently requires alternative therapeutic strategies. Here, we identified the FDA-approved cancer drug sorafenib to show a dose-dependent, broad-spectrum efficacy against many pneumococcal serotypes, including multidrug-resistant clinical strains. screening and molecular dynamics simulations indicated potential interaction with the catalytic cleft of the pneumococcal serine/threonine kinase StkP, a central regulator of cell division and peptidoglycan synthesis. kinase assays using purified recombinant StkP kinase domain and p-Thr-specific immunoblotting revealed dose-dependent inhibition of kinase activity by sorafenib in pneumococci. Ectopic expression of StkP partially rescued growth inhibition by sorafenib, and the direct interaction was assessed by isothermal titration calorimetry, suggesting StkP as one of the potential targets in . Sorafenib-treated bacteria showed abnormal morphology, increased membrane permeability, enhanced complement C3 deposition, and reduced adherence and invasion into lung epithelial cells without significant host cytotoxicity. Serial passaging of bacteria with sorafenib suggested low resistance potential. , sorafenib administration at 10% of the clinically relevant dose delayed mortality and significantly reduced bacterial burden in a murine pneumonia model, supporting its further preclinical development for therapeutic intervention. , a WHO priority pathogen and causative of pneumonia, meningitis, and sepsis worldwide, has developed resistance to several commonly used antibiotics, limiting available treatment options. In this study, we show that sorafenib, a drug currently approved for cancer treatment, can also inhibit the growth and disease-causing ability of , including clinical strains. Our findings reveal that sorafenib interferes with a key bacterial regulatory enzyme that controls cell division and cell wall formation, exposing a previously underexplored vulnerability in this pathogen. Because sorafenib is already clinically approved, this work highlights the potential of drug repurposing as a faster route to identify new antimicrobial therapies. More broadly, our results demonstrate that bacterial kinases represent promising targets for developing next-generation treatments against key bacterial pathogens.

Intrastrain genetic and phenotypic diversity within Pseudomonas aeruginosa populations is common in chronic pulmonary infections. While this intrastrain heterogeneity is a hallmark of chronic infection, its consequences for the spatial organization of P. aeruginosa within the airways remain unclear. Here, we demonstrate that the loss of O-specific antigen in a subpopulation of P. aeruginosa significantly alters the spatial architecture of P. aeruginosa , without changing the total population size or composition. Using a combination of tissue clearing and hybridization chain reaction RNA-FISH in a murine lung infection model, we mapped the localization of genetically distinct P. aeruginosa variants in mixed populations in vivo . These findings reveal that genetic diversification within a strain can reshape the infection landscape at the micron scale, highlighting the overlooked role of intrastrain dynamics in shaping the microbiogeography of infections and influencing host-pathogen interactions.

Dust inhalation can lead to health effects, especially when toxic chemicals and microbes mix in with the dust particles. As California's Salton Sea dries up, it exposes lake bottom sediments to wind, which disperses the dried sediments. To mimic the effect of inhaling Salton Sea dust, we collected and filtered airborne dust to use in exposure experiments with mice in environmental chambers. We predicted that inhaling small dust particles, chemicals, and microbial residues found in this dust would affect mouse respiratory health or change the microbes found inside their lungs. We found that inhaling dust led to lung inflammation, and the dust source influenced the type of microbes found inside mouse lungs. As lakes continue to dry out, we expect greater health risks and changes to lung microbiomes.

Dietary zinc deficiency is a major risk factor for infection worldwide. In the United States, hospitalized patients are at increased risk of zinc deficiency and A. baumannii pneumonia. In this study, A. baumannii purine biosynthesis was required for lung infection of mice, independent of dietary zinc. Therefore, bacterial purine biosynthesis is an attractive drug target for treating lung infections in patients with variable dietary zinc statuses, such as in hospitalized patients.

Therapeutics that target the virulence of pathogens rather than their viability offer a promising alternative for treating infectious diseases and circumventing antibiotic resistance. In this study, we searched for anti-virulence compounds against Pseudomonas aeruginosa from Chinese herbs and investigated baicalin from Scutellariae radix as such an active anti-virulence compound. The effect of baicalin on a range of important virulence factors in P. aeruginosa was assessed using luxCDABE-based reporters and by phenotypical assays. The molecular mechanism of the virulence inhibition by baicalin was investigated using genetic approaches. The impact of baicalin on P. aeruginosa pathogenicity was evaluated by both in vitro assays and in vivo animal models. The results show that baicalin diminished a plenty of important virulence factors in P. aeruginosa, including the Type III secretion system (T3SS). Baicalin treatment reduced the cellular toxicity of P. aeruginosa on the mammalian cells and attenuated in vivo pathogenicity in a Drosophila melanogaster infection model. In a rat pulmonary infection model, baicalin significantly reduced the severity of lung pathology and accelerated lung bacterial clearance. The PqsR of the Pseudomonas quinolone signal (PQS) system was found to be required for baicalin’s impact on T3SS. These findings indicate that baicalin is a promising therapeutic candidate for treating P. aeruginosa infections.

is the main causative pathogen of nosocomial infections that causes severe infections in the lungs. In this study, we analyzed the histopathological characteristics of lung infection with two strains of (ATCC 19606 and the clinical isolate TK1090) and PAO-1 in C3H/HeN mice to evaluate the virulence of . Survival was evaluated over 14 days. At 1, 2, 5, or 14 days postinfection, mice of C3H/HeN were sacrificed, and histopathological analysis of lung specimens was also performed. Histopathological changes and accumulation of neutrophils and macrophages in the lungs after infection with and were analyzed. Following intratracheal inoculation, the lethality of ATCC 19606- and TK1090-infected mice was lower than that of PAO-1-infected mice. However, when mice were inoculated with a sub-lethal dose of , the lung bacterial burden remained in the mice until 14 days post-infection. Additionally, histopathological analysis revealed that macrophages infiltrated the lung foci of ATCC 19606-, TK1090-, and PAO-1-infected mice. Although neutrophils infiltrated the lung foci of ATCC 19606- and TK1090-infected mice, they poorly infiltrated the lung foci of PAO-1-infected mice. Accumulation of these cells in the lung foci of ATCC 19606- and TK1090-infected mice, but not PAO-1-infected mice, was observed for 14 days post-infection. These results suggest that is not completely eliminated despite the infiltration of immune cells in the lungs and that inflammation lasts for prolonged periods in the lungs. Further studies are required to understand the mechanism of infection, and novel drugs and vaccines should be developed to prevent infection.