Infection and Immunity最新文献

Metabolic adaptation to the host environment is a key determinant of bacterial pathogenesis, enabling both colonization and invasive disease. This is particularly true for Neisseria gonorrhoeae (Gc), the causative agent of gonorrhea, which lacks effector-injecting secretion systems or toxins. Gc infection triggers a rapid influx of neutrophils (polymorphonuclear cells [PMNs) that typically kill bacteria through multiple mechanisms, including a potent oxidative burst. Despite this, Gc exhibits remarkable resistance to reactive oxygen species and readily replicates in the presence of PMNs, which is in part due to the consumption of PMN-derived lactate. Previous studies demonstrated that the lactate permease, LctP, is required for oxidative stress resistance in Gc and host colonization in a murine model of gonorrhea, suggesting that lactate utilization contributes to virulence. Gc encodes four lactate dehydrogenases (LDHs) with distinct regulation and mechanisms, including two L-LDHs, LldD and LutACB. Although either enzyme alone supports L-lactate utilization, we found that both are required for full fitness during co-colonization with PMNs, indicating some non-redundant roles. Furthermore, LldD enhances oxidative stress resistance and is required for Gc colonization in a murine model of gonorrhea, whereas LutACB is dispensable. These findings identify LldD as a key factor promoting oxidative stress resistance, survival during PMN challenge, and host colonization.

Group B Streptococcus (Streptococcus agalactiae, GBS) is a leading cause of invasive infections in neonates and adults. The adult gastrointestinal (GI) tract represents an understudied site of asymptomatic carriage with potential relevance for both transmission and disease. Here, we establish a murine model of GBS colonization in the adult GI tract, which provides a tractable system for probing host-microbe interactions within this niche. Using this model, we establish that GI carriage is generalizable to diverse GBS isolates and leverage transposon sequencing (Tn-Seq) to identify candidate GBS factors important for GI colonization. Informed by these Tn-Seq data, we identify GBS capsule as a critical colonization factor of the adult murine GI tract. Taken together, this work highlights the GI tract as a reservoir for GBS and introduces a new experimental framework for investigating the bacterial and host determinants of GBS GI carriage.

Staphylococcus aureus is a leading cause of prosthetic joint infection (PJI) typified by biofilm formation. Anti-inflammatory granulocytic myeloid-derived suppressor cells (G-MDSCs) represent the main leukocyte population in a mouse model of S. aureus PJI, followed by neutrophils (PMNs), and macrophages (Mφs), which is also seen during human PJI. Defining how each leukocyte population responds to S. aureus biofilm vs planktonic bacteria could have important implications for how S. aureus evades immune detection to facilitate biofilm persistence. This study compared the kinetics of leukocyte death and relationship to mitochondrial ROS (mtROS) production following exposure to planktonic S. aureus or biofilm. Mφs were exquisitely sensitive to S. aureus biofilm with toxicity observed within 15 min following biofilm co-culture, whereas G-MDSCs and PMNs were more resilient, with appreciable survival out to 6 h. In contrast, G-MDSC viability was significantly decreased after extended exposure to planktonic S. aureus compared to PMNs and Mφs. Although leukocyte death coincided with increased mtROS production across all leukocyte populations, inhibiting mtROS had no impact on leukocyte survival following biofilm co-culture, suggesting alternative cell death triggers. Caspase-1-dependent pyroptosis was observed in PMNs, whereas Mφs and G-MDSCs were targeted by necrosis since an inhibitor of H₂O₂-induced necrosis improved cell survival of both populations, whereas programmed cell death inhibitors had no effect. These findings may account, in part, for the abundance of G-MDSCs and PMNs, but not Mφs, during PJI based on differential susceptibility to biofilm-induced cytotoxicity.

Klebsiella pneumoniae bacteremia is a significant public health burden with a 26% mortality rate, which increases when the infecting isolate is multidrug resistant. An important virulence factor of K. pneumoniae is its capsule, the protective polysaccharide coat that surrounds the outer membrane and is made up of individual capsular polysaccharide (CPS) chains. The capsule can differ in composition, abundance, surface attachment, and length of the individual CPS chains. Long, uniform CPS chains are associated with a high level of mucoidy. Typically, mucoidy is produced by the hypervirulent K. pneumoniae (hvKp) pathotype, which is associated with invasive community-acquired infections. In contrast, the classical K. pneumoniae (cKp) pathotype tends to be less mucoid or non-mucoid and is associated with nosocomial infections and multidrug resistance. There are over 80 serotypes of K. pneumoniae capsule. Capsule swap experiments have begun to reveal the effect of serotype on virulence and immune interactions. Clinically, the K2 capsule serotype is a common serotype associated with neonatal bloodstream infections. Both cKp and hvKp can produce K2 capsule, but how K2-encoding cKp and hvKp strains differ in a bloodstream infection remains unknown. To fill this gap in knowledge, we characterized the surface properties of K2 serotype cKp and hvKp bloodstream infection isolates then tested the fitness of these strains in bloodstream infection-related in vitro and in vivo assays. Understanding how K2 cKp and hvKp strains differ in pathogenic potential provides further insights into how K. pneumoniae capsule properties influence bloodstream infection pathogenesis.

Non-receptor tyrosine kinase c-Abl is critical for host defense against bacterial and viral infections, yet its role in antifungal immunity remains elusive. Here, we report that inhibition of c-Abl with flumatinib mesylate significantly impairs the survival rate and exacerbates fungal burden in mice infected with Candida albicans. Our findings reveal that c-Abl inhibition reduces production of TNF-α, IL-10, and IL-12 in bone marrow-derived dendritic cells (BMDCs) after stimulation with fungal β-glucan or α-mannan. Mechanistically, c-Abl inhibition significantly blocks p38 and extracellular signal-regulated kinases 1/2 (ERK1/2) activation in BMDCs after α-mannan stimulation in a c-Cbl dependent manner. Collectively, our study uncovers a c-Abl/c-Cbl/MAPK signaling axis in dendritic cells that governs antifungal innate immunity, highlighting c-Cbl as a critical downstream mediator linking c-Abl to host defense against C. albicans. Our findings provide a mechanistic basis for fungal risk assessment in cancer patients treated with c-Abl inhibitors.

Key bacterial vaginosis (BV)-associated bacteria implicated in biofilm formation include Gardnerella species, Prevotella bivia, and Fannyhessea vaginae. We investigated their spatial organization in the BV biofilm over time from longitudinal vaginal specimens obtained from women with incident BV (iBV) using peptide nucleic acid-fluorescence in situ hybridization (PNA-FISH). Heterosexual women with optimal vaginal microbiota self-collected vaginal specimens twice daily for 60 days or until iBV development (Nugent score 7-10 on ≥4 consecutive specimens). Women who developed iBV were matched to healthy controls by age, race, and contraceptive method. Gardnerella spp., P. bivia, and F. vaginae were quantified using PNA-FISH 2 days pre-iBV, the day of iBV, and 2 days post-iBV across five optical layers (z, z + 2, z + 4, z + 6, and z + 8 μm). Total counts of all three bacterial species were significantly higher on the day of iBV compared to 2 days pre-iBV (P = 0.011) and remained elevated 2 days post-iBV. Across most layers and time points, pooled mean Gardnerella spp. counts were significantly higher than F. vaginae counts (P ≤ 0.022-0.0003). On the day of iBV and 2 days post-iBV, pooled mean counts of Gardnerella spp. and F. vaginae progressively increased across most biofilm layers (P ≤ 0.043-0.0012). Controls had significantly lower counts of Gardnerella spp. and F. vaginae. P. bivia had low counts in all specimens. During the critical time period surrounding iBV, Gardnerella spp. are abundant throughout the developing biofilm and facilitate F. vaginae incorporation at later time points and higher biofilm layers. Additional research, including other Prevotella spp., is needed.IMPORTANCEBacterial vaginosis (BV) is the most common vaginal infection in reproductive-age women worldwide with a global prevalence of 30%. Recurrence rates can be up to 60% within 1 year of treatment. While BV is characterized as a polymicrobial biofilm infection, the exact etiology remains unknown. The BV biofilm may persist after antibiotic treatment, possibly due to incomplete eradication by current antimicrobial therapies, contributing to recurrent infection. Data are limited in evaluating the spatial formation of the BV biofilm around the time of incident BV. Providing a better understanding of this critical time period in incident BV pathogenesis is necessary to inform the development of prevention methods aimed at inhibiting biofilm formation and improving long-term treatment outcomes.

Mortality in very-low birth-weight (VLBW) infants accounts for up to 50%-70% of the neonatal mortality and up to 25%-30% of infant mortality. Despite the global increase in survival rates, this population remains at heightened risk for developing long-term neurodevelopmental delays, chronic lung disease, malnutrition, and visual and hearing disabilities. The gut microbial composition of VLBW differs from full-term infants and is typically dominated by pathobionts. In this study, we characterized the bacterial composition of the VLBW infant microbiota born at Pereira Rossell Children's Hospital (academic, tertiary referral center) in Montevideo, Uruguay by sequencing the full-length 16S rRNA gene using Oxford Nanopore Technologies. We describe a high predominance of Klebsiella pneumoniae and Escherichia coli in these infants. By sequencing stool samples from two time points, we show that the microbial community diversity increases over time with a higher relative abundance of Bacteroides and Veillonella. Moreover, we describe the effect on the microbial composition of long antibiotic exposure. Different species of the Klebsiella genus, along with Escherichia coli, Enterobacter cloacae, Citrobacter freundii, and Veillonella parvula were observed at a higher relative abundance in patients with more than 5 days of antibiotic treatment. Taken together, our findings shed light on the development and establishment of microbial communities in early-life microbial communities in South America. Our results point to postnatal antibiotics as a major factor orchestrating this process. The integration of microbial community health considerations into preterm clinical care is crucial for improving long-term infant development.

The human immune system employs both innate and adaptive mechanisms to control pathogens, with antibodies playing a pivotal role in immune memory and defense, in particular against viral infections. In tuberculosis, antibody titers have long been used to assess immune responses, but their presence alone fails to predict protective efficacy. Recent studies highlight that antibody functionality is critical for effective immune activity. Despite widespread detection of Mycobacterium tuberculosis (Mtb)-reactive antibodies in individuals with active disease, Mtb infection, and even in healthy controls, their potential to control Mtb growth is variable and only detected in a proportion of individuals. This perspective emphasizes the need for robust functional assessment of antibodies to better understand their role in mycobacterial control and inform vaccine development. Notably, antibodies binding to purified protein derivative of Mtb, a mixture of degraded antigens from Mtb cultures, are widespread but not universally functional, underscoring the importance of Fc characteristics and epitope specificity. Initial high-throughput screening using phagocytosis and direct mycobacterial binding assays is an active indicator of antibody function. By refining and combining existing assays, as recommended in this perspective, we can better characterize antibody contributions, particularly their immunomodulatory potential, toward improved control of Mtb. Albeit antibodies may not be essential in natural protection, functional antibodies induced by vaccination may be of added value and contribute to host protection.

Neurosyphilis is an infectious disease of the nervous system caused by Treponema pallidum. With the resurgence of syphilis worldwide, neurosyphilis has become prevalent again, but research on its pathogenesis remains challenging. T. pallidum exhibits remarkable invasive potential and immune evasion properties, which enable it to rapidly penetrate the blood-brain barrier (BBB) and infiltrate the central nervous system. Meanwhile, the immune response induced by this pathogen may cause tissue damage and accelerate disease progression. Additionally, host factors and the genotypes of T. pallidum strains are associated with susceptibility to neurosyphilis. This review systematically summarizes the latest literature on neurosyphilis, outlines recent advances in research on the effects of T. pallidum on the BBB, its immune interactions with the host, and omics-related studies, and aims to provide directions for future research on the pathogenesis of neurosyphilis.