An Immunological Stairway to Severe Tissue Complication Assembly in Bothrops atrox Snakebites

Abstract

Snakebites are a serious public health problem and, in the Amazon, the Bothrops atrox snake is the most frequent cause of envenomation. B. atrox venom (BaV) causes pathophysiological changes with intense, local inflammatory processes, such as severe tissue complication (STC). However, mechanisms associated with the inflammatory process in humans are still poorly understood. Thus, in this study, we sought to describe the profile of local and systemic immunological soluble molecules in Bothrops envenomation patients treated at a specialist tertiary healthcare unit in the Brazilian Amazon. An analytical and prospective study was performed with patients who had snakebites with different clinical outcomes (STC and Mild Tissue Complication—MTC) using venous blood and blister exudate in order to measure immunological soluble molecules present in the response process. Twenty STC patients and 20 MTC patients were eligible for the study. In addition, 20 healthy donors (HD) who had never been bitten by a snake were used as controls. The biomarkers CXCL-8, CCL-5, CXCL-9, CCL-2 and CXCL-10; C3a, C4a, and C5a; IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, TNF, IFN-γ and IL-17A were quantified using flow cytometry and ELISA. The circulating response profile differs between the studied groups, with MTC patients presenting a mixed profile and STC patients presenting a more polarized profile for Th1 response. In addition, individuals who develop STC have a more intense local immune response, because the tissue response differs from the circulating immunological soluble molecules and presents Th1/Th2/Th17 response polarization. Furthermore, these results suggest that CCL-2 and CXCL-10 are biomarkers for STC and the response profile they assume against Bothrops snakebite should reflect in the clinical practice for the patient.

Correlating Fibrinogen Consumption and Profiles of Inflammatory Molecules in Human Envenomation's by Bothrops atrox in the Brazilian Amazon

“…In addition, decreased concentrations of TNF and IFN-γ were observed. These findings demonstrate a high chemotactic and inflammatory response to exposure to venom in patients and corroborate data previously described in B. atrox snakebites, which shows a plasma increase in inflammatory mediators CXCL-8, CCL-5, CXCL-9, CCL-2, CXCL10, IL-6, TNF-α, IL-1β, and IL-10 ( 27 ). We observed in our study a low production of INF-γ, which could be associated with the main cell type producing this molecule (NK cells).…”

“…Patients bitten by B. atrox snakes in the Amazonas State, Brazil, presented the installation of a consumption coagulopathy, in which 85% of the patients showed hypofibrinogenemia ( 26 ). In addition, increased levels of soluble inflammatory mediators in patients have been demonstrated, and are associated with increased severity of the accident ( 27 ).…”

Bleeding Disorders in Bothrops atrox Envenomations in the Brazilian Amazon: Participation of Hemostatic Factors and the Impact of Tissue Factor

“…Venom has been detected in blister aspirates collected from the bite site in Bothrops snakebite patients [18,48]. Moreover, local manifestations such as severe edema, blister formation, and necrosis at the bite site have been observed in Bothrops envenomations, which were classified as moderate/severe cases [49]. The most abundant components found in venoms from the B. atrox of Brazilian Amazon are metalloproteinases, c-type lectin-like, phospholipases A 2 and serine proteinases, and are frequently involved in the hemostatic disorders observed in snakebite patients [26,50,51].…”

“…The coefficient correlation factor was considered significant when p < 0.05. The correlation index (r) was used to categorize the correlation strength as being weak (r ≤ 0.35), moderate (r ≥ 0.36 to r ≤ 0.67), or strong (r ≥ 0.90), as previously described [49,62].…”

Current Knowledge on Snake Dry Bites

“…A recent study from Manaus showed that detection of cell-free nucleic acids may be used to discriminate patients envenomed by Bothrops and healthy controls [ 75 ]. Levels of the inflammatory biomarkers CXCL-9, CXCL-10, IL-6, and IL-10 were higher in Bothrops -envenomed patients when compared to the healthy controls on admission [ 76 ]. Furthermore, there is a number of interactions of CXCL-8, CXCL-9, CCL-2, IL-6, and IFN-γ and fibrinogen levels in patients bitten by viperids, suggesting these cytokines as biomarkers for this type of envenoming [ 77 ].…”