Abstract
Feeding and transmission of tick-borne disease (TBD) agents by ticks are facilitated by tick saliva proteins (TSP). Thus, defining functional roles of TSPs in tick evasion is expected to reveal potential targets in tick-antigen based vaccines to prevent TBD infections. This study describes two types of Amblyomma americanum TSPs: those that are similar to LPS activate macrophage (MΦ) to express pro-inflammation (PI) markers and another set that suppresses PI marker expression by activated MΦ. We show that similar to LPS, three recombinant (r) A. americanum insulin-like growth factor binding-related proteins (rAamIGFBP-rP1, rAamIGFBP-rP6S, and rAamIGFBP-rP6L), hereafter designated as PI-rTSPs, stimulated both PBMC -derived MΦ and mice RAW 267.4 MΦ to express PI co-stimulatory markers, CD40, CD80, and CD86 and cytokines, TNFα, IL-1, and IL-6. In contrast, two A. americanum tick saliva serine protease inhibitors (serpins), AAS27 and AAS41, hereafter designated as anti-inflammatory (AI) rTSPs, on their own did not affect MΦ function or suppress expression of PI markers, but enhanced expression of AI cytokines (IL-10 and TGFβ) in MΦ that were pre-activated by LPS or PI-rTSPs. Mice paw edema test demonstrated that in vitro validated PI- and AI-rTSPs are functional in vivo since injection of HEK293-expressed PI-rTSPs (individually or as a cocktail) induced edema comparable to carrageenan-induced edema and was characterized by upregulation of CD40, CD80, CD86, TNF-α, IL-1, IL-6, and chemokines: CXCL1, CCL2, CCL3, CCL5, and CCL11, whereas the AI-rTSPs (individually and cocktail) were suppressive. We propose that the tick may utilize countervailing PI and AI TSPs to regulate evasion of host immune defenses whereby TSPs such as rAamIGFBP-rPs activate host immune cells and proteins such as AAS27 and AAS41 suppress the activated immune cells.
Highlights
Ticks are among the most important ecto-parasites with global public and veterinary health impact
We have shown that A. americanum injects two groups of functionally opposed tick saliva proteins: those that could counter-intuitively be characterized as pro-host defense, and those that are expected to have anti-host immune defense functions
We propose that the tick evades host defense using countervailing pro- and anti- inflammatory proteins in which the pro-host defense tick saliva proteins stimulate host immune cells such as macrophages, and the anti-host defense tick saliva proteins suppress functions of the activated immune cells
Summary
Ticks are among the most important ecto-parasites with global public and veterinary health impact. Of the 23 human vector-borne diseases (VBD) that were listed by the World Health Organization, seven are TBD agents: Crimean-Congo hemorrhagic fever, Lyme disease, relapsing fever (borreliosis), rickettsial diseases (spotted fever and Q fever), tick-borne encephalitis, and tularemia (http://www.who.int/mediacentre/factsheets/fs387/en/). In the United States, the Centers for Disease Control (CDC) listed 16 human TBD agents Six human TBD agents were listed on the 2018 National Notifiable human VBD in the USA and its territories. From 2004 to 2016, the six human TBDs accounted for nearly 77% of human VBDs in the USA and its territories [3]
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