Abstract
Our previous study showed that cells from medically important arthropods, such as ticks, secrete extracellular vesicles (EVs) including exosomes that mediate transmission of flavivirus RNA and proteins to the human cells. Understanding the molecular determinants and mechanism(s) of arthropod-borne flavivirus transmission via exosome biogenesis is very important. In this current study, we showed that in the presence of tick-borne Langat Virus (LGTV; a member of tick-borne encephalitis virus complex), the expression of arthropod IsSMase, a sphingomyelinase D (SMase D) that catalyzes the hydrolytic cleavage of substrates like sphingomyelin (SM) lipids, was significantly reduced in both Ixodes scapularis ticks (in vivo) and in tick cells (in vitro). The IsSMase reduced levels correlated with down-regulation of its activity upon LGTV replication in tick cells. Our data show that LGTV-mediated suppression of IsSMase allowed accumulation of SM lipid levels that supported membrane-associated viral replication and exosome biogenesis. Inhibition of viral loads and SM lipid built up upon GW4869 inhibitor treatment reversed the IsSMase levels and restored its activity. Our results suggest an important role for this spider venomous ortholog IsSMase in regulating viral replication associated with membrane-bound SM lipids in ticks. In summary, our study not only suggests a novel role for arthropod IsSMase in tick-LGTV interactions but also provides new insights into its important function in vector defense mechanism(s) against tick-borne virus infection and in anti-viral pathway(s).
Highlights
Vector-borne diseases that account for high morbidity and mortality throughout the world have been of major concern (Powell, 2019; Qurollo, 2019; Scalway et al, 2019; Shaw and Catteruccia, 2019; Spence Beaulieu, 2019; Wilke et al, 2019; Wilson et al, 2019)
Combing of I. scapularis genome revealed the presence of several sphingomyelinaselike enzymes of both acidic and basic types; we addressed the spider venomous sphingomyelinase D (SMase D) ortholog I. scapularis sphingomyelinase-like enzyme (IsSMase) that was previously identified in ticks (Alarcon-Chaidez et al, 2009)
GW4869 treatment significantly (P < 0.05) inhibited Langat Virus (LGTV)-induced SM lipid buildup at both 24 and 72 h p.i. in comparison to the respective mock LGTV-infected control groups (Figure 6D). These data indicate that GW4869 treatment inhibited LGTV loads resulting in increased IsSMase expression and activity that subsequently lead to reduction in SM lipid levels. These results suggest that a tickborne flavivirus suppresses IsSMase expression and its activity to induce SM lipid levels that perhaps facilitate LGTV replication, packaging of viral RNA genomes and proteins, and budding of these virally activated exosomes
Summary
Vector-borne diseases that account for high morbidity and mortality throughout the world have been of major concern (Powell, 2019; Qurollo, 2019; Scalway et al, 2019; Shaw and Catteruccia, 2019; Spence Beaulieu, 2019; Wilke et al, 2019; Wilson et al, 2019). A study has identified a novel sphingomyelinase-like enzyme (IsSMase) in I. scapularis tick saliva that modulates the adaptive immune response by inclining the host CD4+ T-cells to result in a shift from a neutralizing Th1 cytokine response toward a Th2-induced cytokine profile response (Alarcon-Chaidez et al, 2009). This Mg+2-dependent, neutral form of IsSMase directly (independent of its enzymatic activity) programmed the CD4+ T cells in order to express interleukin 4 (IL-4), which is a hallmark of Th2 effects (Alarcon-Chaidez et al, 2009). It is interesting to note that spider’s SMase D is responsible for local skin necrosis in general, and in occasional cases, it results in severe systemic manifestations, such as acute kidney failure and death (Paixao-Cavalcante et al, 2007; Zobel-Thropp et al, 2010; Correa et al, 2016)
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