Explore the vast range of titles available.

Persistent bacterial infections evade host immunity and resist antibiotic treatments through various mechanisms that are difficult to evaluate in a living host. Pseudomonas aeruginosa is a main cause of chronic infections in patients with cystic fibrosis (CF) and wounds. Here, by immersing wounded zebrafish embryos in a suspension of P. aeruginosa isolates from CF patients, we established a model of persistent infection that mimics a murine chronic skin infection model. Live and electron microscopy revealed persisting aggregated P. aeruginosa inside zebrafish cells, including macrophages, at unprecedented resolution. Persistent P. aeruginosa exhibited adaptive resistance to several antibiotics, host cell permeable drugs being the most efficient. Moreover, persistent bacteria could be partly re-sensitized to antibiotics upon addition of anti-biofilm molecules that dispersed the bacterial aggregates in vivo . Collectively, this study demonstrates that an intracellular location protects persistent P. aeruginosa in vivo in wounded zebrafish embryos from host innate immunity and antibiotics, and provides new insights into efficient treatments against chronic infections.

Persistent SARS-CoV-2 infections may act as viral reservoirs that could seed future outbreaks 1 – 5 , give rise to highly divergent lineages 6 – 8 and contribute to cases with post-acute COVID-19 sequelae (long COVID) 9 , 10 . However, the population prevalence of persistent infections, their viral load kinetics and evolutionary dynamics over the course of infections remain largely unknown. Here, using viral sequence data collected as part of a national infection survey, we identified 381 individuals with SARS-CoV-2 RNA at high titre persisting for at least 30 days, of which 54 had viral RNA persisting at least 60 days. We refer to these as ‘persistent infections’ as available evidence suggests that they represent ongoing viral replication, although the persistence of non-replicating RNA cannot be ruled out in all. Individuals with persistent infection had more than 50% higher odds of self-reporting long COVID than individuals with non-persistent infection. We estimate that 0.1–0.5% of infections may become persistent with typically rebounding high viral loads and last for at least 60 days. In some individuals, we identified many viral amino acid substitutions, indicating periods of strong positive selection, whereas others had no consensus change in the sequences for prolonged periods, consistent with weak selection. Substitutions included mutations that are lineage defining for SARS-CoV-2 variants, at target sites for monoclonal antibodies and/or are commonly found in immunocompromised people 11 – 14 . This work has profound implications for understanding and characterizing SARS-CoV-2 infection, epidemiology and evolution. Using viral sequence data, individuals with persistent SARS-CoV-2 infections were identified, and had higher odds of self-reporting long COVID, in a large community surveillance study.

Pseudomonas aeruginosa is an opportunistic pathogen that synthesizes and secretes a wide range of virulence factors. P. aeruginosa poses a potential threat to human health worldwide due to its omnipresent nature, robust host accumulation, high virulence, and significant resistance to multiple antibiotics. The pathogenicity of P. aeruginosa, which is associated with acute and chronic infections, is linked with multiple virulence factors and associated secretion systems, such as the ability to form and utilize a biofilm, pili, flagella, alginate, pyocyanin, proteases, and toxins. Two-component systems (TCSs) of P. aeruginosa perform an essential role in controlling virulence factors in response to internal and external stimuli. Therefore, understanding the mechanism of TCSs to perceive and respond to signals from the environment and control the production of virulence factors during infection is essential to understanding the diseases caused by P. aeruginosa infection and further develop new antibiotics to treat this pathogen. This review discusses the important virulence factors of P. aeruginosa and the understanding of their regulation through TCSs by focusing on biofilm, motility, pyocyanin, and cytotoxins.

Interstitial lung disease (ILD) is characterized by chronic inflammation and scarring of the lungs, of which idiopathic pulmonary fibrosis (IPF) is the most devastating pathologic form. Idiopathic pulmonary fibrosis pathogenesis leads to loss of lung function and eventual death in 50% of patients, making it the leading cause of ILD-associated mortality worldwide. Persistent and subclinical microbial infections are implicated in the acute exacerbation of chronic lung diseases. However, while epidemiological studies have highlighted pollutants, gastric aspirate, and microbial infections as major causes for the progression and exacerbation of IPF, the role of persistent microbial infections in the pathogenesis of IPF remains unclear. In this review, we have focused on the role of persistent microbial infections, including viral, bacterial, and fungal infections, and their mechanisms of action in the pathogenesis of IPF. In particular, the mechanisms and pathogenesis of the Gram-negative bacteria Non-typeable Haemophilus influenzae ( NTHi ) in ILDs are discussed, along with growing evidence of its role in IPF, given its unique ability to establish persistent intracellular infections by leveraging its non-capsulated nature to evade host defenses. While antibiotic treatments are presumably beneficial to target the extracellular, interstitial, and systemic burden of pathogens, their effects are significantly reduced in combating pathogens that reside in the intracellular compartments. The review also includes recent clinical trials, which center on combinatorial treatments involving antimicrobials and immunosuppressants, along with antifibrotic drugs that help mitigate disease progression in IPF patients. Finally, future directions focus on mRNA-based therapeutics, given their demonstrated effectiveness across a wide range of clinical applications and feasibility in targeting intracellular pathogens.

Prevalence of Mycobacterium abscessus infections is increasing in patients with respiratory comorbidities. After initial colonisation, M. abscessus smooth colony (S) variants can undergo an irreversible genetic switch into highly inflammatory, rough colony (R) variants, often associated with a decline in pulmonary function. Here, we use an adult zebrafish model of chronic infection with R and S variants to study M. abscessus pathogenesis in the context of fully functioning host immunity. We show that infection with an R variant causes an inflammatory immune response that drives necrotic granuloma formation through host TNF signalling, mediated by the tnfa , tnfr1 and tnfr2 gene products. T cell-dependent immunity is stronger against the R variant early in infection, and regulatory T cells associate with R variant granulomas and limit bacterial growth. In comparison, an S variant proliferates to high burdens but appears to be controlled by TNF-dependent innate immunity early during infection, resulting in delayed granuloma formation. Thus, our work demonstrates the applicability of adult zebrafish to model persistent M. abscessus infection, and illustrates differences in the immunopathogenesis induced by R and S variants during granulomatous infection. The pathogen Mycobacterium abscessus can switch from a smooth colony form (S) into a highly inflammatory, rough colony form (R) during infection. Here, Kam et al. use an adult zebrafish model of M. abscessus chronic infection to illustrate differences in the immunopathogenesis induced by R and S variants.

Phocine distemper virus caused epizootics of fatal pneumonia in North Sea harbor seals in 1988 and 2002. Two seals that stranded years later were infected with defective phocine distemper virus variants that caused severe encephalomyelitis. Old seal encephalitis resembled subacute sclerosing panencephalitis in humans and old dog encephalitis in canines.

Bovine viral diarrhea virus (BVDV) is a globally prevalent pathogen causing severe detriment to the cattle industry. Vertical infection occurring before the development of the fetal adaptive immune response, before 125 days of gestation, results in an immunotolerant, persistently infected (PI) calf. It was hypothesized that epigenetic alterations observed in the splenic tissue of PI fetuses at gestational day 245 would persist into the postnatal period. White blood cell DNA from five PI and five control heifers at 4 months of age was subjected to reduced representation bisulfite sequencing and interpreted within the context of complete blood count and flow cytometry data herein. Analysis revealed 8367 differentially methylated sites contained within genes associated with the immune and cardiac system, as well as hematopoiesis. Differences observed in the complete blood counts of PI heifers include increased monocytes, microcytic anemia, and elevated platelets with decreased mean platelet volume. Flow cytometry revealed increased classical monocytes, B cells, and CD4+/CD8B+ and CD25+/CD127− T cells, as well as decreased γδ+, CD4+, and CD4−/CD8B− T cells. Investigation of the PI methylome provides a new perspective on the mechanisms of pathologies and provides potential biomarkers for the rapid identification of PI cattle.

Foot-and-mouth disease is a devastating disease of cattle that is caused by foot-and-mouth disease virus (FMDV). After acute infection, FMDV persists in the upper respiratory tract of about 50% of infected cattle. The persistent infection is characterized by very localized viral replication in the absence of clinical signs, but the underlying mechanisms are still not clear. In our study, we investigated tissue samples collected from 20 cattle which had been experimentally infected with FMDV O/FRA/1/2001. In 17 animals, the infection persisted for longer than 28 days. Epithelial tissue from the dorsal nasopharynx and the dorsal soft palate (DSP), the two main locations for persistent infection, was collected at necropsy. Five biological replicates from each animal and location were screened by FMDV specific RT-qPCR, and subsets of the samples were selected for transcriptome sequencing (n = 52) and protein mass spectrometry (n = 18). There was a good correlation between the expression patterns identified by the transcriptomic and proteomic analysis. Higher loads of viral genome were detected in DSP samples. Overexpression of cellular markers for follicle-associated epithelium (FAE) and downregulated genes of epithelial integrity and keratinization correlated with viral genome loads, confirming the microanatomic localization of persistent FMDV infection in follicle-associated epithelium (FAE) in lymphoid tissue of the nasopharynx. An upregulation of genes which negatively influence T-cell responses indicates a T-cell exhaustion, most likely caused by prolonged immune stimulation. Moreover, decreased expression levels of RIG-I and TRAF6 probably resulted in inhibited detection of viral RNA by the innate immune system and ultimately an impeded type I interferon response. These observations are in line with the hypothesis that FMDV actively suppresses the local immunity in FAE to maintain a persistent infection in the bovine nasopharynx.

Background Staphylococcus aureus bacteremia (SAB) is a prevalent life-threatening infection often caused by methicillin-resistant S. aureus (MRSA). Up to 30% of SAB patients fail to clear infection even with gold-standard anti-MRSA antibiotics. This phenomenon is termed antibiotic-persistent MRSA bacteremia (APMB). The mechanisms driving APMB are complex and involve host phenotypes significantly impacting the immune response. Thus, defining early immune signatures and clinical phenotypes that differentiate APMB from antibiotic resolving (AR)MB could aid therapeutic success. Methods We assessed 38 circulating cytokines and chemokines using affinity proteomics in 74 matched pairs of vancomycin-treated SAB cases identified as ARMB or APMB after 5 days of blood culture. Results Unsupervised hierarchical clustering segregated APMB from ARMB based on differential levels of IL-10, IL-12p40, IL-13, CCL4, and TGFα. Additionally, CXCL1, CCL22 and IL-17A significantly differed between APMB and ARMB when correlated with diabetes, dialysis, metastatic infection, or cardiac vegetation. Combining immune signatures with these relevant clinical phenotypes sharply increased accuracy of discriminating APMB outcome to 79.1% via logistic regression modeling. Finally, classification-regression tree analysis revealed explicit analyte thresholds associated with APMB outcome at presentation especially in patients with metastatic infection. Conclusions Collectively, this study identifies previously unrecognized cytokine and chemokine signatures that distinguish APMB and ARMB at presentation and in the context of host clinical characteristics associated with increased disease severity. Validation of a biomarker signature that accurately predicts outcomes could guide early therapeutic strategies and interventions to reduce risks of persistent SAB that are associated with worsened morbidity and mortality.

This study examines the origin and differentiation of stem-like CD8 + T cells that are essential for sustained T cell immunity in chronic viral infections and cancer and also have a key role in PD-1 directed immunotherapy 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 – 10 . These PD-1 + TCF-1 + TOX + stem-like CD8 + T cells (also known as precursors of exhausted T cells 8 , 9 ) have a distinct program that enables them to adapt to chronic antigen stimulation. Here, using the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection, we find that virus-specific stem-like CD8 + T cells are generated early (day 5) during chronic infection, suggesting that this crucial fate commitment occurs irrespective of the infection outcome. Indeed, we find that nearly identical populations of stem-like CD8 + T cells were generated early during acute or chronic LCMV infection, and that antigen was essential for maintaining the stem-like phenotype. We performed reciprocal adoptive transfer experiments to determine the fate of these early stem-like CD8 + T cells after viral clearance versus persistence. After transfer of day 5 stem-like CD8 + T cells from chronically infected mice into acutely infected mice, these cells downregulated canonical markers of the chronic stem-like CD8 + T cells and expressed markers (CD127 and CD62L) associated with central memory CD8 + T cells. Reciprocally, when day 5 stem-like cells from acutely infected mice were transferred into chronically infected mice, these CD8 + T cells functioned like chronic resource cells and responded effectively to PD-1 therapy. These findings highlight the ability of these early PD-1 + TCF-1 + TOX + stem-like CD8 + T cells to adapt their differentiation trajectory to either an acute or a chronic viral infection. Importantly, our study shows that the host is prepared a priori to deal with a potential chronic infection. Stem-like CD8 + T cells specific for lymphocytic choriomeningitis virus are generated early during chronic infection, suggesting that this crucial fate commitment occurs irrespective of the infection outcome.