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<i>Ixodes scapularis</i> is a blood-feeding obligate ectoparasite responsible for transmitting the Lyme disease (LD) agent, <i>Borrelia burgdorferi</i>. During the feeding process, <i>I. scapularis</i> injects <i>B. burgdorferi</i> into the host along with its saliva, facilitating the transmission and colonization of the LD agent. Tick calreticulin (CRT) is one of the earliest tick saliva proteins identified and is currently utilized as a biomarker for tick bites. Our recent findings revealed elevated levels of CRT in the saliva proteome of <i>B. burgdorferi</i>-infected <i>I. scapularis</i> nymphs compared to uninfected ticks. Differential precipitation of proteins (DiffPOP) and LC-MS/MS analyses were used to identify the interactions between <i>Ixs</i> (<i>I. scapularis</i>) CRT and human plasma proteins and further explore its potential role in shielding <i>B. burgdorferi</i> from complement killing. We observed that although yeast-expressed recombinant (r) <i>Ixs</i>CRT binds to the C1 complex (C1q, C1r, and C1s), the activator of complement via the classical cascade, it did not inhibit the deposition of the membrane attack complex (MAC) via the classical pathway. Intriguingly, r<i>Ixs</i>CRT binds intermediate complement proteins (C3, C5, and C9) and reduces MAC deposition through the lectin pathway. Despite the inhibition of MAC deposition in the lectin pathway, r<i>Ixs</i>CRT did not protect a serum-sensitive <i>B. burgdorferi</i> strain (B314/pBBE22<i>Luc</i>) from complement-induced killing. As <i>B. burgdorferi</i> establishes a local dermal infection before disseminating to secondary organs, it is noteworthy that r<i>Ixs</i>CRT promotes the replication of <i>B. burgdorferi</i> in culture. We hypothesize that r<i>Ixs</i>CRT may contribute to the transmission and/or host colonization of <i>B. burgdorferi</i> by acting as a decoy activator of complement and by fostering <i>B. burgdorferi</i> replication at the transmission site.