Date Published: February 13, 2018
Publisher: Public Library of Science
Author(s): Kim E. Schmidt, Janina M. Kuepper, Beatrix Schumak, Judith Alferink, Andrea Hofmann, Shanshan W. Howland, Laurent Rénia, Andreas Limmer, Sabine Specht, Achim Hoerauf, Leonardo Jose de Moura Carvalho.
Malaria ranks among the most important infectious diseases worldwide and affects mostly people living in tropical countries. Mechanisms involved in disease progression are still not fully understood and specific treatments that might interfere with cerebral malaria (CM) are limited. Here we show that administration of doxycycline (DOX) prevented experimental CM (ECM) in Plasmodium berghei ANKA (PbA)-infected C57BL/6 wildtype (WT) mice in an IL-10-independent manner. DOX-treated mice showed an intact blood-brain barrier (BBB) and attenuated brain inflammation. Importantly, if WT mice were infected with a 20-fold increased parasite load, they could be still protected from ECM if they received DOX from day 4–6 post infection, despite similar parasitemia compared to control-infected mice that did not receive DOX and developed ECM. Infiltration of T cells and cytotoxic responses were reduced in brains of DOX-treated mice. Analysis of brain tissue by RNA-array revealed reduced expression of chemokines and tumour necrosis factor (TNF) in brains of DOX-treated mice. Furthermore, DOX-administration resulted in brains of the mice in reduced expression of matrix metalloproteinase 2 (MMP2) and granzyme B, which are both factors associated with ECM pathology. Systemic interferon gamma production was reduced and activated peripheral T cells accumulated in the spleen in DOX-treated mice. Our results suggest that DOX targeted inflammatory processes in the central nervous system (CNS) and prevented ECM by impaired brain access of effector T cells in addition to its anti-parasitic effect, thereby expanding the understanding of molecular events that underlie DOX-mediated therapeutic interventions.
Malaria is caused by the vector-borne transmission of Plasmodium ssp. parasites and remains one of the major infectious diseases in the world. The disease constitutes not only a major health burden but also has negative socio-economic consequences, especially in developing sub-Saharan countries. Of the five human pathogens, P. vivax, P. malariae, P. ovale, P. knowlesi and P. falciparum, the latter is clinically the most relevant parasite. P. falciparum causes malaria tropica, which is often characterized by severe pathologies such as severe anaemia, respiratory distress, organ failure or cerebral malaria, subsequently leading to coma and death especially in children under the age of five years . It is widely accepted that CM is not only caused by sequestration of parasitized red blood cells but also is a result of overwhelming inflammatory responses of the host that trigger additional effector mechanisms leading to immune-mediated pathology . However, the molecular mechanisms and detailed processes during disease progression to cerebral malaria are not fully understood. Evaluation of the infection in humans is very limited i.e. to the analysis of blood-samples and of post-mortem material due to ethical reasons.
Here we show that the tetracycline DOX, in addition to its described anti-parasitic effects, is able to ameliorate inflammation in PbA-infected mice resulting in protection from ECM.