Complexity in Association of Virus and Immune Regulators on the Development of Atherosclerosis via Formation of Foam Cells

Atherosclerosis is a chronic condition characterized by the deposition of lipid in the artery. The pathophysiological similarities between atherosclerosis and infection spark the impetus for research among clinical practitioners and researchers. Viral and bacterial agents have been associated with the aggravation of atherogenesis via studies on the epidemiology, local identification of pathogens in atherosclerotic plaque, and experimental demonstrations in vivo [1-11]. Infectious agents may participate in atherogenesis development by direct or indirect mechanisms. Direct pathogen infection takes place in the intima of blood vessel which results in primary inflammation that leads to the initiation or progression of atherosclerosis plaque [12].


Introduction
Atherosclerosis is a chronic condition characterized by the deposition of lipid in the artery. The pathophysiological similarities between atherosclerosis and infection spark the impetus for research among clinical practitioners and researchers. Viral and bacterial agents have been associated with the aggravation of atherogenesis via studies on the epidemiology, local identification of pathogens in atherosclerotic plaque, and experimental demonstrations in vivo [1][2][3][4][5][6][7][8][9][10][11]. Infectious agents may participate in atherogenesis development by direct or indirect mechanisms. Direct pathogen infection takes place in the intima of blood vessel which results in primary inflammation that leads to the initiation or progression of atherosclerosis plaque [12].
Direct pathogen involvement is indicated by infection of pathogens in atherosclerosis lesion, microbial demonstration within atherosclerosis plaque, and acceleration of plaque progression in atherosclerotic mouse models post-infection [1]. Indirect mechanism refers to an inflammation caused by pathogens at non-vascular sites that contributes to the increase of cytokines and acute phase proteins that results in the progression of atherosclerosis develop ment [1,12]. Immunoregulators of both the humoral and cellular immunities are involved at all atherogenesis stages [13]. Cytokines  [3,17,18]. HIV protein Nef, which is associated with the pathogenesis of atherosclerosis in patients infected with HIV was found to play a role in dyslipidemia and the formation of foam cells within blood vessel walls of mice [19]. Infection of murine CMV in ApoE -/mice was shown to result in a more advanced atherosclerosis lesion and an increase in the level of P38 mitogen-activated protein kinase in aortas compared to atherosclerotic mice that are not infected with murine CMV [20]. HCV perturbs the equilibrium between cellular and humoral immunity and increases ratio of proinflammatory to anti-inflammatory cytokines which has been associated with a heightened cardiovascular risk in patients infected with HCV [21,22]. id droplets [23,24], transforming them into lipid-laden foam cells [25].

Murine norovirus (MNV) in Atherosclerosis
Development MNV, the surrogate to human norovirus manifests tropism for dendritic cells and macrophages. MNV infection has been shown to be prevalent in laboratory mouse colonies around the world and has been demonstrated to cause biases in studies involving mouse models [26][27][28]. MNV-4 has been demonstrated to increase the size and accumulation of macrophages in aortic sinus lesion area in Ldlr -/mice suffering from hyperlipidemia [29]. In another study in 2015 [30], the authors reported that MNV-4 infection in Ldlr -/mice did Besides, an in vivo study using ApoE -/demonstrated an increased size of atherosclerosis lesion [17].
However, in a second study where the authors used a low-passage MNV-4 preparation, they did not observe the similar outcomes as in the first study. The authors contributed the discrepancy to the different virus passages used which revealed mutations corresponding to two changes of amino acids, where the two preparations resulted in a notably different regulation of cytokines and chemokines in ApoE -/-BMDM as well as contrasting effects on atherosclerosis lesion progression [17]. Indeed, different MNV strains, some even with a single substitution of amino acid, may be markedly dissimilar in their replication, virulence, and persistence in infected mice [17,31]. Additionally, [17], MNV-4 infection in ApoE -/mice has shown to result in increased percentages of Ly6C-positive monocytes, which has been linked with proinflammatory responses correlated to the enhancement of monocyte recruitment into atherosclerotic plaques, differentiation into macrophages, and foam cell formation. MNV-4 RNA was also detected locally on the aggravated lesion of the aortic sinus of ApoE -/mice [17].

Effect of MNV-3 on Foam Cell Formation
However, in the mentioned studies [17,30]

Am J Biomed Sci & Res
Copyright@ Muhammad Amir Yunus 285 In our study with MNV-3, we infected RAW 264.7 with low-passage MNV-3 (passage 4) and our observation is supported by [17] that did not find lesion development in ApoE -/mice infected with low-passage MNV-4. Furthermore, MNV-4 has shown to only exacerbate established lesion [30] which further supports our finding on MNV-3 did not facilitate the formation of macrophage foam cells in vitro. Additionally, despite the upregulated mRNA expressions of interferon stimulated genes following MNV infection, their translation has been shown to be suppressed which was associated to the activities of MNV NS6 protease [33], implying the lack of inflammatory signaling following MNV infection which further supports our observation on MNV-3 in the regulation of foam cell formation.

Conclusion
MNV has shown variable effect in the development of atherosclerosis in vivo and in vitro [17,29,30,32]. In our own studies on MNV-3 and MNV-1 we have verified that these strains do not assist the formation of macrophage foam cells in vitro. Based on our review, the variable effects on atherosclerosis development observed in MNV infection might probably be highly dependent on the stage of atherosclerosis development and virus strain or passage.