Dysregulated neutrophils failed to control bacteria in an intradermal murine model of Orientia tsutsugamushi infection

Abstract

Abstract Scrub typhus is a vector-borne febrile illness caused by the obligately intracellular bacterium, Orientia tsutsugamushi that are transmitted by the larvae of trombiculid mites. Approximately 1 million people are infected every year in an Asia-Pacific region. Patients without appropriate treatment may develop severe damage in various organs and lead to death. However, the host protective immunity against this infection is still not understood. Using an intradermal infection mouse model and CFSE-labeled bacteria, we found that neutrophils and monocytes were the majority of infected cells in the skin infection site at 4 and 8 hours post-infection (hpi). However, very few of them can migrate to local lymph node at 24 hpi. Instead, the infected langerhans cells were observed in local lymph nodes, but not in other organs including lung, bone marrow and spleen, as well as blood. To investigate the role of neutrophils in Orientia infection, we treated the infected mice with Anti-Ly6G antibody daily from −1 to 3 dpi. However, the bodyweight loss was comparable between control and neutrophil-depleted mice until 14 dpi. No significant difference of bacterial loads were found in organs including lung and brain. Our in vitro study showed that Orientia infection induced an immunosuppressive neutrophil phenotype and increased neutrophil death. Collectively, our data suggest that infected-neutrophil may undergo the functional dysregulation and not be able to control bacteria efficiently, while antigen-presenting cells may contribute to bacterial dissemination from skin to systemic infection in scrub typhus.