Infection and Immunity最新文献

Chronic infections involving bacterial biofilms are a major clinical challenge due to the ability of biofilm to resist antimicrobial treatments and host immune responses. The resulting persistent infections are often accompanied by collateral damage mainly executed by activated components of the innate immune system in response to the infectious biofilm. The innate immune system responds to the recognition of pathogen-associated molecular patterns (PAMPs), which are broadly expressed by both planktonic and biofilm-forming bacteria. However, the expression of special PAMPs in association with biofilms remains poorly defined. Here, we review prior studies that provide experimental evidence of the existence of immune-activating molecular patterns that are expressed at immunostimulatory levels in biofilms but not in planktonic bacteria. Accordingly, we introduce the concept of biofilm-associated molecular patterns (BAMPs) as a subset of PAMPs that are expressed in biofilms. Identifying BAMPs and elucidating their role in innate immune activation may inform the development of targeted therapies to reduce collateral tissue damage in biofilm-associated infections.

Mobile genetic elements play an essential part in the infectious process of major pathogens, yet the role of prophage dynamics in Staphylococcus aureus pathogenesis is still not well understood. Here, we studied the impact of the Φ13 hlb-converting prophage, whose integration inactivates the hlb β-toxin gene, on staphylococcal pathogenesis. We showed that prophage Φ13 is lost in approximately half the bacterial population during the course of infection. Inactivation of the Φ13 int recombinase gene, essential for insertion/excision, locked the prophage in the bacterial chromosome, leading to a significant loss of virulence in a murine systemic infection model. In contrast, the non-lysogen strain (ΔΦ13), where the hlb beta-hemolysin gene is reconstituted, displayed strongly increased virulence. Accordingly, histopathological analyses revealed more severe nephritis in mice infected with bacteria lacking prophage Φ13 (ΔΦ13), compared to infection with the parental strain. Infection with the ∆int mutant, where beta-hemolysin production is abolished, led to the least severe renal lesions. Cytokine induction in a human neutrophil model showed significantly increased IL-6 expression following infection with the beta-hemolysin producing strain (ΔΦ13). Our results indicate that timely in vivo excision of the Φ13 prophage is essential for progression of the S. aureus infectious process: early excision leads to rapid host death, whereas the inability to excise the prophage significantly reduces staphylococcal virulence.IMPORTANCEThis study highlights prophage Φ13 excision as a critical factor in Staphylococcus aureus pathogenesis, influencing infection outcomes by balancing rapid host killing with reduced bacterial virulence. This mechanism may represent a bet-hedging strategy in genetic regulation, resulting in a mixed bacterial population capable of rapidly switching between two processes: bacterial colonization and host damage. Unraveling this dynamic opens new possibilities for developing targeted therapies to disrupt or modulate prophage activity, offering a novel approach to mitigating S. aureus infections.

Chlamydia trachomatis (CT) infection can lead to pelvic inflammatory disease, infertility, and other reproductive sequelae when it ascends to the upper genital tract. Factors including chlamydial burden, coinfection with other sexually transmitted bacterial pathogens, and oral contraceptive use influence risk for upper genital tract spread. Cervicovaginal microbiome composition influences CT susceptibility, and we investigated if it contributes to spread by analyzing amplicon sequence variants (ASVs) derived from the V4 region of 16S rRNA genes in vaginal samples collected from women at high risk for CT infection and for whom endometrial infection had been determined. Participants were classified as CT negative (CT-, n = 70), CT positive at the cervix (Endo-, n = 79), or CT positive at both cervix and endometrium (Endo+, n = 68). Although we were unable to identify many significant differences between CT-infected and -uninfected women, differences in abundance of ASVs representing Lactobacillus iners and Lactobacillus crispatus subspecies but not dominant lactobacilli were detected. Thirteen informative ASVs predicted endometrial chlamydial infection (area under the curve = 0.72), with CT ASV abundance emerging as a key predictor. We also observed a positive correlation between levels of cervically secreted cytokines previously associated with CT ascension and abundance of the informative ASVs. Our findings suggest that vaginal microbial community members may influence chlamydial spread directly by nutrient limitation and/or disrupting endocervical epithelial integrity and indirectly by modulating proinflammatory signaling and/or homeostasis of adaptive immunity. Further investigation of these predictive microbial factors may lead to cervicovaginal microbiome biomarkers useful for identifying women at increased risk for disease.

Preterm infants are highly susceptible to bacterial infections and inflammatory diseases. These vulnerabilities arise from disruptions in gut microbiome structure and function, immune system immaturity, and underdeveloped organ systems. In this review, we explore the role of the gut microbiome in neonatal health. With a specific focus on preterm infants, we outline how microbiome disruption contributes to negative clinical outcomes. First, we provide an overview of infant gut microbiome development, highlighting key factors that influence its trajectory. Next, we examine the interplay between the infant gut microbiome and the development of systemic and intestinal immune systems, with emphasis on how microbiome perturbations related to preterm birth alter host-microbiome interactions and the overall immune landscape. We then discuss the role of altered gut composition in disease states common to preterm infants, such as sepsis, bacterial infections, and necrotizing enterocolitis. Finally, we discuss current and future diagnostics and treatments and offer our perspective on future research to untangle the host-microbiome interface in early life.

Entamoeba histolytica is a major cause of diarrheal disease. E. histolytica trophozoites ("amoebae") can invade the intestine and disseminate via the bloodstream, resisting complement lysis through unknown mechanisms. Amoebae kill human cells by performing trogocytosis. After performing trogocytosis, amoebae display human proteins on their own surface and are resistant to lysis by human serum. In this study, we sought to further evaluate the mechanism by which amoebae resist complement lysis. To test if complement is responsible for lysis of amoebae, C3-depleted serum was compared to replete serum, and C3 was indeed required for lysis. Amoebae were allowed to perform trogocytosis of human cells and exposed to mouse serum. Although they had performed trogocytosis on a different species than the source of the serum, they were protected from lysis. To test if the protection from lysis by mouse serum was due to the functional interchangeability of human and mouse complement pathway proteins, human CD46 or CD55 (negative regulators of complement activation) were exogenously expressed. Amoebae that expressed human CD46 or CD55 were protected from lysis by mouse serum, indicating that display of human proteins was sufficient to inhibit mouse complement activation. Finally, amoebae were allowed to perform trogocytosis of a cell type in which the complement pathway is not conserved, and they did not become resistant to lysis. Overall, these findings are consistent with the model that trogocytosis enables amoebic acquisition and display of host proteins, including negative regulators of the complement pathway, that provide protection from complement lysis. Since other microbes can perform trogocytosis, this novel mechanism for complement resistance might apply to other infections.

Bloodstream infections caused by Pseudomonas aeruginosa are associated with high mortality rates. The complement system, a key component of the innate immune response, plays a major role in eliminating P. aeruginosa from human blood. However, the sensitivity of P. aeruginosa strains to plasma varies widely, ranging from highly sensitive to persistent or fully resistant. Although most studies use model strains, the species genomic and phenotypic diversities suggest more complex interactions with complement than previously appreciated. In this study, we characterized the plasma resistome of P. aeruginosa using Tn-seq in three strains with varying levels of plasma sensitivity. A gain-of-function screen in the plasma-sensitive strain PA14 revealed numerous bacterial factors influencing plasma resistance, including components of the RetS-LadS/Gac/Rsm regulatory pathway and outer membrane porins. In the plasma-resistant strains CHA and YIK, Tn-seq analysis indicated that each strain relies on a distinct, limited set of proteins to evade complement-mediated killing. Despite these differences, we identified common mechanisms across all three strains. These include the production of exopolysaccharides (EPSs), the presence of surface appendages, and modifications in the O-specific antigen. Notably, we identified Ssg and Crc as shared contributors to plasma resistance. Although deletion mutants lacking ssg and/or crc exhibited reduced survival in plasma, a subpopulation of these mutants was able to persist during prolonged exposure. Overall, this work provides new insights into the complex interplay between P. aeruginosa and the human complement system in the context of bloodstream infections and raises concerns regarding the efficacy of therapies that target individual virulence factors.

The guanylate-binding protein (GBP) family, a group of interferon-induced GTPases, is pivotal in pathogen defense, inflammation regulation, and tumor immunity. Among them, GBP5 has emerged as a key player due to its distinctive roles in various diseases. However, existing studies reveal significant gaps, particularly regarding its expression, regulatory mechanisms, and functional dynamics across diverse diseases and patient populations, limiting its reliability as a biomarker or therapeutic target. This review provides a comprehensive synthesis of GBP5 functions across infectious diseases, cancer, immune disorders, and inflammation, with dedicated analysis of its context-dependent functional variability in distinct immune landscapes, genetic backgrounds, and disease progression stages. This systematic evaluation provides a critical foundation for future research, highlighting GBP5's promise as both a biomarker and therapeutic target in precision medicine.

Leishmania infantum causes human visceral leishmaniasis and leishmaniosis (CanL) in reservoir host, dogs. As infection progresses to disease in both humans and dogs, there is a shift from controlling type 1 immunity to a regulatory, exhausted T cell phenotype. In endemic areas, the association between tick-borne coinfections (TBCs) and Leishmania diagnosis and/or clinical severity has been demonstrated. To identify immune factors correlating with disease progression, we prospectively evaluated a cohort of L. infantum-infected dogs from 2019 to 2022. The cohort was TBC-negative with asymptomatic leishmaniosis at the time of enrollment. We measured TBC serology, anti-Leishmania antigen T cell immunity, CanL serological response, parasitemia, and disease severity to probe how nascent TBC perturbs the immune state. At the conclusion, TBC+ dogs with CanL experienced greater increases in anti-Leishmania antibody reactivity and parasite burden compared to dogs that did not have incident TBC during the study. TBC+ dogs were twice as likely to experience moderate (LeishVet stage 2) or severe/terminal disease (LeishVet stage 3/4). Prolonged exposure to TBC was associated with a shift in Leishmania antigen-induced interferon gamma (IFN-γ)/interleukin-10 (IL-10) and enhanced CD8 T cell proliferation. Frequency of proliferating CD8 T cells significantly correlated with parasitemia and antibody reactivity. TBC exacerbated parasite burden and immune exhaustion. These findings highlight the need for combined vector control efforts as prevention programs for dogs in Leishmania endemic areas to reduce transmission to humans. Public health education efforts should aim to increase awareness of the connection between TBC and leishmaniosis.

Invasive pulmonary aspergillosis (IPA) is a severe fungal disease caused by Aspergillus fumigatus (Af) that may spread hematogenously to extrapulmonary organs. IPA is typically associated with a broad spectrum of immunocompromised conditions and constitutes a high mortality rate. While the association of influenza as a risk for secondary bacterial infections is well appreciated, emerging evidence indicates that influenza-hospitalized patients demonstrate increased susceptibility to severe aspergillosis infection. In this study, we developed a murine Influenza A Virus (IAV)-Af co-infection model and investigated the role of IAV host response in promoting invasive Af infection. Our data show that IAV temporarily suppresses neutrophil recruitment in the early phase of Af co-infection (24 hours), followed by a subsequent increase in neutrophil levels (48 hours). RNA sequencing analysis of neutrophils from IAV-Af co-infected lungs (48 hours) reveals enrichment of pathways regulating inflammatory responses and phagocytosis. Despite higher inflammatory response and phagocytosis, the host response from IAV-Af co-infected lungs had suppressive effects on neutrophil conidial killing, correlating with lung fungal load and invasion. However, the increased fungal invasion observed at 24 hours post co-infection, despite similar fungal loads in both groups (Af vs. IAV-Af), suggests that IAV-induced pathologic lung inflammation and vascular damage likely promote Af invasiveness during the initial phase of co-infection, and subsequently, the defects in neutrophil fungicidal response and exacerbated lung damage lead to sustained and fatal IPA pathogenesis in the later phase of co-infection.

CRISPR-based genetic tools have revolutionized our ability to interrogate and manipulate genes. These tools can be applied to both host and microbial cells, and their use can enhance our understanding of the dynamic nature of host-microbe interactions by uncovering their genetic underpinnings. As reviewed here, CRISPR-based tools are being used to explore the microbiome in an efficient, accurate, and high-throughput manner. By employing CRISPR screens, targeted genome editing, and recording systems to the study of host cells and microorganisms, we can gain critical insights into host defense mechanisms, potential vulnerabilities, and microbial pathogenesis, as well as essential or condition-specific genes involved in host-microbe interactions. Additionally, CRISPR-based genetic tools are being used in animal models to study host-microbe interactions in vivo. Recent advancements in CRISPR-derived technology can be combined with emerging techniques, such as single-cell RNA sequencing, to examine the complex interactions between hosts and microbes, shedding light on the role of the microbiome in health and disease. This review aims to provide a comprehensive overview of how these cutting-edge genetic tools are being used to investigate host-microbial systems, as well as their current limitations. Current research is likely to yield even more advanced genetic toolkits than those presently available, and these can serve researchers in identifying and exploring new therapeutic targets for diseases related to host-microbe interactions.