Infection and Immunity最新文献

Over the past 30 years, a distinct pathotype of hypervirulent Klebsiella pneumoniae (hvKp) has emerged, characterized by its ability to cause severe tissue-invasive infections, including liver abscesses in otherwise healthy individuals. Klebsiella liver abscesses (KLA) are most prevalent in East and Southeast Asia; however, their global incidence is rising, with hvKp now recognized as an important pathogen in Europe and the United States. While K. pneumoniae often colonizes the gut asymptomatically, KLAs develop when hvKp disseminates from the gut to the liver via the portal vein. Strains expressing K1 and K2 capsule types demonstrate the highest resistance to clearance by Kupffer cells, the liver resident macrophages, and are responsible for most KLA cases. KLAs present as fibrously encapsulated lesions composed of bacteria, pus, and immune cells. Treatment typically involves a combination of abscess drainage and antibiotic therapy; however, clinical outcomes are often poor, even in the absence of antibiotic resistance. This is due, in part, to significant barriers to achieving effective antibiotic efficacy within abscesses that can result in devastating complications such as metastatic infection, liver resection, or death. The emergence of KLA caused by multidrug-resistant hvKp strains, although still rare, represents an additional and alarming therapeutic challenge. This review explores the pathogenesis of KLA and highlights critical obstacles to effective management and therapy.

Tuberculosis (TB) relapse after appropriate drug treatment is poorly understood but critical to developing shorter treatment regimens. Using a cynomolgus macaque model of human TB, macaques with active TB disease were treated with a short course of isoniazid and rifampin and subsequently infected with SIV. Serial clinical, microbiologic, immunologic, and position emission and computed tomography (PET CT) assessments were performed to identify risk factors of relapse. Of the 12 animals, eight developed radiologically defined relapse, including four that had clinical and/or microbiologic signs. Greater gross pathology and bacterial burden were observed in relapse animals. PET CT characteristics before, during, and at the end of the treatment were similar among relapse and non-relapse animals. We show that complete sterilization or very low Mtb burden is protective against SIV-induced TB relapse but cannot be predicted by PET CT. Using barcoded M. tuberculosis, we found that Mtb dissemination during relapse originated from both lung and thoracic lymph nodes, underscoring the importance of lymph nodes as a reservoir. By matching barcoded Mtb and serial PET CT, we also demonstrate that not every site of persistent Mtb growth after drug treatment is capable of dissemination and relapse, underscoring the complex nature of drug treatment and relapse.

Toxoplasma gondii is an obligate intracellular protozoan parasite that can establish lifelong infections and cause severe disease in immunocompromised individuals. Interferon gamma (IFNγ) is a key host defense cytokine that induces a variety of toxoplasmacidal mechanisms. Recent CRISPR/Cas9 loss-of-function screens identified multiple Toxoplasma genes important for fitness in IFNγ-stimulated cells. One consistent hit in several screens was the parasite surface antigen, SAG1. Here, we used CRISPR/Cas9 to generate a SAG1 knockout strain and found that SAG1 is important for parasite fitness specifically in IFNγ-stimulated cells. Mechanistic studies revealed that host surface sialic acids are important for parasite attachment, especially in IFNγ-stimulated cells. SAG1-deficient parasites had reduced attachment efficiency, which was exacerbated in IFNγ-treated cells. These findings highlight the role of SAG1 in mediating robust parasite attachment, especially in the context of immune pressure.

Maternal and infant microbiome dysbiosis is associated with poor health outcomes-gut, vaginal, and placental microbiome disruptions in the gut, vaginal, and potentially placental microbiomes-though the existence of a distinct placental microbiome remains controversial-have been linked to pregnancy difficulties and neonatal infections. Dysbiosis leads to inflammation, oxidative stress, and disruptions in the gut-brain axis, which in turn affect immunological control, metabolic balance, and neurodevelopment. Maternal age, antibiotic exposure, and cesarean delivery increase microbial imbalances, raising the risk of preterm birth, gestational diabetes, and neurodevelopmental disorders. New research highlights the importance of systems-level microbial interactions in the gut-vagina axis and maternal-fetal health. Probiotics, prebiotics, and microbiota transplants may treat microbiome disorders. To reduce dysbiosis risks, research should focus on microbiome-based biomarkers, predictive AI models, and global health policy. Understanding microbial interactions at the system level is essential for maternal and child health.

Edwardsiella ictaluri is a gram-negative enteric pathogen responsible for enteric septicemia of catfish. One of the critical virulence factors identified in E. ictaluri is its type III secretion system (T3SS). In this study, we report that the T3SS effector protein EseG requires the small chaperone protein EscB for translocation. EseG shows partial homology to two Salmonella T3SS effectors, SseG and SseF, as well as to the Edwardsiella piscicida effector EseG, all of which also require chaperones for translocation. Functionally, EseG interacts with and inactivates Ras homolog family member A (RhoA), a small GTPase that regulates the dynamic organization of the microtubule and actin cytoskeleton. The cytoskeleton is vital for cell morphology, polarity, adhesion, exocytosis, endocytosis, cytokinesis, and transcriptional control. We demonstrate that inactivation of RhoA by EseG leads to the disassembly of both the microtubule and actin cytoskeleton. Moreover, EseG was found to modulate immune responses by altering the expression of several pro-inflammatory interleukins and transcription factors, as well as cyclooxygenase-2 (COX-2). Reduced expression of COX-2 leads to decreased production of prostaglandin E2, a key mediator of inflammation. Additionally, a ΔeseG mutant strain exhibited reduced virulence and persistence in channel catfish (Ictalurus punctatus), underscoring the importance of EseG in the disease process. Collectively, our data highlight EseG as a critical factor in E. ictaluri pathogenesis, particularly in its ability to modulate host immune responses. By elucidating the function of EseG, this study contributes to a deeper understanding of E. ictaluri pathogenesis.

Malaria, caused by Plasmodium spp., is a global health concern linked to anemia and increased mortality. Compensatory erythropoiesis seen during acute anemia results in an increased circulating reticulocyte count (i.e., immature RBC), a key factor in understanding the relationship between pre-existing anemia and Plasmodium burden. Reticulocytes in mice are marked by transferrin receptor (CD71⁺) and glycophorin A-associated protein (Ter119⁺). To model acute anemia with increased reticulocytes, C57BL/6J mice were either bled (i.e., phlebotomized) or administered phenylhydrazine before being infected with Plasmodium yoelii (P. yoelii), a mouse-specific strain with a preference for reticulocytes. In P. yoelii-infected anemic mice, we observed heightened parasitemia and significant body weight loss compared with non-anemic P. yoelii-infected mice. Additionally, serum inflammatory cytokines, erythropoietin, and liver injury markers, along with hemozoin deposition, significantly increased in anemic P. yoelii-infected mice. Blood transfusion from healthy normal donors to P. yoelii-infected anemic recipient mice ameliorated anemia by reducing overall reticulocyte count and increasing mature RBC count. Blood transfusion rescued body weight loss, decreased parasitemia, and reduced serum erythropoietin levels. Finally, to confirm the role of reticulocytes in P. yoelii infection, reticulocytes were depleted using anti-CD71 monoclonal antibody in P. yoelii-infected mice. We observed improvement in hematologic parameters and stark reduction in parasitemia in both pre-existing anemic and non-anemic P. yoelii-infected mice. Collectively, our results suggest that pre-existing anemia may increase the risk of Plasmodium infection due to the greater reticulocyte population. Anti-CD71 treatment in Plasmodium infection may offer a novel therapeutic strategy to combat Plasmodium infection and malaria.

The joy of every mother is to survive a healthy pregnancy and give birth to a healthy baby. However, until today, many couples are finding it difficult to welcome a baby. Among the factors that cause infertility and recurrent pregnancy loss (RPL) is the microbiome composition that inhabits the vaginal space. These microbiomes occupying the vaginal space play a role in balancing acids, pH, and metabolites to ensure a healthy vaginal environment that can prevent pregnancy loss. What is even more evident is that these microbiomes, when dominated by Lactobacillus spp., prevent the growth of vaginal pathogens and reduce the risk of developing drug resistance. Although there is compelling evidence centered on the vaginal microbiome in promoting a healthy vagina, RPL is attributed to their altered or reduced Lactobacillus spp. While there are discrepancies in the literature, this review aimed to summarize the recent findings on vaginal microbiome and RPL. In addition, this mini review further revealed vaginal microbiota as biomarkers that can predict a healthy vagina and the risk of vaginal microbiome causing RPL. In addition, the immune response and metabolite changes in vaginal microbiome-related RPL, as well as some limitations to this intervention and prospective studies, are summarized.

A major risk factor for acquiring Clostridioides difficile is antibiotic usage that disrupts a healthy microbial gut community, facilitating the establishment of infection. Once established, C. difficile secretes exotoxins (TcdA and TcdB) that are internalized into host colonic epithelial cells where they disrupt gut barrier function and induce hyperinflammation resulting in severe diarrhea and possibly leading to death. We employed three different platforms to explore gene expression of cells in the gut when exposed to C. difficile or its toxins, TcdA and TcdB. An antibiotic-treated mouse model of Clostridioides difficile infection (CDI) was used to identify differential gene expression with a NanoString Technologies mouse inflammatory gene panel consisting of 770 genes, including a subset of bile acid (BA) homeostasis and nuclear receptor genes. In the cecal tissue of mice with CDI, reduced expression was observed for genes involved in peroxisome proliferator-activated receptor (PPAR) signaling and cholesterol and glucose metabolism, while a significant increase in expression was observed for IL-17 related inflammatory genes. Similarly, Caco-2 cell culture and primary human colonic epithelial cells (hCE) exposed to toxins for 24 h showed altered expression in several PPAR-regulated and cholesterol metabolic genes similar to those found in mice. These cell culture experiments also revealed significant alterations in gene expression of the Farnesoid X receptor BA regulatory pathway. Together, these data suggest that exposure to C. difficile and its toxins may alter host cholesterol metabolic processes, including BA transport and synthesis.

Neutrophils are the most abundant leukocytes at sites of inflammation and form the front line of the innate immune response. Neutrophils have a relatively short lifespan compared to other cell types, as they have streamlined their metabolic processes to support an arsenal of antimicrobial functions to combat invading pathogens at the cost of maximizing ATP output. To elicit antimicrobial stress, neutrophils rewire their glycolytic pathways to sustain phagocytosis and the oxidative burst and modify their mitochondrial metabolism to dictate degranulation or release of neutrophil extracellular traps. While many of these effector functions are sufficient to protect the "healthy" host from infection, chronic diseases disrupting metabolic and inflammatory homeostasis render the host susceptible to more frequent and severe bacterial infections. With the growing incidence of many metabolic and autoimmune diseases, a clearer understanding of the mechanisms regulating or disrupting neutrophil antimicrobial processes is required. This review focuses on the relationship between neutrophil function and metabolism and what is known about how this impacts autoimmune and metabolic diseases and/or disorders in the case of bacterial infection.