Ixodes scapularis saliva mitigates inflammatory cytokine secretion during Anaplasma phagocytophilum stimulation of immune cells

Abstract

BackgroundIxodes scapularis saliva enables the transmission of infectious agents to the mammalian host due to its immunomodulatory, anesthetic and anti-coagulant properties. However, how I. scapularis saliva influences host cytokine secretion in the presence of the obligate intracellular rickettsial pathogen Anaplasma phagocytophilum remains elusive.MethodsBone marrow derived macrophages (BMDMs) were stimulated with pathogen associated molecular patterns (PAMPs) and A. phagocytophilum. Cytokine secretion was measured in the presence and absence of I. scapularis saliva. Human peripheral blood mononuclear cells (PBMCs) were also stimulated with Tumor Necrosis Factor (TNF)-α in the presence and absence of I. scapularis saliva and interleukin (IL)-8 was measured.ResultsI. scapularis saliva inhibits inflammatory cytokine secretion by macrophages during stimulation of Toll-like (TLR) and Nod-like receptor (NLR) signaling pathways. The effect of I. scapularis saliva on immune cells is not restricted to murine macrophages because decreasing levels of interleukin (IL)-8 were observed after TNF-α stimulation of human peripheral blood mononuclear cells. I. scapularis saliva also mitigates pro-inflammatory cytokine response by murine macrophages during challenge with A. phagocytophilum.ConclusionsThese findings suggest that I. scapularis may inhibit inflammatory cytokine secretion during rickettsial transmission at the vector-host interface.

The Tick Salivary Protein Sialostatin L2 Inhibits Caspase-1-Mediated Inflammation during Anaplasma phagocytophilum Infection

“…A. phagocytophilum stimulation of macrophages did not require LPS prim- ing for IL-1␤ secretion. These results corroborated the notions that A. phagocytophilum lacks genes for LPS synthesis in the genome (41) and that molecules other than LPS prime macrophages for production of pro-IL-1␤ during infection (21). The effect of sialostatin L2 on inflammasome signaling also appeared to be specific for A. phagocytophilum, because caspase-1 activation and IL-1␤ and IL-18 secretion were not inhibited when macrophages were stimulated by known NLRP3 (e.g., nigericin), NLRC4 (e.g., P. aeruginosa), and AIM2 (e.g., F. tularensis LVS) agonists ( Fig.…”

“…How disease vectors inhibit inflammasome signaling during pathogen infection remains poorly understood (20). Because we uncovered that Ixodes scapularis saliva inhibits cytokine secretion during stimulation of NLRs in macrophages (21), we hypothesized that tick saliva manipulates inflammation through caspase-1 activity during A. phagocytophilum infection. Here we show that the tick salivary protein sialostatin L2 inhibits inflammasome signaling during A. phagocytophilum infection.…”

Smuggling across the Border: How Arthropod-Borne Pathogens Evade and Exploit the Host Defense System of the Skin

“…The tick saliva of Ixodes can also facilitate the transmission of the bacteria, Anaplasma phagocytophilum, by downregulating cytokine expression of MOs (Chen et al, 2012). A similar phenomenon has been observed for tickborne encephalitis, in which the virus modifies the composition of tick saliva to improve the infection by increasing the DC infection efficiency.…”

Modulation of host immunity by tick saliva

“…It was further reported to inhibit IL-8 secretion by human peripheral blood mononuclear cells (PBMCs) after TNF stimulation [61] and NO synthesis upon LPS stimulation [62]. …”