Oral Route Driven Acute Trypanosoma cruzi Infection Unravels an IL-6 Dependent Hemostatic Derangement

Abstract

Oral transmission of Trypanosoma cruzi , the etiologic agent of Chagas disease, is presently the most important route of infection in Brazilian Amazon. Other South American countries have also reported outbreaks of acute Chagas disease associated with food consumption. A conspicuous feature of this route of transmission is presenting symptoms such as facial and lower limbs edema, in some cases bleeding manifestations and risk of thromboembolism are evident. Notwithstanding, studies that address this route of infection are largely lacking regarding its pathogenesis and, more specifically, the crosstalk between immune and hemostatic systems. Here, BALB/c mice were orally infected with metacyclic trypomastigotes of T. cruzi Tulahuén strain and used to evaluate the cytokine response, primary and secondary hemostasis during acute T. cruzi infection. When compared with control uninfected animals, orally infected mice presented higher pro-inflammatory cytokine (TNF-α, IFN-γ, and IL-6) serum levels. The highest concentrations were obtained concomitantly to the increase of parasitemia, between 14 and 28 days post-infection (dpi). Blood counts in the oral infected group revealed concomitant leukocytosis and thrombocytopenia, the latter resulting in increased bleeding at 21 dpi. Hematological changes paralleled with prolonged activated partial thromboplastin time, Factor VIII consumption and increased D-dimer levels, suggest that oral T. cruzi infection relies on disseminated intravascular coagulation. Remarkably, blockade of the IL-6 receptor blunted hematological abnormalities, revealing a critical role of IL-6 in the course of oral infection. These results unravel that acute T. cruzi oral infection results in significant alterations in the hemostatic system and indicates the relevance of the crosstalk between inflammation and hemostasis in this parasitic disease.

Benznidazole and amiodarone combined treatment attenuates cytoskeletal damage in Trypanosoma cruzi-infected cardiac cells

“…The transmission of this protozoan is primarily through contact with feces of triatomine insects after biting. Furthermore, transmission can also occur via non-vectorial route, by ingestion of contaminated food, congenitally and through blood transfusion or organ transplantation ( Antunes et al., 2019 ).…”

Platelets, Macrophages, and Thromboinflammation in Chagas Disease

“…2 , 3 The oral route of transmission is noted to result in a much higher mortality rate of 8%–35% than is generally observed by vectorial transmission, which is <5%–10%. 4 Due to the high rate of migration from endemic countries, it is estimated that 68,000–120,000 people with CD are currently living in Europe. 5 The Centers for Disease Control and Prevention (CDC) estimates >300,000 immigrants with T. cruzi infection are living in the US, with up to 45,000 cardiomyopathy cases occurring yearly.…”

Human acute Chagas disease: changes in factor VII, activated protein C and hepatic enzymes from patients of oral outbreaks in Pará State (Brazilian Amazon)

“…In agreement with a previous study from the Pará State, the most common electrocardiographic change in ACD patients contaminated by oral transmission corresponded to alterations in ventricular repolarisation (72.6%); actually, we observed this disturbance in 84.3% of the patients. (19) Haematological symptoms, including epistaxis, gum bleed and hemorrhagic manifestations were found in 2% of patients. In accordance, an outbreak of oral infection in the Northeast of Brazil, Ceará, hemorrhagic manifestations concomitant with high levels of transaminases were reported in three patients out of eight subjects.…”

“…In this study, oral ACD induced low platelet count, increased bleeding and coagulation time, in parallel with high parasitaemia. (19) Moreover, haematological changes occurred with prolonged activated partial thromboplastin time, Factor VIII consumption and increased D-dimer levels, suggesting signs of disseminated intravascular coagulation. (20) In the present study gastrointestinal bleeding was not seen, thus differing from the symptoms observed in the outbreak in the State of Santa Catarina, southern Brazil, in March 2005 where three fatal cases were disclosed.…”