A novel sphingomyelinase‐like enzyme in Ixodes scapularis tick saliva drives host CD4⁺ T cells to express IL‐4

Abstract

Tick feeding modulates host immune responses. Tick-induced skewing of host CD4+ T cells towards a Th2 cytokine profile facilitates transmission of tick-borne pathogens that would otherwise be neutralized by Th1 cytokines. Tick-derived factors that drive this Th2 response have not previously been characterized. In the current study, we examined an I. scapularis cDNA library prepared at 18-24 hours of feeding and identified and expressed a tick gene with homology to Loxosceles spider venom proteins with sphingomyelinase activity. This I. scapularis sphingomyelinase-like (IsSMase) protein is a Mg +2 -dependent, neutral (pH 7.4) form of sphingomyelinase. Significantly, in an in vivo TCR transgenic adoptive transfer assay IsSMase programmed host CD4+ T cells to express the hallmark Th2 effector cytokine IL-4. IsSMase appears to directly program host CD4 T cell IL-4 expression (as opposed to its metabolic byproducts) because induced IL-4 expression was not altered when enzymatic activity was neutralized. TCR transgenic CD4 T cell proliferation (CFSE-dilution) was also significantly increased by IsSMase. Furthermore, a Th2 response is superimposed onto a virally-primed Th1 response by IsSMase. Thus, IsSMase is the first identified tick molecule capable of programming host CD4+ T cells to express IL-4.

Rhipicephalus microplus salivary gland molecules induce differential CD86 expression in murine macrophages

“…The first tick molecule identified to drive IL-4 response by host CD4 T cells was a spingomyelinase-like enzyme in I. scapularis [55]. The authors speculate that the structure could potentially bind Toll-like receptors (TLRs) or other pathogen associated molecular pattern (PAMP) binding molecules.…”

Blood feeding by the Rocky Mountain spotted fever vector, Dermacentor andersoni, induces interleukin-4 expression by cognate antigen responding CD4+ T cells

“…Subsequent functional analyses were performed as previously described [20-22,24,25]. Briefly, TCR transgenic CD4 T cells harvested from draining brachial and axillary lymph nodes (identified as CD4 + Thy1.1 + ) on day 4 post-adoptive transfer were analyzed directly ex vivo for proliferation via dilution of CFSE.…”

Influence of pH control in the formation of inclusion bodies during production of recombinant sphingomyelinase-D in Escherichia coli

“…This is globally distributed with an important presence in Asia, parts of Australia, Madagascar, Southeastern Africa, the Caribbean, South and Central America and Mexico [49,50]. Tick saliva contains numerous molecules like sphingomyelinase-D (SMD) that might modulate host immune responses [51] and combined with other proteins has been proposed as blood meal strategy for the tick [52]. The SMD from tick B. microplus has a molecular weight of 33.1 kDa, a conserved structure of (α/β)8, and a theoretical pI of 6.04.…”