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We analyzed the reservoir host\u2019s local and systemic immune responses to Bb during tick feeding. C3H\/HeN mice were challenged via infected or uninfected nymphal\n                      <jats:italic toggle=\"yes\">Ixodes scapularis<\/jats:italic>\n                      ticks or by subcutaneous injection of cultured multi-strain Bb. Skin and spleen tissues were evaluated by flow cytometry, serum was evaluated by cytokine proteome array, and all data were analyzed by comparison between each of the three challenged groups against the subcutaneously inoculated PBS control. Flow cytometry profiling shows that neutrophils, Langerhans cells, macrophages, B cells, and Natural Killer cells were mobilized in the three challenged groups in the skin and spleen, dendritic cells were increased in tick-transmitted groups, and T cells were engaged in Bb-challenged groups. Regarding soluble chemotaxis mediators in blood, all chemokines and cytokines induced by subcutaneously delivered Bb and uninfected tick were also induced by tick-transmitted Bb. However, tick-transmitted Bb induced unique factors absent in the other groups, which included chemokines involved in recruitment of phagocytic cells and T cell engagement, and cytokines associated with broader T cell activation. Regarding anti-inflammatory mediators, although IL-1ra was increased in the three challenged groups, IL-10 was only increased in tick-challenged groups with or without Bb. The data suggest that tick-transmitted Bb induced much more dynamic but regulated immune responses during tick-feeding, compared to subcutaneously delivered Bb, which may explain Bb persistence in the reservoir host.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Current knowledge on immune cell interactions with\n                        <jats:italic toggle=\"yes\">Borrelia burgdorferi<\/jats:italic>\n                        (Bb) derives mostly from studies done\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        and\n                        <jats:italic toggle=\"yes\">ex vivo,<\/jats:italic>\n                        which cannot assess host immunity to natural tick-delivered Bb within the complex architecture of host tissues. We report the first\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        study on local and systemic immune responses to Bb during tick feeding on a surrogate reservoir host, in comparison with uninfected-tick and subcutaneously delivered Bb. We show that uninfected-tick and tick-transmitted Bb engaged mixed type-1\/type-2\/type-17 immune responses in the presence of anti-inflammatory IL-10, in contrast to a type-1 response induced by subcutaneously delivered Bb. Analyses of immune responses to tick-transmitted Bb in a reservoir host can enlighten immunity mechanisms that mediate persistence of Bb.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.03971-25","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:55:57Z","timestamp":1776678957000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Innate immune responses to\n                    <i>Borrelia burgdorferi<\/i>\n                    during tick-feeding: mechanistic insights relevant to Lyme disease"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8591-1166","authenticated-orcid":true,"given":"Suman","family":"Kundu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center","place":["Memphis, USA"]},{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"Flow Cytometry and Cell Sorting Core, University of Tennessee Health Science Center","place":["Memphis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Joyner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center","place":["Memphis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3715-4543","authenticated-orcid":true,"given":"Maria","family":"Gomes-Solecki","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0011qv509","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center","place":["Memphis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","first-page":"263","article-title":"Kinetics of Borrelia burgdorferi dissemination and evolution of disease after intradermal inoculation of mice","volume":"139","author":"Barthold SW","year":"1991","unstructured":"Barthold SW, Persing DH, Armstrong AL, Peeples RA. 1991. 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