Systemic impact of intramuscular snake envenomation and intravenous immunoglobulin‐based antivenom treatment on murine plasma proteome and peptidome

Abstract

Snake envenomation remains a critical global public health challenge. In Brazil, the genus Bothrops is responsible for most accidents, typically resulting in coagulopathy, hemorrhage, and renal failure. Despite its clinical prevalence, the molecular mechanisms driving plasma protein disturbances remain poorly understood. In this study, we applied mass spectrometry to characterize the plasma proteome and peptidome of mice following a sub‐lethal dose of Bothrops jararaca venom and subsequent single dose antivenom treatment at timepoints 3, 6 and 24 h. From a total of 781 identified proteins, quantification of 590 revealed systemic pathological signatures such as the lower abundance of key coagulation and complement proteins, indicating coagulopathy and immune disruption. Simultaneously, an increase in tissue damage markers, innate immune response proteins, and Damage‐Associated Molecular Patterns was detected. In the acute phase, the biological response was highly conserved regardless of antivenom administration, while by 24 h the group treated only with venom exhibited prolonged inflammation and metabolic stress, whereas the venom + antivenom group transitioned to cellular recovery and detoxification. The peptidomic analysis identified a large degradome of 1964 unique peptides, showing proteolysis of fibrinogen, apolipoprotein A‐I, complement factors and protease inhibitors, among others. The analysis of cleavage sites implicated the activity of cysteine‐, metallo‐, and serine proteases in this process. Our results demonstrate that B. jararaca venom induced a rapid, dramatic systemic imbalance and proteostasis disruption that was only partially mitigated by antivenom. These findings underscore the necessity of developing complementary therapies that target both the primary toxins and secondary host‐driven pathology.