Interaction Between the Complement System and Infectious Agents – A Potential Mechanistic Link to Neurodegeneration and Dementia

Shinjyo, Noriko; Kagaya, Wataru; Pekna, Marcela

doi:10.3389/fncel.2021.710390

Cited by 25 publications

(20 citation statements)

References 252 publications

(352 reference statements)

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“…T. gondii and Plasmodium spp. are obligate intracellular protozoan parasites that can significantly lead to the dysfunction and injury in the brain due to the interactions between these protozoa and complement system ( Table 1 ) [ 51 ]. It seems that the overactivation or overexpression of host’s complement components by Plasmodium parasites (or even on the parasite surface) participates in cerebral malaria (CM) pathogenesis.…”

Section: Parasite’s Complement Regulatory and Evasion Moleculesmentioning

confidence: 99%

The Defensive Interactions of Prominent Infectious Protozoan Parasites: The Host’s Complement System

et al. 2022

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The complement system exerts crucial functions both in innate immune responses and adaptive humoral immunity. This pivotal system plays a major role dealing with pathogen invasions including protozoan parasites. Different pathogens including parasites have developed sophisticated strategies to defend themselves against complement killing. Some of these strategies include the employment, mimicking or inhibition of host’s complement regulatory proteins, leading to complement evasion. Therefore, parasites are proven to use the manipulation of the complement system to assist them during infection and persistence. Herein, we attempt to study the interaction´s mechanisms of some prominent infectious protozoan parasites including Plasmodium, Toxoplasma, Trypanosoma, and Leishmania dealing with the complement system. Moreover, several crucial proteins that are expressed, recruited or hijacked by parasites and are involved in the modulation of the host´s complement system are selected and their role for efficient complement killing or lysis evasion is discussed. In addition, parasite’s complement regulatory proteins appear as plausible therapeutic and vaccine targets in protozoan parasitic infections. Accordingly, we also suggest some perspectives and insights useful in guiding future investigations.

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Section: Parasite’s Complement Regulatory and Evasion Moleculesmentioning

confidence: 99%

The Defensive Interactions of Prominent Infectious Protozoan Parasites: The Host’s Complement System

et al. 2022

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“…Mounting evidence has suggested the importance of EBV and HHV-6 infection in the pathogenesis of MS ( Stuve et al, 2004 ; Virtanen et al, 2011 ; Tzartos et al, 2012 ; Meier et al, 2021 ; Bjornevik et al, 2022 ). As reviewed by Shinjyo et al (2021) viral infections, including HIV, herpes viruses, measles, TMEV, WNV, Zika, among other infectious agents, can modulate the complement system in the CNS, and this interaction may be involved in neurodegeneration and dementia. Therefore, one can assume that complement activation may also be playing an important role in the pathogenic effects of viral infections in MS.…”

Section: Understanding the Role Of Early Complement Components And It...mentioning

confidence: 99%

The validity of animal models to explore the pathogenic role of the complement system in multiple sclerosis: A review

Saez-Calveras

Brewster

Stüve

2022

Front. Mol. Neurosci.

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Animal models of multiple sclerosis (MS) have been extensively used to characterize the disease mechanisms in MS, as well as to identify potential pharmacologic targets for this condition. In recent years, the immune complement system has gained increased attention as an important effector in the pathogenesis of MS. Evidence from histological, serum, and CSF studies of patients supports an involvement of complement in both relapsing-remitting and progressive MS. In this review, we discuss the history and advances made on the use of MS animal models to profile the effects of the complement system in this condition. The first studies that explored the complement system in the context of MS used cobra venom factor (CVF) as a complement depleting agent in experimental autoimmune encephalomyelitis (EAE) Lewis rats. Since then, multiple mice and rat models of MS have revealed a role of C3 and the alternative complement cascade in the opsonization and phagocytosis of myelin by microglia and myeloid cells. Studies using viral vectors, genetic knockouts and pharmacologic complement inhibitors have also shown an effect of complement in synaptic loss. Antibody-mediated EAE models have revealed an involvement of the C1 complex and the classical complement as an effector of the humoral response in this disease. C1q itself may also be involved in modulating microglia activation and oligodendrocyte differentiation in these animals. In addition, animal and in vitro models have revealed that multiple complement factors may act as modulators of both the innate and adaptive immune responses. Finally, evidence gathered from mice models suggests that the membrane attack complex (MAC) may even exert protective roles in the chronic stages of EAE. Overall, this review summarizes the importance of MS animal models to better characterize the role of the complement system and guide future therapeutic approaches in this condition.

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“…Growing evidence suggests that insulin and leptin play significant physiological roles in cognition ( Paz-Filho et al, 2008 ; Morrison, 2009 ; Gray et al, 2014 ; Arnold et al, 2018 ), and these signaling pathways may be promising therapeutic targets to alleviate cognitive impairment accompanied by obesity and MetS ( Mejido et al, 2020 ). On the other hand, obesity, visceral adiposity in particular, is frequently associated with immune dysregulation and infection susceptibility ( Hamdy et al, 2006 ; Conde et al, 2010 ; Kumari et al, 2019 ; Obradovic et al, 2021 ), while infection increases the risk of neurodegeneration and dementia ( Heneka et al, 2020 ; Shinjyo et al, 2021 ), suggesting the link between MetS, infection, and cognitive impairment.…”

Section: Metabolic Disturbance and Cognitive Impairmentmentioning

confidence: 99%

“…Recently, it has been shown that Aβ, a hallmark of AD, is an antimicrobial peptide, part of innate immunity to protect the host from various infectious agents ( Soscia et al, 2010 ; Kumar et al, 2016 ; Gosztyla et al, 2018 ), suggesting the necessity to revisit the role of amyloid plaque formation in AD pathogenesis. Above mentioned neurotropic viruses, such as HSV-1, HSV-2 and CMV, certain bacterial species, including spirochetes and P. gingivalis , fungi (e.g., Candida albicans ), and neurotropic parasite (e.g., T. gondii ), may cause disruption of brain functions via chronic inflammation and immune dysregulation in the brain ( Sochocka et al, 2017 ; Shinjyo et al, 2021 ). The antimicrobial hypothesis for AD proposes that Aβ generation and amyloid plaque formation are not the major culprit in AD pathogenesis, but rather a defense against such infectious agents ( Moir et al, 2018 ; Iqbal et al, 2020 ; Fulop et al, 2021 ).…”

Section: Insulin and Leptin Mediating The Link Between Infection And Neurodegenerative Disordersmentioning

confidence: 99%

Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia

Shinjyo

Kita

2021

Front. Cell. Neurosci.

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Metabolic syndromes are frequently associated with dementia, suggesting that the dysregulation of energy metabolism can increase the risk of neurodegeneration and cognitive impairment. In addition, growing evidence suggests the link between infections and brain disorders, including Alzheimer’s disease. The immune system and energy metabolism are in an intricate relationship. Infection triggers immune responses, which are accompanied by imbalance in cellular and organismal energy metabolism, while metabolic disorders can lead to immune dysregulation and higher infection susceptibility. In the brain, the activities of brain-resident immune cells, including microglia, are associated with their metabolic signatures, which may be affected by central nervous system (CNS) infection. Conversely, metabolic dysregulation can compromise innate immunity in the brain, leading to enhanced CNS infection susceptibility. Thus, infection and metabolic imbalance can be intertwined to each other in the etiology of brain disorders, including dementia. Insulin and leptin play pivotal roles in the regulation of immunometabolism in the CNS and periphery, and dysfunction of these signaling pathways are associated with cognitive impairment. Meanwhile, infectious complications are often comorbid with diabetes and obesity, which are characterized by insulin resistance and leptin signaling deficiency. Examples include human immunodeficiency virus (HIV) infection and periodontal disease caused by an oral pathogen Porphyromonas gingivalis. This review explores potential interactions between infectious agents and insulin and leptin signaling pathways, and discuss possible mechanisms underlying the relationship between infection, metabolic dysregulation, and brain disorders, particularly focusing on the roles of insulin and leptin.

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Interaction Between the Complement System and Infectious Agents – A Potential Mechanistic Link to Neurodegeneration and Dementia

Cited by 25 publications

References 252 publications

The Defensive Interactions of Prominent Infectious Protozoan Parasites: The Host’s Complement System

The Defensive Interactions of Prominent Infectious Protozoan Parasites: The Host’s Complement System

The validity of animal models to explore the pathogenic role of the complement system in multiple sclerosis: A review

Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia

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