Advances in Cardiovascular Disease Lipid Research Can Provide Novel Insights Into Mycobacterial Pathogenesis

REVIEW published: 18 April 2019 doi: 10.3389/fcimb.2019.00116 Advances in Cardiovascular Disease Lipid Research Can Provide Novel Insights Into Mycobacterial Pathogenesis Shyamala Thirunavukkarasu and Shabaana A. Khader* Department of Molecular Microbiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States Edited by: Stephane Canaan, Centre National de la Recherche Scientifique (CNRS), France Reviewed by: Xuwen Peng, Penn State Milton S. Hershey Medical Center, United States Evgeniya V. Nazarova, Immunology Discovery, Genentech, United States Natalie Garton, University of Leicester, United Kingdom *Correspondence: Shabaana A. Khader Specialty section: This article was submitted to Molecular Bacterial Pathogenesis, a section of the journal Frontiers in Cellular and Infection Microbiology Received: 20 November 2018 Accepted: 02 April 2019 Published: 18 April 2019 Citation: Thirunavukkarasu S and Khader SA (2019) Advances in Cardiovascular Disease Lipid Research Can Provide Novel Insights Into Mycobacterial Pathogenesis. Front. Cell. Infect. Microbiol. 9:116. doi: 10.3389/fcimb.2019.00116 Cardiovascular disease (CVD) is the leading cause of death in industrialized nations and an emerging health problem in the developing world. Systemic inflammatory processes associated with alterations in lipid metabolism are a major contributing factor that mediates the development of CVDs, especially atherosclerosis. Therefore, the pathways promoting alterations in lipid metabolism and the interplay between varying cellular types, signaling agents, and effector molecules have been well-studied. Mycobacterial species are the causative agents of various infectious diseases in both humans and animals. Modulation of host lipid metabolism by mycobacteria plays a prominent role in its survival strategy within the host as well as in disease pathogenesis. However, there are still several knowledge gaps in the mechanistic understanding of how mycobacteria can alter host lipid metabolism. Considering the in-depth research available in the area of cardiovascular research, this review presents an overview of the parallel areas of research in host lipid-mediated immunological changes that might be extrapolated and explored to understand the underlying basis of mycobacterial pathogenesis. Keywords: mycobacterium, tuberculosis, granuloma, lipid, cardiovascular, plaque, arachidonic acid, foam cell INTRODUCTION One of the leading causes of morbidity and mortality in westernized countries is cardiovascular disease (CVD), such as atherosclerosis (Yeates et al., 2015). Atherosclerosis is a complex, chronic, progressive, inflammatory disease involving different cell types resulting in the formation of an atheromatous plaque. Atherosclerosis is characterized by infiltration of the arterial intima by macrophages which scavenge oxidized low density lipoprotein (oxLDL), which further promotes alterations in cholesterol influx, esterification and efflux, ultimately resulting in the progression of the macrophage into a foam cell. The specific contributions of lipids and lipoproteins as well as the influence of cholesterol metabolism in the formation of atheromatous plaques has been extensively researched in the context of atherosclerosis and CVD (Chroni et al., 2011). Mycobacterium tuberculosis (Mtb) is a successful human pathogen due to its ability to cause tuberculosis (TB) in almost 10 million individuals annually (Dye and Williams, 2010). Non-tuberculous mycobacteria (NTM) also cause diseases such as pulmonary and skin infections, in addition to being implicated as putative causative agents of Crohn’s disease in humans (Thirunavukkarasu et al., 2017a). NTM share commonalities with tuberculous mycobacteria with regard to subversion of host macrophage immune responses (Whittington et al., 2012; Thirunavukkarasu et al., 2017a). A primary reason for the ubiquitous spread of mycobacterial Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 April 2019 | Volume 9 | Article 116 Thirunavukkarasu and Khader Interdisciplinary Knowledge and Mycobacterial Pathogenicity infection despite current control strategies is the ability of pathogenic mycobacteria to persist in a non-replicative state both within the host, and sometimes in the environment (Falkinham, 2009). Macrophages play a pivotal role in the immune response against mycobacteria (Pieters, 2008; Thirunavukkarasu et al., 2015; Mcclean and Tobin, 2016). One of the main mechanisms of the successful intra-macrophage survival of mycobacteria including Mtb, M. avium, M. bovis, M. paratuberculosis, M. ulcerans, and M. leprae is their capacity to manipulate the host cellular metabolism to utilize intracellular substrates including fatty acids and cholesterol (Mendum et al., 2015). This manipulation of the host macrophage lipid metabolic pathway is a hallmark of several mycobacterial infections including TB (Peyron et al., 2008; Russell et al., 2009; Almeida et al., 2012; Caire-Brändli et al., 2014). Dysregulated lipid metabolism resulting in foam cell formation in macrophages and other cell types, and its association with steroid hormones as well as granuloma lesion formation, is a critical aspect in understanding mycobacterial pathogenesis. However, current research on the contribution of host lipid metabolic pathways in disease pathogenesis is limited, unlike in cardiovascular research where it has been the focus of extensive studies (Tambo et al., 2016). The similarities in the immune responses in the kinetics of atherosclerotic plaque formation and a granuloma formation in TB is an exposition of how knowledge could be gained by extrapolating ideas from among these fields. NIH has identified interdisciplinarity as an essential contributor to needed knowledge and made it an explicit priority in its roadmap. Considering the several areas of similarities between the immunopathology of atherosclerosis and mycobacteriosis, it would be applicable to explore and extrapolate the plethora of information available in this arena in CVD research to address the knowledge gaps in the area of host lipid metabolism in mycobacterial research. However, comprehensive review articles providing reference pools for promoting scientific knowledge in interdisciplinary applications between CVD and mycobacterial immunopathology are lacking. Therefore, the purpose of this review is to identify and put forth the similarities in relation to alterations in host lipid metabolism contributing to disease pathology induced by cardiovascular and mycobacterial diseases. Furthermore, we highlight the recent advances pertaining to host lipid metabolism in CVD immunopathology that could provide potential avenues to explore for researchers involved in studying mycobacterial pathogenesis. processing and retention of intracellular lipids, and altered reverse cholesterol transport (Remmerie and Scott, 2018). Lipids are not soluble in plasma (...truncated)