Selective Activation of Macrophage Innate Signaling Pathways and Inflammatory Responses to Orientia tsutsugamushi Karp and Gilliam Strains

While Ot infection modulated several common canonical pathways/genes, we identified unique pathway/gene signatures that were highly selective for Karp or Gilliam strain, respectively. Karp infection uniquely upregulated proinflammatory signaling and pattern recognition receptors, including C-type lectin receptors (CLRs), including Mincle/Clec4e and Dectin-2/Clec4n. In contrast, Gilliam infection enhanced MΦ proliferation and DNA replication, and Gilliam strain grew better in M0-like MΦs than Karp strain.

In IFN -primed (M1-like) MΦs, however, Karp exhibited significantly greater resistance against host killing than Gilliam, suggesting its superior ability to evade host immune responses. Overall, Karp strain preferentially upregulated CLRs and activated type 1-skewed inflammatory responses, but it is also relatively resistant to IFN -mediated killing. This study provides new insights into potential mechanisms underlying Ot strain-associated immune responses and disease outcomes.