Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms

Lewis, Lisa A.; Ram, Sanjay

doi:10.1002/1873-3468.13760

Cited by 39 publications

(33 citation statements)

References 226 publications

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“…In the host, FH recognizes specific sialic acid capped glycans on host surfaces to distinguish self from non-self, which importantly restricts AP activation on self surfaces, while allowing AP activity to continue on non-self (pathogen) surfaces. However, pathogens bypass AP (188)(189)(190)].…”

Section: The Role Of Sialylation In Factor H Recruitmentmentioning

confidence: 99%

“…FH exclusively binds Neu5Ac species with α(2,3) linkages ( 43 ), discriminating against pathogens expressing other Neu5Ac linkages including α(2,6) and α(2,8) [reviewed in ( 188 , 189 )]. Neisseria meningitidis and Neisseria gonorrhoeae are Gram-negative bacteria restricted to humans that express α(2,3) linked Neu5Ac which participate in FH binding and other complement evasion tactics [reviewed in ( 188 – 190 )].…”

Section: Mechanisms Of How Pathogens Bind Factor H To Evade the Altermentioning

confidence: 99%

“…Similarly, binding of bovine FH to Histophilus somni increases when bacteria are sialylated with Neu5Ac ( 104 ). While pathogen sialylation promotes FH binding to the cell surface, it still renders pathogens vulnerable to complement-mediated damage because a portion of the deposited C3 fragments involved in binding FH will likely form C3 convertases as opposed to binding FH [reviewed in ( 190 )].…”

Section: Mechanisms Of How Pathogens Bind Factor H To Evade the Altermentioning

confidence: 99%

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Hijacking Factor H for Complement Immune Evasion

et al. 2021

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The complement system is an essential player in innate and adaptive immunity. It consists of three pathways (alternative, classical, and lectin) that initiate either spontaneously (alternative) or in response to danger (all pathways). Complement leads to numerous outcomes detrimental to invaders, including direct killing by formation of the pore-forming membrane attack complex, recruitment of immune cells to sites of invasion, facilitation of phagocytosis, and enhancement of cellular immune responses. Pathogens must overcome the complement system to survive in the host. A common strategy used by pathogens to evade complement is hijacking host complement regulators. Complement regulators prevent attack of host cells and include a collection of membrane-bound and fluid phase proteins. Factor H (FH), a fluid phase complement regulatory protein, controls the alternative pathway (AP) both in the fluid phase of the human body and on cell surfaces. In order to prevent complement activation and amplification on host cells and tissues, FH recognizes host cell-specific polyanionic markers in combination with complement C3 fragments. FH suppresses AP complement-mediated attack by accelerating decay of convertases and by helping to inactivate C3 fragments on host cells. Pathogens, most of which do not have polyanionic markers, are not recognized by FH. Numerous pathogens, including certain bacteria, viruses, protozoa, helminths, and fungi, can recruit FH to protect themselves against host-mediated complement attack, using either specific receptors and/or molecular mimicry to appear more like a host cell. This review will explore pathogen complement evasion mechanisms involving FH recruitment with an emphasis on: (a) characterizing the structural properties and expression patterns of pathogen FH binding proteins, as well as other strategies used by pathogens to capture FH; (b) classifying domains of FH important in pathogen interaction; and (c) discussing existing and potential treatment strategies that target FH interactions with pathogens. Overall, many pathogens use FH to avoid complement attack and appreciating the commonalities across these diverse microorganisms deepens the understanding of complement in microbiology.

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Section: The Role Of Sialylation In Factor H Recruitmentmentioning

confidence: 99%

Section: Mechanisms Of How Pathogens Bind Factor H To Evade the Altermentioning

confidence: 99%

Section: Mechanisms Of How Pathogens Bind Factor H To Evade the Altermentioning

confidence: 99%

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Hijacking Factor H for Complement Immune Evasion

et al. 2021

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“…At the time of its development it was well-known that the terminal components of the complement pathway played an important role in innate immune defenses against invasive meningococcal disease. Based on work in animal models as well as observations in primary immunodeficiency states, it was believed that the terminal sequence of complement was critical for host defense against invasive and recurrent meningococcal infections (15,16). Subsequently it is now known that eculizumab is associated with a 1,000-2,000 times greater risk of Neisseria infections (14).…”

Section: Perspective Lessons Predictable and Unpredictablementioning

confidence: 99%

Infections in the Era of Targeted Therapies: Mapping the Road Ahead

Calabrese

Lenfant

et al. 2020

Front. Med.

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Immunosuppressive treatment strategies for autoimmune diseases have changed drastically with the development of targeted therapies. While targeted therapies have changed the way we manage immune mediated diseases, their use has been attended by a variety of infectious complications-some expected, others unexpected. This perspective examines lessons learned from the use of different targeted therapies over the past several decades, and reviews existing strategies to minimize infectious risk. Several of these infectious complications were predictable in the light of preclinical models and early clinical trials (i.e., tuberculosis and TNF inhibitors; meningococcus; and eculizumab). While these scenarios can potentially help us in terms of enhancing our predictive powers (higher vigilance, earlier detection, and risk mitigation), targeted therapies have also revealed unpredictable toxicities (i.e., natalizumab and progressive multifocal leukoencephalopathy). Severe infectious complications, even if rare, can derail a promising therapeutic and highlight the need for increased awareness and meticulous adjudication. Tools are available to help mitigate infectious risks. The first step is to ensure that infection safety is adequately studied at every level of drug development prior to regulatory approval, with adequate post-marketing surveillance including registries that collect real-world adverse events in a collaborative effort. The second step is to identify high risk patients (using risk calculators such as the RABBIT risk score; big data analyses; artificial intelligence). Finally, the most underutilized interventions to prevent severe infections in patients receiving targeted therapies across the spectrum of immune mediated inflammatory diseases are vaccinations.

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“…Yet Neisseria also utilize complement escape strategies to curb immune attack. Several members of the genus incorporate sialic acids into their capsule to recruit FH and down‐regulate AP activation, evading complement attack (Gulati et al, 2015; Lewis & Ram, 2020). But the repertoire of neisserial engagement of complement regulators does not end with sialic acid.…”

Section: A Play Of Deception and Evasion: Carbohydrate‐targeted Complement Escape By Microbes And Parasitesmentioning

confidence: 99%

Sweet turning bitter: Carbohydrate sensing of complement in host defence and disease

Hevey

Pouw

Harris

et al. 2020

British J Pharmacology

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The complement system plays a major role in threat recognition and in orchestrating responses to microbial intruders and accumulating debris. This immune surveillance is largely driven by lectins that sense carbohydrate signatures on foreign, diseased and healthy host cells and act as complement activators, regulators or receptors to shape appropriate immune responses. While carbohydrate sensing protects our bodies, misguided or impaired recognition can contribute to disease. Moreover, pathogenic microbes have evolved to evade complement by mimicking host signatures. While complement is recognized as a disease factor, we only slowly start to appreciate the role of carbohydrate interactions in the underlying processes. A better understanding of complement's sweet side will contribute to a better description of disease mechanisms and enhanced diagnostic and therapeutic options. This review introduces the key components in complement‐mediated carbohydrate sensing, discusses their role in health and disease, and touches on the potential effects of carbohydrate‐related disease intervention. Linked Articles This article is part of a themed issue on Canonical and non‐canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc

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Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms

Cited by 39 publications

References 226 publications

Hijacking Factor H for Complement Immune Evasion

Hijacking Factor H for Complement Immune Evasion

Infections in the Era of Targeted Therapies: Mapping the Road Ahead

Sweet turning bitter: Carbohydrate sensing of complement in host defence and disease

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