Host pattern recognition receptors (PRRs) are crucial for sensing pathogenic microorganisms, initiating innate responses, and modulating pathogen-specific adaptive immunity during infection. Rickettsia spp., Orientia tsutsugamushi, Anaplasma spp., Ehrlichia spp., and Coxiella burnetii are obligate intracellular bacteria that can replicate only 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 yielded new insights into the types and kinetics of PRR activation during infection with Rickettsia spp., A. phagocytophilum, E. chaffeensis, and C. burnetii. However, much less was known about PRR activation in O. tsutsugamushi infection until the recent discovery of the role of the C-type lectin receptor Mincle during lethal infection in mice and in primary macrophage cultures. This review provides a brief summary of the clinical and epidemiologic features of these five bacterial infections, with a focus on the fundamental biologic facets of infection, and recent advances in host recognition. In addition, knowledge gaps regarding the innate recognition of these bacteria in the context of disease pathogenesis are discussed.

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.

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