Amblyomma americanum ticks utilizes countervailing pro and anti-inflammatory proteins to evade host defense

• Published in: PLoS pathogens Vol. 15; no. 11; p. e1008128
• Main Authors: Bakshi, Mariam, Kim, Tae Kwon, Porter, Lindsay, Mwangi, Waithaka, Mulenga, Albert
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.11.2019; Public Library of Science (PLoS)
• Subjects: Amblyomma americanum; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - metabolism; Antigens; Arachnids; Arthropod Proteins - genetics; Arthropod Proteins - metabolism; Biology and Life Sciences; Carrageenan; CCL3 protein; CD40 antigen; CD80 antigen; CD86 antigen; Chemokines; Cytokines; Disease transmission; Drug dosages; Edema; Female; Fever; Growth factors; Health aspects; HEK293 Cells; Host-Parasite Interactions; Humans; Immune system; In vitro methods and tests; In vivo methods and tests; Infection; Inflammation; Inflammation Mediators - metabolism; Insulin; Insulin-like growth factors; Interleukin 1; Interleukin 10; Interleukin 6; Lipopolysaccharides; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - parasitology; Markers; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Monocyte chemoattractant protein 1; Parasites; Parasitic diseases; Pathogens; Peripheral blood mononuclear cells; Protease inhibitors; Proteases; Protein binding; Proteinase inhibitors; Proteins; Saliva; Saliva - metabolism; Serine; Serine proteinase; Serine proteinase inhibitors; Thrombin; Tick Infestations - immunology; Tick Infestations - metabolism; Tick Infestations - parasitology; Tick-borne diseases; Ticks; Ticks - pathogenicity; Transforming growth factors; Tumor necrosis factor-α; Vaccines; Veterinary colleges; Veterinary medicine; United States > US; Texas; Kansas
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008128

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.