Ethanolic extract of the fungus Trichoderma stromaticum decreases inflammation and ameliorates experimental cerebral malaria in C57BL/6 mice

Yusmaris Cariaco,Wesley Luzetti Fotoran,Gerhard Wunderlich,Romulo Sousa,Wânia Rezende Lima,Marisol Pallete Briceño,Neide Maria Silva,Jane Lima Dos Santos,Layane Alencar Costa Nascimento

doi:10.1038/s41598-018-19840-x

Abstract

Increased resistance to the first-line treatment against P. falciparum malaria, artemisinin-based combination therapies, has been reported. Here, we tested the effect of crude ethanolic extract of the fungus Trichoderma stromaticum (Ext-Ts) on the growth of P. falciparum NF54 in infected human red blood cells (ihRBCs) and its anti-malarial and anti-inflammatory properties in a mouse model of experimental cerebral malaria. For this purpose, ihRBCs were treated with Ext-Ts and analysed for parasitaemia; C57BL/6 mice were infected with P. berghei ANKA (PbA), treated daily with Ext-Ts, and clinical, biochemical, histological and immunological features of the disease were monitored. It was observed that Ext-Ts presented a dose-dependent ability to control P. falciparum in ihRBCs. In addition, it was demonstrated that Ext-Ts treatment of PbA-infected mice was able to increase survival, prevent neurological signs and decrease parasitaemia at the beginning of infection. These effects were associated with systemically decreased levels of lipids and IFN-γ, ICAM-1, VCAM-1 and CCR5 cerebral expression, preserving blood brain barrier integrity and attenuating the inflammatory lesions in the brain, liver and lungs. These results suggest that Ext-Ts could be a source of immunomodulatory and antimalarial compounds that could improve the treatment of cerebral malaria.

Highlights

Malaria cases globally fell over the last 16 years, the WHO estimated that 216 million new cases and 445,000 deaths from malaria occurred worldwide in 20161
We investigated the effects of the administration of crude ethanolic extract of T. stromaticum (Ext-Ts) in an experimental cerebral malaria (ECM) animal model
To determine whether the extract could interfere in the immune response induced by Plasmodium and ameliorate ECM, C57BL/6 mice were inoculated with 5 × 104 P. berghei ANKA (PbA)-infected red blood cells (RBCs) and treated with 50 mg/kg/day of extract of the fungus Trichoderma stromaticum (Ext-Ts) for 10 days, 100 mg/kg/day of Ext-Ts for 10 or 18 days or 200 mg/kg/day of Ext-Ts for 10 days

Summary

Introduction

Malaria cases globally fell over the last 16 years, the WHO estimated that 216 million new cases and 445,000 deaths from malaria occurred worldwide in 20161. Some anti-plasmodial drugs, such as quinine, chloroquine and mefloquine, exert a direct effect on the immune system by decreasing the production of pro-inflammatory cytokines such as TNF and IL-2, which are involved in the pathogenesis of severe malaria (reviewed by ref.[19]). In this sense, studies of immunomodulators for treatment of cerebral malaria as an adjunct therapy to control pro-inflammatory cytokine production and diminish the expression of adhesion molecules regulating parasite sequestration could improve the survival of individuals (reviewed by ref.[20]).

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