Infection and Immunity最新文献

Streptococcus agalactiae (Group B Streptococcus or GBS), a Gram-positive bacterium, and Candida albicans, a polymorphic fungus, are commensal microbes in most of the population they colonize. However, for certain patients, they can cause severe and sometimes fatal infections. Previous research has indicated that GBS and C. albicans can synergize to enhance the colonization of GBS in the bladders of mice, but not much was known prior to this study about how interactions between GBS and C. albicans alter treatment effectiveness and infection outcome in vivo. Results showed that interactions between the two opportunistic pathogens were influenced by media nutrient availability and that the presence of C. albicans in a culture reduces the effectiveness of certain antibiotics against GBS in vitro. This study also utilized a larval zebrafish model to investigate differences in virulence in solo infections vs co-infections with both pathogens in vivo. Co-infections of GBS and C. albicans into the otic vesicle were found to have increased virulence compared to solo infections of either pathogen. Co-infection also led to an increased GBS burden compared to solo GBS infections. Co-infections of GBS and C. albicans by yolk sac injection were not more virulent than solo infections with either pathogen. However, the antibiotic clindamycin was less effective in preventing mortality in co-infections compared to solo GBS infections. Overall, these findings highlight how interactions between GBS and C. albicans can influence treatment effectiveness and virulence during infection.

Pathogenic chlamydial species restrict their peptidoglycan (PG) to the division septum of their replicative forms. PG is a microbe-associated molecular pattern, and two of its major pattern recognition receptors in human cells are nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1 and NOD2, respectively). It has been proposed that this unique morphological feature is evidence of pathoadaptation by the microbe, permitting PG-dependent cell division while also reducing the bacterium's recognition by innate immune receptors. Chlamydia trachomatis-infected cells activate NOD1 signaling within 8-12 hours of exposure to the bacterium, roughly coinciding with the microbe's transition from its infectious to replicative forms. Here, we report that, unlike NOD1 signaling, Chlamydia-induced NOD2 signaling does not occur until later in the pathogen's developmental cycle. Both C. trachomatis and the related murine pathogen Chlamydia muridarum signal late in infection in HEK293 reporter cell lines expressing either human or murine-derived NOD2 receptors. NOD2 signaling can be modulated by disruption of the chlamydial amidase enzyme, AmiA_CT, interrupting the microbe's developmental cycle, and treatment with inhibitors of lipooligosaccharide or PG biosynthesis/assembly. These results mirror prior observations with Chlamydia-induced TLR9 signaling, leading us to hypothesize that Chlamydia-induced NOD2 signaling results from lytic events that occur sporadically during the transition between the pathogen's developmental forms. Given our finding that pre-treating cells with NOD2-stimulatory ligands reduces chlamydial inclusion size and delays the developmental cycle, we hypothesize that the microbe preferentially degrades its PG during development to reduce the generation of NOD2 ligands.

Neutrophils are dominant cells during acute immune response to Clostridioides difficile infection (CDI). A higher number of infiltrating colonic neutrophils is clearly linked to greater tissue damage and severe CDI (3, 4). However, the mechanism(s) by which neutrophils exacerbate tissue damage in CDI remain unknown. We investigated the role of a neutrophil subset marked by Olfactomedin-4 expression (OLFM4⁺ neutrophils) during CDI. Single-cell transcriptomics reveal that Olfm4 is increased in blood neutrophils of infected mice, and these cells exhibit gene signatures characterized by high expression of degranulation genes. In C. difficile-infected mice, OLFM4⁺ neutrophils aggregate to areas of severe intestinal epithelial cell (IEC) damage, and plasma OLFM4 was significantly increased in both C. difficile-infected mice and patients. In vitro, OLFM4⁺ neutrophils and recombinant OLFM4 protein exacerbated C. difficile toxin-induced IEC damage. In sum, our studies provide novel insights into neutrophil-mediated pathology and highlight the role of OLFM4⁺ neutrophils in worsening CDI-induced IEC damage.

Avoiding lysosomal degradation is vital to the success of intracellular pathogens. The Gram-negative bacterium Coxiella burnetii and protozoan parasites of the Leishmania genus are unique in being able to replicate within the mature phagolysosomal compartment of host cells, though the exact mechanisms utilized to withstand this hostile environment are not clearly defined. We recently reported that C. burnetii removes the lysosomal protease cathepsin B during infection of mammalian cells. Here, we aimed to determine if this virulence strategy was also employed by the intralysosomal pathogen, Leishmania mexicana. In contrast to C. burnetii, decreases in the activity of specific cathepsins were not detected in L. mexicana-infected host cells as determined using immunoblotting and protease activity-based probes. Co-infection of THP-1 macrophage-like cells with both pathogens resulted in a proteolytic and secretory phenotype consistent with C. burnetii infection, suggesting that C. burnetii-induced remodeling of the lysosome is not influenced by L. mexicana. The host cell proteome and secretome of L. mexicana-infected cells were defined using mass spectrometry. This confirmed that, unlike C. burnetii, L. mexicana does not induce increased abundance of lysosomal proteins either intracellularly or in the extracellular milieu. Collectively, this study reveals that although C. burnetii and L. mexicana reside in a phagolysosomal intracellular niche, they employ divergent mechanisms to survive within this hostile compartment.

Biological metals are vital trace elements required by metalloproteins, which are involved in virtually every cellular, structural, and catalytic function of the bacterial cell. Bacterial pathogenesis involves a tug-of-war between the host's nutritional immunity sequestering essential metals and the invading pathogens that deploy adapted high-metal affinity uptake strategies, such as metallophores, in order to efficiently circumvent these defense mechanisms. Pseudopaline is a metallophore produced and secreted by Pseudomonas aeruginosa to acquire zinc when the bioavailability of this metal is severely restricted, as in the presence of a strong metal chelator such as EDTA, or during infections when the nutritional immunity of the host is active. We show that when facing strong metal chelation, the general Znu zinc uptake pathway becomes ineffective and only the pseudopaline pathway is capable of supplying the bacteria with the necessary zinc to maintain their growth, establishing that the pseudopaline pathway is the last-resort pathway for the bacteria to acquire zinc under such restricted growth conditions. Based on this statement, the present study explores the pleiotropic role of pseudopaline-mediated zinc acquisition on clinically relevant phenotypes such as biofilm formation and associated antibiotic tolerance, as well as its capacity to determine infection outcomes using cell-culture and murine models. The expression of pseudopaline-dependent phenotypes in such a diversity of biological contexts demonstrates the essentiality of this specific metal uptake system for P. aeruginosa pathogenicity during infection. We therefore identify this machinery as a promising therapeutic target for P. aeruginosa infections.

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.

Salmonella enterica infections are a major cause of morbidity and mortality worldwide, especially in sub-Saharan Africa and in the Asian continent, and are increasingly associated with antimicrobial resistance. Salmonella enterica serovars Typhi and Paratyphi A, B, and C cause enteric fever, while non-typhoidal Salmonella serovars (usually Typhimurium and Enteritidis) cause mainly gastroenteritis which can lead to systemic infections. Vaccines are only licensed against S. Typhi, but different combinations are in clinical development to prevent S. Typhi and S. Paratyphi A or S. Typhi and non-typhoidal Salmonella. Here, we describe elements of the pathogenesis of and immunity to Salmonella that are critical to guide the rational design of vaccines. We highlight how the choice of appropriate immunogenic and protective antigens would be essential to achieve the maximum coverage of serovars in a multivalent Salmonella vaccine. The principal vaccines under development at the preclinical and clinical stages are described, together with considerations on the technical and clinical feasibility of moving combination vaccines toward licensure.

In a non-lethal, 10% total body surface area, full-thickness flame mouse model, infections with Pseudomonas aeruginosa (PA) increased mortality post-burn, suggesting an impaired host immune response. The presence of a seroma beneath the burn wound sequesters CD45⁺ cells. Furthermore, in the case of burn and infection, PA was found to be in proximity to these cells but was not phagocytosed, suggesting leukocyte dysfunction. In this study, leukocytes isolated from the circulation and seroma of burned mice had a decreased ability to kill PA compared to the circulating leukocytes of Sham mice. Both Sham and burned mouse leukocytes lost the ability to kill when incubated in vitro with seroma fluid. Leukocytes from the seroma had a decreased ability to produce reactive oxygen species (ROS) following stimulation when compared to leukocytes isolated from the circulation of the same burned mice. Sham leukocytes incubated with sera from burned mice and burned and infected mice, but not with sera from Sham mice, significantly produce ROS at rest, which may be correlated with the pro-inflammatory danger-associated molecular pattern (DAMP) HMGB1 in the sera of burned mice. These data suggest that a non-lethal burn can prematurely activate leukocytes while in circulation, reducing their functionality at the infected burn site, and that leukocytes at the burn site (seroma) also have impaired function. We conclude that an otherwise non-lethal burn prematurely activates circulating leukocytes and that the seroma environment further inhibits the leukocytes that arrive at the burn site. This results in an impaired immune response and the development of lethal sepsis.

Cell death is an integral part of homeostasis, removing damaged and infected cells and replenishing healthy cells. It is a process well understood from a host perspective, with clearly delineated pathways and an expansive literature as to how it interacts with other immune and tissue mechanisms. However, the interaction between cell death and the microbial community is less well explored. There is an understanding of how bacterial pathogens are able to induce death and can have a detrimental impact on tissue resolution and repair but little on how bacteria respond to homeostatic cell death or death caused by non-bacterial stimuli. This review will cover recent advances in the understanding of host-microbe communication during cell death and will discuss how bacteria modulate/are modulated by cell death-related phenomena. The interplay between the microbiota and the fundamental processes involved in host cell death presents an exciting opportunity to discover how modulation of host mechanisms can beneficially modulate the microbiota, and therefore concurrently offer potential routes to control a number of conditions that have been linked to aberrant microbiota composition, including inflammatory bowel disease and cancer.

Maternal microbial ecosystems play critical roles in shaping reproductive physiology and pregnancy outcomes. During the pre-conception and prenatal periods, these communities modulate maternal physiology by regulating immune tolerance, nutrient metabolism, and susceptibility to pregnancy complications such as preterm birth, hypertensive disorders, and gestational diabetes. While the gut microbiota has been extensively studied, the roles of cervicovaginal, urinary, respiratory, oral, and upper reproductive tract microbiomes remain less clear. In this minireview, we synthesize current knowledge on these underexplored maternal microbiomes, with an emphasis on the cervicovaginal and urinary microbiota and their interactions with the placenta and fetus. We discuss cross-niche microbial signaling, the role of environmental and social determinants in shaping these ecosystems, and mechanisms by which microbes or their products influence host physiology without direct colonization. We also consider the translational potential of microbiota-based interventions to safely improve pregnancy outcomes. Finally, we identify major knowledge gaps and research priorities necessary to advance a more integrated understanding of maternal microbial influences on reproductive and neonatal health. Our synthesis reframes the maternal microbiome as a coordinated, multi-site network that modulates systemic immune and metabolic pathways critical for reproductive success. Understanding these connections will open new avenues for predicting, preventing, and treating pregnancy-related disorders through precision microbiome science.