ABSTRACT
Harvester ants (genus Pogonomyrmex) are renowned for their stings which cause intense, long-lasting pain, and other neurotoxic symptoms in vertebrates. Here, we show that harvester ant venoms are relatively simple and composed largely of peptide toxins. One class of peptides is primarily responsible for the long-lasting local pain of envenomation via activation of peripheral sensory neurons. These hydrophobic, cysteine-free peptides potently modulate mammalian voltage-gated sodium (NaV) channels, reducing the voltage threshold for activation and inhibiting channel inactivation. These toxins appear to have evolved specifically to deter vertebrates.
Subject(s)
Ants , Bites and Stings , Pain , Peptides , Toxins, Biological , Voltage-Gated Sodium Channel Blockers , Voltage-Gated Sodium Channels , Animals , Ants/pathogenicity , Ants/physiology , Bites and Stings/complications , Pain/chemically induced , Pain/complications , Peptides/chemistry , Peptides/pharmacology , Peptides/toxicity , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/physiology , Toxins, Biological/chemistry , Toxins, Biological/pharmacology , Toxins, Biological/toxicity , Vertebrates , Voltage-Gated Sodium Channel Blockers/chemistry , Voltage-Gated Sodium Channel Blockers/pharmacology , Voltage-Gated Sodium Channel Blockers/toxicity , Voltage-Gated Sodium Channels/metabolismABSTRACT
Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the self-destruction of insulin-producing ß cells. Recently, studies have revealed that neutrophils contribute to the early pathological injury to the pancreas, predominantly via the formation of neutrophil extracellular traps (NETs). To determine whether early intervention targeting NETs with staphylococcal nuclease (SNase) can delay the onset of T1DM, non-obese diabetic (NOD) mice were orally administered recombinant Lactococcus lactis (L. lactis) expressing SNase. The results showed that NETs were effectively disrupted by SNase both in vivo and in vitro, leading to a significant decrease in neutrophil-derived circulating free DNA (cf-DNA/NETs), neutrophil elastase (NE), and protease 3 (PR3) in the serum compared with the controls. In addition, SNase effectively regulated the blood glucose levels of NOD mice, and the onset of diabetes was postponed with reduced mortality and morbidity. Recombinant L. lactis also ameliorated inflammation in NOD mice, as evidenced by the remarkable increase in IL-4 and reductions in TNF-α and CRP. Moreover, HE staining results showed that L. lactis expressing SNase exerted protective effects on pancreatic islets and relieved inflammation of the small intestine in NOD mice. Hence, the present study indicates that the oral delivery of SNase by L. lactis can effectively prevent T1DM, ameliorate inflammation, and contribute to immunomodulatory balance in NOD mice.
