Introduction
Traditionally atherogenesis has been considered within the domain of non communicable lifestyle diseases affecting the affluent sections of human population while communicable diseases and infections have been the cause of languish in the developing world. However the lines of division between these two high mortality disease causing pathologies are increasingly becoming blurred compelling us to possibly investigate a causative interdependency between infections and the process of atherogenesis.
Burden of atherosclerosis
Cerebral vasculature Atherogenesis has been implicated in the causation of various common neurological disorders such as recurrent strokes, dementia and Alzheimer’s disease.(1), (2)
The burden of these diseases in the present world is indeed very high with statistics from India for the duration from 1960 to 2018 showing that the prevalence rate of stroke in the Indian population inclusive of urban and rural population, varied from 44.54 to 150/100000 during this time period. The 30 days case fatality rate of stroke was also quite high and came up to around 42%.(3)
Hence it indeed becomes absolutely imperative for us as citizens of a developing country that is fast pacing on the road to becoming a developed country to look into how do infections influence the risk of strokes and Alzheimer’s as our population is exposed to both a high burden of infection as well as a rapidly developing obesity and lifestyle disorder epidemic.(4)
Mechanisms of atherogenesis in cerebral vasculature
Ischemic Strokes have been classified into the following 5 types by the TOAST classification – 1) large-artery atherosclerosis, 2) small-vessel occlusion, 3) cardioembolism, 4) stroke of other determined etiology, and 5) stroke of undetermined etiology.(5)
In blood vessels the Pathogenesis of atherosclerosis is explained by the response to injury hypothesis whereby endothelial injury causes lipid deposition and plaque formation in vessel walls which eventually cause arteries to become critically stenosed or plaques to rupture thereby compromising the blood supply to various organs and causing as a result of ischemia various clinical syndromes. (6)
What is also interesting is that it has been noticed that intracranial vessels tend to develop atherosclerosis about 20 years later than extracranial vessels due to low endothelial permeability, a special glycocalyx, and other enhanced protective mechanisms against oxidative stress which can suggest the presence of a barrier function. In early years of life, the compliance of the aorta and carotids tend to maintain a low pulse pressure in the intracranial arteries, retarding the development of intracranial atherosclerosis. With increasing age and accelerated by other risk factors like hypertension, diabetes mellitus, and an enhanced stiffness of aorta and carotid arteries, the protective effect of a low pulse pressure is lost, and the enhanced pulsed-wave propagation may become a major driver of intracranial atherosclerosis.(7)
Atherosclerosis currently is fast developing a reputation as a disease which is no longer solely attributed to the high lipid content of the body. New insight into the disease pathogenesis has demonstrated it to be a disease of much greater ramifications. Novel risk factors such as hyperhomocysteinemia, infections and systemic lupus erythematosus have also emerged. Hence as per the new thinking atherosclerosis has come to be regarded as a chronic inflammatory disease with an autoimmune component.(8)
Role of Infection as a key player in the Pathogenesis of atherosclerosis
It has been hypothesised that low grade infections might be one of the causes of the inflammatory reaction observed in atherosclerotic lesions reflected in raised concentrations of CRP. Studies have shown that CRP might promote atherosclerosis locally by activating the complement system and inducing foam cell formation.(9) Several studies have shown that recent infection including upper respiratory tract infections and UTI’s have been associated with an increased risk of acute strokes in the immediate period following the infection. (10) There are several reasonable biological explanations that exist to explain the increased risk of ischemic stroke associated with infections.
It is a well known fact that severe infections are associated with hypercoagulability and platelet activation that contribute to tissue ischemia and necrosis of organs during sepsis and even subseptic infections increase platelet reactivity and platelet – leukocyte interactions, leading to a greater risk of platelet aggregation, potentially precipitating stroke.(11) (12)Additionally infections also impair endothelial function. Studies have shown that raised Leukocyte count (indirect marker of infection) is associated with reduced endothelial reactivity(13).Infections may also transiently impair endothelium-dependent relaxation. In addition not infrequently one hears of the term ‘aspirin failure’ used to describe the patient who despite taking aspirin regularly had an ischemic stroke. One plausible explanation for this could be that the dose of aspirin being used is appropriate at most times, but that at one particular point in time, perhaps due to the transient presence of a stroke- prone state in the patient due to infections the dose becomes insufficient and ‘breakthrough’ strokes may occur. Hence this could justify the thinking that the threshold of disease may change transiently due to infective etiologies, and therapy may need to be altered accordingly. (12)
Bacterial infections and their role in cerebral atherogenesis
Chlamydia pneumoniae
The idea that bacteria could cause atherogenesis surfaced in 1988 when a study published in the The Lancet observed that the bacterium Chlamydophila pneumonia was frequently present in artery-clogging deposits. C pneumonia is a common respiratory pathogen causing community-acquired pneumonia, bronchitis, sinusitis, and upper respiratory tract symptoms. Animal experiments have demonstrated that C. pneumoniae can initiate early atherosclerotic changes in the aorta without hyperlipidemia (14) and can accelerate atherosclerosis in the presence of hyperlipidemia.(15)
In order to play a causative role in chronic disease, C. pneumoniae would need to persist within infected tissue for long periods of time hence stimulating a chronic inflammatory response. It disseminates systemically from the lungs through infected mononuclear cells and tends to localize in arteries where it infects endothelial cells, vascular smooth muscle cells, monocytes/macrophages and promote inflammatory atherogenous process (16)Chlamydiae is notorious for causing chronic infections, and treatment failure is common. These infections and failures may be due to its unique ability to establish of a nonreplicating and noncultivable intracellular growth stage resulting in a long-term relationship with the infected host cell. Atherosclerotic disease progression is associated with higher levels of antibodies due to chronic infection and repeated infections. In a relatively large case-control study, the presence of antibodies to C. pneumonia was found to be associated with stroke or transient cerebral ischemia (17) and Chronic C. pneumoniae infection itself may be associated with a serum lipid profile that predisposes to atherosclerosis(18). The mechanisms by which C pneumoniae causes atherogenesis include – infected macrophages chronically exposed to C. pneumoniae lipopolysacharride (cLPS) may accumulate excess cholesterol to contribute to atheroma development(19), another mechanism includes causing host cells to release HSPs during their lytic phases of development which also activates human vascular cell functions relevant to atherogenesis and lesional complications(20), it also serves as a link between high serum LDL levels and an event critical to the development of the atheroma, such as the cellular oxidation of LDL by inhibiting respiratory burst and induces a selective release of myeloperoxidase without promoting superoxide production and this myeloperoxidase has been proposed to play an important role in the oxidation of LDL in vivo.(21), (22) and lastly it also upregulates production of gelatinise by macrophages causing extra cellular matrix destruction and tissue damage.(23). Trials of antibiotic therapy for secondary prevention has been studied in MI and unstable angina and showed a reduction in secondary event at 1 month follow up which was however lost at 6 months follow up. suggested a benefit of newer macrolides after acute myocardial infarction or in unstable angina. (24), (25)
Helicobacter Pylori
Studies have found that Anti–H pylori IgG antibodies correlated significantly with carotid atherosclerosis when the statistical analysis was restricted to low socioeconomic status populations.(26) Chronic H. pylori infection induces a pro-inflammatory state, resulting into an increase in cytokines levels such as TNF-α, Interleukins, gamma interferons, coagulant factors – fibrinogen, thrombin and soluble adhesion molecules such as intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1) which predisposes to atherogenesis.(27),(28)Also H. pylori causes atrophic gastritis, which is associated with malabsorption of vitamin B12 and folic acid. Deficiency of these vitamins causes hyper-homocysteinaemia due to interruption of re-methylation pathway. Hence, it may have a role in the pathogenesis of premature atherosclerosis.(29) H. pylori infection is associated with lower HDL cholesterol (HDL-C) and higher total cholesterol (TC), LDL cholesterol (LDL-C) and triglyceride levels.(30)H pylori also causes hypertension and increased arterial stiffness(31) with the effect being more pronounced in young patients and eradication of the bacteria results in significant reduction of blood pressure. (32)
Many studies found a higher prevalence of H. pylori seropositivity in stroke cases compared to controls. (33) There was an association between H. pylori infection and large vessel disease and lacunar stroke irrespective of other confounding factors. Cag-A positivity has also raised an interest in the infectious theory of atherosclerosis. Several studies had shown a significant relationship between Cag-A strain and CAD or stroke and carotid plaque instability.(34)
Streptococcus pneumoniae
The third bacteria associated with atherogenesis is Streptococcus pneumoniae. Clinical studies consistently find an increase in the risk of acute coronary syndrome (ACS) in the weeks following pneumonia. Pneumococcal infections are associated with increased atherosclerotic plaque macrophage content, a marker of plaque instability, at 2 weeks post infection. (35) S. pneumoniae infection has been shown to augment atherosclerosis and exacerbate ischemic brain injury via IL-1 and platelet-mediated systemic inflammation.(36)
Periodontal infections
Various periodontal pathogens such as Porphyromonas gingivalis have also shown to play a role in atherogenesis via causing increased prothrombotic states, oxidative stress, production of HSP60, vascular endothelial activation and Activation of Innate Immune Signaling Associated with Atherosclerosis.(37)
Viral infections and their role in cerebral atherogenesis
Cytomegalovirus
CMV is an all too common viral infection and hence the finding that CMV associated inflammation could cause atherogensis has indeed been a subject of much interest among researchers.
Studies have demonstrated that although CMV infection is associated with elevated CRP levels, individuals vary in their capacity to control CMV inflammatory and the risk of atherogenesis is greatest in individuals who are seropositive for CMV and who also have highly elevated CRP levels.(38) Yet another study demonstrated that CMV infection predisposed women to developing hypertension, atherosclerosis and consequent strokes.(39) Interestingly it has also been accused of causing restenosis and atherosclerosis of arteries in transplanted hearts.(40)
Herpes Simplex Virus
This virus which has been traditionally associated with temporal lobe sporadic encephalitis showing periodic lateralising epileptiform discharges on EEG has been implicated to be a major causative factor in acute ischemic stroke in children.(41)
Hepatitis Viruses
HBV shares the characteristics of an infectious agent that are required for it to be implicated in atherogenesis: HBV is an intracellular pathogen, causes systemic effects and immune responses, and may colonize in the vascular tissues; furthermore, a substantial proportion of those infected in early life go on to develop a chronic phase. Some studies argue that HBV causes a pro inflammatory and procoagulant state causing atherogenesis and ischemic stroke(42) while other studies say that it leads to anticoagulant effects and increased risk of haemorrhagic stroke.(43)
As far as HCV is concerned there are many proposed pathogenic mechanisms connecting it to atherogenesis and stroke such as HCV colonization and replication within arterial walls, liver steatosis and fibrosis, enhanced and imbalanced secretion of inflammatory cytokines, oxidative stress, endotoxemia, mixed cryoglobulinemia, perturbed cellular and humoral immunity, hyperhomocysteinemia, hypo-adiponectinaemia, insulin resistance, type 2 diabetes and other components of the metabolic syndrome. In fact interferon and ribavirin treatment appears to decrease the risk of ischemic stroke.(44)
Varicella zoster and Herpes Zoster
There has been found a relationship between high levels of anti-Varicella Zoster Virus (VZV) IgG in cerebrospinal fluid (CSF) and cerebrovascular atherosclerosis.(45) as well as waxing and waning vasculitis.(46)Herpes Zoster Ophthalmicus has also been implicated to cause stroke with Individuals exposed to HZ or HZO having 1.3 to 4-fold increased risks which was especially true in younger patients.(47)
Parvovirus B19
This virus that usually causes fifth disease (Erythema Infectiosum) among children and aplastic crises in SCD has also been found to cause young stroke in children and adults however this is predominantly due to its procoagulant effect causing thrombosis in cerebral vasculature especially in the MCA.(48),(49)
HIV
HIV is notorious for being an infection with myriad manifestations. HIV predisposes a patient to developing other opportunistic viral infections such as CMV and Herpes Zoster which as we have seen above predispose to atherogenesis. 75% of the strokes that occur in PLHIV are ischemic strokes. (52)HIV itself when associated with CD4 counts lower than 200/micro litre is associated with an increased risk for developing ischemic stroke compared to those with CD4 counts of at least 500 cells/micro litre who had no such excessive risk.(50) HIV mediates increased atherosclerosis via pathways such as the NLRP3 inflammasome hyper activation, endothelial dysfunction via HIV proteins causing instability of calcium in the endothelial cells and ER stress mediated apoptosis. It also suppresses autophagy which is essential for plaque stability and removal of foam cells.(51)
COVID-19
Finally we shall end our discussion on viruses causing atherosclerosis by talking about the infamous virus that brought our world to a virtual standstill. So everyone knows how COVID-19 contributes to atherogenesis- of course by forcing all of us to lead a sedentary life at home, binging on our favourite snacks whilst engaging in Netflix and Chill! Well keeping jokes aside recent studies have in fact found a link between infection with SARS-CoV-2 and increased vessel wall stiffness in the carotid arteries which is a known risk factor for increased atherosclerotic progression. (53) Inflammation which often spirals into a deadly SIRS seen in COVID may also affect atherosclerotic plaques, induce prothrombotic changes in blood and endothelium and lead to their instability.(54) Neuropilin1 which is a coreceptor for the virus entry into the brain is also shown to increase risk of Ischemic stroke and could be the linking bio marker between the two.(55)
Fungal infections and their role in cerebral atherogenesis
The fungi of genus Candida, which are present on all parts of the body, are conditional-pathogens and cause candidiasis when host immunity is compromised. IgG antibodies to candida were associated with increased risk for ACS, and it is possible that candida can induce inflammation mediated atherosclerosis as evidenced by its presence in plaques however the causality is yet to be proven conclusively.(56)
Parasitic infections and their role in cerebral atherogenesis
There are reports of parasites causing acute ischemic stroke and brain infarcts. Cerebral malaria is thought to cause stroke owing to the occlusion of cerebral arteries by parasitised RBCs and dysregulated coagulation.(57)Neurotrichinelliasis is also known to cause microinfarcts.(58)However just as is the case with fungi causality in developing atherosclerosis has not been proven.
Vaccinations and the risk of stroke
Since infections have been found to have a plausible causative relationship with atherogenesis in all vessels of the body then it is reasonable to hypothesise that vaccinations should decrease this risk. However in reality this is a matter of debate among researchers. Pneumococcal vaccination has been shown to cause production of anti oxidised LDL antibodies in murine models. (59)One meta analysis showed that the pneumococcal vaccine reduced the risk of atherosclerosis and ACS but not of stroke. (60) However other contradictory studies claim that there is no reduced risk of stroke and atherosclerosis following pneumococcal vaccination.(61) Influenza vaccine too has been shown to afford protection against atherosclerosis through unknown mechanisms which may probably be due to reducing the risk of concomitant bacterial infections that leads to inflammation and prothrombotic states.(62)
Another interesting development is the production of primary anti atherosclerotic vaccines against HSPs in the form of oral vaccines(mycobacteria hsp) and sublingual vaccines(p gingivalis) which showed atheroprotective effects.(63)(64) Multitarget vaccines have also been in the works against epitopes from ApoB (p45), HSP60, and Chlamydophila pneumoniae.(65)
Post stroke immune modulation
By now the causal relationship between infections and stroke has been well established by the above explanation but what is really interesting is that severe stroke itself causes changes in brain that predispose to immunodepression and the development of infections post stroke and this occurs as an adaptive response to brain ischemia.(66) and trials have shown the efficacy of administering preventive antibiotic therapy in the prevention of post stroke infections in an anticipatory basis.(67)
Gut microbiota and their influence on cerebral atherogenesis
While we have spoken of the role played by exogenous pathogens in the development of atherogenesis it is also appropriate to give a short account of the influence of gut micro biome on the same. Because the gut microbiota has close relation to inflammation and many chronic diseases, it has drawn a lot of attention and intercommunication pathways connecting the brain and the gut exist in the human body, known as the gut–brain axis. Gut microbiota dysbiosis leads to the proliferation of pathogenic bacteria, Short Chain Fatty Acid decrease and TMAO increase, resulting in atherosclerosis, systemic inflammation, and platelet hyperresponsiveness, which directly contributes to the occurrence and development of ischemic stroke. It also affects the pathogenesis of disease like hypertension, obesity and type 2 diabetes which also are risk factors for ischemic stroke.(68)This has also opened up potential therapeutic strategies including probiotics supplementation and fecal microbiota transfer to regulate the gut micro biome and reduce the risk of as well as treat ischemic stroke.(69) Acute brain lesions in turn also induce dysbiosis of the microbiome which in turn affect neuroinflammatory and functional outcome after brain injury and this impact is also transmissible by microbiota transplantation.(70)
Conclusion
In the present world the line of demarcation between infectious diseases and non communicable diseases like stroke have become increasingly indistinct and the discovery of the intricate interdependence between these two previously considered polar opposite pathogenetic mechanisms have opened up exciting new therapeutic opportunities which may with further refinement be the future of treatment for ischemic strokes and other diseases caused due to cerebral atherosclerosis.
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Nanditha’s Neural Nebula 