INFLAMMATORY RESPONSE TO MICROORGANISMS AND NEUROLOGICAL DYSFUNCTION

S.K. Kritas *

Department of Microbiology and Infectious Diseases, Aristotle University of Thessaloniki, Greece.

*Correspondence to:
Dr. S.K. Kritas,
Department of Microbiology and Infectious Diseases,
Aristotle University of Thessaloniki,
54250 Macedonia, Greece.
e-mail: skritas@vet.auth.gr

Received: 13 March, 2019 Accepted: 28 April, 2019

2279-5855 (2019) Copyright © by BIOLIFE This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Infectious agents such as pathogenic microorganisms enter our body, activate the immune system and generate an inflammatory response with tissue damage, causing diseases. The commensal microorganisms that house our intestines live symbiosis with the host and regulate homeostasis. The alteration of the balance between microorganisms and the immune system leads to the activation of the latter, with critical consequences. Numerous studies indicate that the gut-brain axis is implicated in neurological diseases, an important crosstalk involving the gut microbiota and the whole body. Dysbiosis, an imbalance of the microbiota, can generate inflammation with increased intestinal permeability, resulting in the entry of microorganisms and bacterial products, aggravating the inflammatory state. In these cases, pro-inflammatory cytokines are produced, which can reach the central nervous system (CNS), generating brain diseases, including encephalitis. The microbiota regulates the function of immune cells, including T lymphocytes, which act to control the pathogenesis of the neurological disease. In cerebral inflammation, it releases neurotransmitters such as substance P, which act on specific receptors located on immune cells, which are activated to produce pro-inflammatory cytokines. Therefore, the alteration of the gut-brain axis contributes to inflammation and aggravates the pathogenesis of neurological disease. In this article, we describe the immune and inflammatory effects of pathogenic bacteria in relation to neurological disease.

KEYWORDS: inflammation, microorganism, neurological dysfunction, immune, CNS

INTRODUCTION

The number of neurological infectious diseases is constantly evolving due to the significant trafficking of travelers across the globe (1,2). The increase of these and other pathologies of the central nervous system (CNS) is also due to antibiotic resistance, the lack of vaccines, immunodeficiency, and unavailable or ineffective therapies (3). Microorganisms from the external environment infect the host and alter the immune system by activating microglia, influencing neuronal pathologies (4). The dysregulation of the microbiome, composed of over 700 microbial species and protects the intestine, can communicate with the brain through the vagal nerve that innervates the villi of the intestinal mucosa, causing inflammation (5). In humans, bacterial infections of the CNS are an important cause of morbidity and mortality. Therefore, understanding the pathophysiological damage induced by bacteria can represent an important weapon for diagnosis and therapy.

DISCUSSION

A large number of microorganisms, including bacteria and viruses, can cause damage to the CNS, such as vasculitis, encephalopathies, strokes, convulsions, migraines, ischemia, aneurysms, subdural empyema, etc. (6). Different types of microorganisms can cause different pathologies which can affect the brain and the whole body. When infecting the CNS, bacteria primarily attack the meninges and brain parenchyma, causing various brain damage, including meningitis, seizures, and epilepsy (7,8). Bacterial infection in the CNS can occur via the bloodstream crossing the blood-brain barrier (BBB), and if the cerebral cortex is damaged, seizures can occur (9). Some bacteria, such as tuberculosis, reach the brain via the bloodstream from the lungs (10). These infections can cause ischemia and inflammation by producing inflammatory mediators such as cytokines and arachidonic acid compounds.

The pathogenic signs of inflammation can occur a few hours after the infection, reaching the acute phase response, an effect that must be counteracted by taking antibiotics or, occasionally, neurosurgical interventions. Damage-associated molecular patterns (DAMPs) from damaged neurons and microglia, and the activation of pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) expressed by these cells, participate in the inflammatory process with cellular dysfunction (11). DAMPs can activate the NLR family pyrin domain containing 3 (NLRP3), contributing to the cerebral pathogenic process (12). In this dynamic event, transcriptional upregulation of pro-inflammatory cytokines occurs. In the brain, NOD-like receptors respond to a variety of pathogen associated molecular patterns (PAMPs) which are linked to various microorganisms, as well as DAMPs that are generated during a tissue insult (13).

IL-1 is a cytokine produced essentially by macrophagic cells after activation with microorganisms, and it causes neuroinflammation by activating microglia and astrocytes, but these cells also can generate IL-1, producing an autocrine effect. IL-1 activates cells to produce chemokines and other pro-inflammatory proteins by recruiting microglia to the CNS, resulting in tissue neurodegeneration (14). NOD-like receptors, also called NLRs, ranging from 1 to 12, form the inflammasome and mediate the release of pro-inflammatory cytokines such as IL-1 and IL-18 that play a crucial role in cerebral inflammation (12) (Fig.1).

Fig. 1. The microorganism, or active part of it, binds to the toll-like receptor (TLR) and causes the activation of the NLRP3, which initiates the cleavage of pro-caspase and subsequently, the mature form caspase-1, which cleaves pro-IL-1 and pro-IL-18 with consequent generation of the mature forms IL-1 and IL-18 that are implicated in brain inflammation induced by microorganisms.

In infections caused by microorganisms, high levels of NLRP1 that are expressed by brain tissue can occur, and this inflammasome is important for the study of inflammatory diseases, and it can also represent a therapeutic target (15). In addition to causing brain inflammation, IL-1 activation through the inflammasome can cause dizziness, cognitive impairment (16), headache, memory impairments, behavioral changes, and fever, symptoms that can be resolved with accurate anti-microbial therapy. These reactions lead to the extracellular loss of potassium, water, and glutamate, promoting the formation of reactive oxygen species (ROS). The inflammatory process is activated by the cytokines IL-1, TNF, and IL-6 that are produced by microglia and neurons and also cause changes in cell receptors. Bacterial meningitis and convulsions can cause purulent edema with strong inflammation that can provoke very serious neuropathological states. Brain abscesses that form as a result of the infection can cause damage to the ear (otitis), to the nasal cavities (sinusitis), and to the heart (heart disease). It should be emphasized that ear infections and sinusitis are generally caused by anaerobic bacteria.

Microbial products can be detected in the brain tissue with the reverse transcription polymerase chain reaction (RT-PCR) technique. Microorganisms can lead to inflammation of the CNS resulting in encephalopathy, convulsions, neuromuscular pain, neuropathy, myopathy, Guillain-Barré syndrome (with weakness of the limbs and sensory changes), and others. (17). The infections can be serious, slightly symptomatic, or asymptomatic, and can aggravate neurological diseases due to other causes including drugs, metabolic dysfunctions, hypoxia, toxic products, etc. Often these pathologies lead to a complete recovery of the patient, although sometimes they are irreversible. In addition, encephalopathy and other symptoms caused by microorganisms and their compounds lead to inflammation of the brain caused by an infection or the generation of self-antibodies (18). Microorganisms can also cause vascular disease in the brain, vasculitis that can be detected with different diagnostic tests, including brain angiography and blood tests. If the infection becomes chronic, neuronal loss and death can occur, followed by neuroinflammation involving microglia and astrocytes with oxidative stress, mitochondrial dysfunction, cytokine production, and BBB disruption.

CONCLUSIONS

In light of these results, we can state that since brain antibacterial therapies are not very effective, they still remain a challenge in medical therapy (19). This article offers a basic review of neurological diseases due to microorganism infections, with an approach to diagnostic, therapeutic, and prognostic strategies.

Conflict of interest

The author declares that they have no conflict of interest.

REFERENCES

1. Izadi M, Is’haqi A, Is’haqi MA, Jafari NJ, Rahamaty F, Banki A. An overview of travel-associated central nervous system infectious diseases: risk assessment, general considerations and future directions. Asian Pacific Journal of Tropical Biomedicine. 2014;4(8):589-596. doi:https://doi.org/10.12980/apjtb.4.2014apjtb-2014-0065
2. Awada A, Kojan S. Neurological disorders and travel. International Journal of Antimicrobial Agents. 2003;21(2):189-192. doi:https://doi.org/10.1016/s0924-8579(02)00285-6
3. Simons, CS Wong, A Stillwell. Travel risk assessment and risk management. Nurs Times. 2012; 108(20):14-16.
4. Rock RB, Gekker G, Hu S, et al. Role of Microglia in Central Nervous System Infections. Clinical Microbiology Reviews. 2004;17(4):942-964. doi:https://doi.org/10.1128/cmr.17.4.942-964.2004
5. Bonaz B, Bazin T, Pellissier S. The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Frontiers in Neuroscience. 2018;12(49). doi:https://doi.org/10.3389/fnins.2018.00049
6. Archibald LK, Quisling RG. Central Nervous System Infections. Textbook of Neurointensive Care. 2013;7:427-517. doi:https://doi.org/10.1007/978-1-4471-5226-2_22
7. Vezzani A, Fujinami RS, White HS, et al. Infections, inflammation and epilepsy. Acta neuropathologica. 2016;131(2):211-234. doi:https://doi.org/10.1007/s00401-015-1481-5
8. van de Beek D, Brouwer M, Hasbun R, Koedel U, Whitney CG, Wijdicks E. Community-acquired bacterial meningitis. Nature Reviews Disease Primers. 2016;2:16074. doi:https://doi.org/10.1038/nrdp.2016.74
9. Marchi N, Granata T, Ghosh C, Janigro D. Blood-brain barrier dysfunction and epilepsy: Pathophysiologic role and therapeutic approaches. Epilepsia. 2012;53(11):1877-1886. doi:https://doi.org/10.1111/j.1528-1167.2012.03637.x
10. Be N, Kim K, Bishai W, Jain S. Pathogenesis of Central Nervous System Tuberculosis. Current Molecular Medicine. 2009;9(2):94-99. doi:https://doi.org/10.2174/156652409787581655
11. Roh JS, Sohn DH. Damage-Associated Molecular Patterns in Inflammatory Diseases. Immune Network. 2018;18(4). doi:https://doi.org/10.4110/in.2018.18.e27
12. Freeman LC, Ting JPY . The pathogenic role of the inflammasome in neurodegenerative diseases. Journal of Neurochemistry. 2015;136:29-38. doi:https://doi.org/10.1111/jnc.13217
13. Kim YK, Shin JS, Nahm MH. NOD-Like Receptors in Infection, Immunity, and Diseases. Yonsei Medical Journal. 2016;57(1):5. doi:https://doi.org/10.3349/ymj.2016.57.1.5
14. Domingues C, da Cruz e Silva OAB, Henriques AG. Impact of Cytokines and Chemokines on Alzheimer’s Disease Neuropathological Hallmarks. Current Alzheimer Research. 2017;14(8). doi:https://doi.org/10.2174/1567205014666170317113606
15. de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM, Dietrich WD, Keane RW. Therapeutic Neutralization of the NLRP1 Inflammasome Reduces the Innate Immune Response and Improves Histopathology after Traumatic Brain Injury. Journal of Cerebral Blood Flow & Metabolism. 2009;29(7):1251-1261. doi:https://doi.org/10.1038/jcbfm.2009.46
16. Capuron L, Lamarque D, Dantzer R, Goodall G. Attentional and mnemonic deficits associated with infectious disease in humans. Psychological Medicine. 1999;29(2):291-297. doi:https://doi.org/10.1017/s0033291798007740
17. Dando SJ, Mackay-Sim A, Norton R, et al. Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion. Clinical Microbiology Reviews. 2014;27(4):691-726. doi:https://doi.org/10.1128/cmr.00118-13
18. Diamond B, Honig G, Mader S, Brimberg L, Volpe BT. Brain-Reactive Antibodies and Disease. Annual Review of Immunology. 2013;31(1):345-385. doi:https://doi.org/10.1146/annurev-immunol-020711-075041
19. Suthar R, Sankhyan N. Bacterial Infections of the Central Nervous System. The Indian Journal of Pediatrics. 2018;86(1):60-69. doi:https://doi.org/10.1007/s12098-017-2477-z