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In Vivo Dual RNA-Seq identifies a novel AB Toxin-like as a key effector of Leptospira interrogans barrier disruption (or host colonization)

ABSTRACT: The ability to evade host immune responses and disrupt epithelial barriers is essential for microbial pathogenesis, yet the underlying mechanisms of these processes in extracellular pathogens remain poorly understood. Through in vivo dual RNA-Seq profiling, we reveal how Leptospira interrogans compromises cell barrier integrity and disseminates within its host. Unlike most pathogens that trigger a rapid immune response, L. interrogans employs a stealth strategy, delaying host recognition even as it establishes tissue colonization. Through our analysis, we identify a novel family of bacterial effectors, the Virulence-Modifying (VM) proteins, as key mediators of barrier disruption. These AB toxin-like proteins, also identified in other extracellular pathogens, induce intracellular calcium influx in epithelial cells, activating calmodulin and myosin light chain kinase to disrupt tight junctions. Mutants deficient in VM proteins show a loss of virulence in animals, underscoring their essential role in pathogenicity. This study uncovers a unique strategy by which an extracellular pathogen exploits host calcium signaling to breach epithelial barriers through a novel class of AB toxin-like proteins. These findings offer new possibilities for therapeutic targeting and our understanding of microbial pathogenesis.

ORGANISM(S): Mesocricetus auratus Leptospira interrogans

PROVIDER: GSE295802 | GEO | 2025/12/23

REPOSITORIES: GEO

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Project description:Meningitis is a life-threatening condition characterized by the inflammation of the leptomeningeal membranes surrounding the brain and spinal cord. The term meningitis is an umbrella term and includes several different etiologies. The majorities of meningitis cases are caused by viruses (viral meningitis; VM) and are often associated with low mortality rates and low risk of developing neurological. In contrast, meningitis caused by some viral infections, such as tick-borne encephalitis (TBE), can be life-threatening when left untreated with increased risk of developing neurological sequelae. Acute bacterial meningitis (ABM), however, is one of the leading causes of death due to infectious diseases worldwide and is associated with rapid disease progression, high mortality rates and increased risk of long-term neurological sequelae in survivors. As meningitis is caused by numerous different pathogens, the host-response is typically highly variable and it is currently unknown if different pathogens can introduce specific proteome changes in the cerebrospinal fluid (CSF). In this study we applied DIA-MS to provide novel insights for in-depth understanding of central nervous system functioning and host response during meningitis in a cohort of patients with differential diagnosis of meningitis, to account for variability contributed by different disease-causing pathogens. The results reveal drastic changes in the CSF proteome during meningitis, where in particular a massive increase of neutrophil derived proteins in the CSF correlated with ABM, suggesting that activated neutrophils play a particular role in ABM. Additionally both ABM and VM result in marked reduction of brain-specific proteins in the CSF, which could be indicative of pathophysiological mechanisms leading to brain damage. Furthermore, generation of lasso regression model enables separation of ABM with high sensitivity and specificity, demonstrating that several proteins are required to confidently discriminate between ABM, VM and BM.

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In Vivo Dual RNA-Seq identifies a novel AB Toxin-like as a key effector of Leptospira interrogans barrier disruption (or host colonization)

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