Genetic Profiling of Malaria and Lipid Mediator Quantification of Mouse Striated Muscles Infected with Malaria Parasites
Authors: Marrelli Mauro T. , Wang Zhiying , Fiedler Matthew , Huang Jian , Brotto Marco 
Published: April 2020

Malaria remains one of the most important infectious diseases in the world. The pathogenesis of malaria parasites causes illness, abnormal function and damage in the hosts. Among the several complications, the effects of malaria seem to target the skeletal muscle system, leading to symptoms, such as muscle aches, muscle contractures, muscle fatigue, muscle pain, and muscle weakness. Long‐term impacts of malaria include death, disability, and significant socioeconomic burden on societies where the disease is prevalent. A better understanding of the biological processes underlying the progression of infection to disease is urgently needed to reduce the morbidity and mortality of malaria. Considering the vital importance of the skeletal muscles as the largest organ‐system in the body, comprising nearly 50% of its mass and largely responsible for the regulation and modulation of overall metabolism, we investigated the potential molecular mechanisms of plasmodia infection affecting skeletal muscles of mice infected with Plasmodium berghei and P. chabaudi, using the Mouse Signal Transduction Pathway Finder PCR Array, which was implemented to monitor gene expression changes of 10 essential signaling pathways, and also applied our new targeted lipidomic approach using liquid chromatography with tandem mass spectrometry (LC‐MS/MS) to profile total 158 LMs, mostly eicosanoids and docosanoids, and further quantify 16 key LMs directly associated with inflammation and tissue healing in skeletal muscles. Our results showed that seven common genes (Acsl4, Bmp2, Cebpd, Cdkn1a, Sqstm1, Stat1 and Txnrd1) had their expression significantly altered, being some of them related to the inflammatory and immune response of the host. We hypothesized that the higher number of altered genes in skeletal muscles of P. chabaudi infected mice when compared to P. berghei infected mice be related to the plasmodia strains used, that were selected according to their characteristics and effect on the experimental mice models. In addition to those genes expression results, the lipids found on higher concentrations, compared to the controls, are directly related to inflammatory responses, while the lipids found on lower concentrations help to resolve inflammatory processes. The AA/EPA ratio, an indicator of inflammation and one of the top biomarkers for the morbidity and mortality, was severely higher (by 5–6‐fold) in muscles from malaria infected mice. Our results shed new insights into the mechanisms underlying the molecular mechanisms of malaria‐induced muscle damage and might be useful in future works monitoring of disease progression and development of specific interventions for the mitigation of long‐term chronic effects on skeletal muscle function. We postulate that these results are relevant to other vector borne diseases.

Support or Funding Information

This work was funding by Sabbatical grant from the University of São Paulo, Brazil (MM), and The George W. and Hazel M. Jay and Evanston Research Endowments (MB)