Brain transcriptomics reveal the activation of neuroinflammation pathways during acute Orientia tsutsugamushi infection in mice.

Scrub typhus, an acute febrile illness caused by Orientia tsutsugamushi (Ot), is prevalent in endemic areas with one million new cases annually. Clinical observations suggest central nervous system (CNS) involvement in severe scrub typhus cases. Acute encephalitis syndrome (AES) associated with Ot infection is a major public health problem; however, the underlying mechanisms of neurological disorder remain poorly understood. By using a well-established murine model of severe scrub typhus and brain RNA-seq, we studied the brain transcriptome dynamics and identified the activated neuroinflammation pathways. Our data indicated a strong enrichment of several immune signaling and inflammation-related pathways at the onset of disease and prior to host death. The strongest upregulation of expression included genes involved in interferon (IFN) responses, defense response to bacteria, immunoglobulin-mediated immunity, IL-6/JAK-STAT signaling, and TNF signaling via NF-κB. We also found a significant increase in the expression of core genes related to blood-brain barrier (BBB) disruption and dysregulation in severe Ot infection. Brain tissue immunostaining and in vitro infection of microglia revealed microglial activation and proinflammatory cytokine production, suggesting a crucial role of microglia in neuroinflammation during scrub typhus. This study provides new insights into neuroinflammation in scrub typhus, highlighting the impact of excessive IFN responses, microglial activation, and BBB dysregulation on disease pathogenesis.

Corrigendum to: Pattern Recognition Receptors in Innate Immunity to Obligate Intracellular Bacteria.

[This corrects the article PMC8909792.].

Pattern Recognition Receptors in Innate Immunity to Obligate Intracellular Bacteria.

Host pattern recognition receptors (PRRs) are crucial for sensing pathogenic microorganisms, launching innate responses, and shaping pathogen-specific adaptive immunity during infection. Rickettsia spp., Orientia tsutsugamushi, Anaplasma spp., Ehrlichia spp., and Coxiella burnetii are obligate intracellular bacteria, which can only replicate within host cells and must evade immune detection to successfully propagate. These five bacterial species are zoonotic pathogens of clinical or agricultural importance, yet, uncovering how immune recognition occurs has remained challenging. Recent evidence from in-vitro studies and animal models has offered new insights into the types and kinetics of PRR activation during infection with Rickettsia spp., A. phagocytophilum, E. chaffeensis, and C. burnetii, respectively. However, much less is known in these regards for O. tsutsugamushi infection, until the recent discovery for the role of the C-type lectin receptor Mincle during lethal infection in mice and in primary macrophage cultures. This review gives a brief summary for clinical and epidemiologic features of these five bacterial infections, focuses on fundamental biologic facets of infection, and recent advances in host recognition. In addition, we discuss knowledge gaps for innate recognition of these bacteria in the context of disease pathogenesis.