Re: 구성적 면역기전... 2020 네이처!!

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Nat Rev Immunol

. 2020 Aug 11;21(3):137–150. doi: 10.1038/s41577-020-0391-5

Constitutive immune mechanisms: mediators of host defence and immune regulation

Søren R Paludan 1,2,✉, Thomas Pradeu 3,4, Seth L Masters 5,6, Trine H Mogensen 1,7,8

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PMCID: PMC7418297  PMID: 32782357

Abstract

The immune system enables organisms to combat infections and to eliminate endogenous challenges. Immune responses can be evoked through diverse inducible pathways. However, various constitutive mechanisms are also required for immunocompetence. The inducible responses of pattern recognition receptors of the innate immune system and antigen-specific receptors of the adaptive immune system are highly effective, but they also have the potential to cause extensive immunopathology and tissue damage, as seen in many infectious and autoinflammatory diseases. By contrast, constitutive innate immune mechanisms, including restriction factors, basal autophagy and proteasomal degradation, tend to limit immune responses, with loss-of-function mutations in these pathways leading to inflammation. Although they function through a broad and heterogeneous set of mechanisms, the constitutive immune responses all function as early barriers to infection and aim to minimize any disruption of homeostasis. Supported by recent human and mouse data, in this Review we compare and contrast the inducible and constitutive mechanisms of immunosurveillance.

초록

면역 체계는

생물이 감염과 내인성 위협에 대항할 수 있게 합니다.

면역 반응은

다양한 유도 가능한 경로를 통해 유발될 수 있습니다.

그러나

면역 능력에는 다양한 구성적 메커니즘도 필요합니다.

various constitutive mechanisms

선천성 면역계의 패턴 인식 수용체와

적응성 면역계의 항원 특이적 수용체의 유도성 반응은 매우 효과적이지만,

많은 감염성 및 자가염증성 질환에서 볼 수 있듯이

광범위한 면역병리 및 조직 손상을 유발할 가능성도 있다.

반면, 제한 인자,

기초적 자가포식 및 프로테아좀 분해를 포함한

구성적 선천성 면역 메커니즘은 면역 반응을 제한하는 경향이 있으며,

이러한 경로의 기능 상실 돌연변이는 염증을 유발한다.

constitutive innate immune mechanisms,

including restriction factors,

basal autophagy and

proteasomal degradation,

비록 광범위하고 이질적인 메커니즘을 통해 기능하지만,

구성적 면역 반응은 모두 감염에 대한 초기 장벽 역할을 하며

항상성 교란을 최소화하는 것을 목표로 한다.

최근 인간 및 마우스 데이터를 바탕으로,

본 리뷰에서는 면역 감시의 유도 가능 메커니즘과 구성적 메커니즘을 비교 대조한다.

Subject terms: Infectious diseases, Infection, Innate immunity

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Constitutive innate immune mechanisms, such as restriction factors, RNA interference, antimicrobial peptides, basal autophagy and proteasomal degradation, exert early host defence activities that also aim to minimize tissue damage and homeostatic disruption by limiting the activation of inducible innate immunity.

제한 인자,

RNA 간섭,

항균 펩타이드, 기초적 자가포식 및 프로테아좀 분해와 같은

구성적 선천성 면역 기전은

유도성 선천성 면역의 활성화를 제한함으로써 조직

손상과 항상성 교란을 최소화하는 동시에 초기 숙주 방어 활동을 수행한다.

restriction factors,

RNA interference,

antimicrobial peptides,

basal autophagy and proteasomal degradation

Introduction

A major challenge for living organisms is to maintain homeostasis in response to changes in external and internal environments. These include alterations in nutrient and water supplies, physical stress, temperature changes, physiological stress, infections and malignancies1. Through billions of years of evolution, the forms of life and biological processes that cope with these challenges in the most successful way have been selected. One challenge that all organisms have to deal with is the elimination of microorganisms and of abnormal or damaged cellular material. The ideal immune response would eliminate the potential threat and re-establish homeostasis without causing excessive damage to healthy cells and tissues. However, immune responses to infections are often disruptive and can cause marked tissue damage2,3. Such responses are evolutionarily advantageous when the benefit of eliminating the challenge outweighs the risk of associated tissue damage and the requirement for regeneration. However, for potential challenges that occur frequently but rarely develop into serious homeostasis-altering threats, it is not desirable to mount systemic or potentially disruptive immune responses. In addition, vigorous immune responses are not desirable in organs and tissues that are particularly sensitive to immune-mediated damage, such as the brain. Therefore, the ideal immune response has checks and balances, which allow the organism to modulate the magnitude and duration of the response according to the nature of the threat caused by the challenge.

서론

생물체가 직면한 주요 과제는

외부 및 내부 환경 변화에 대응하여 항상성을 유지하는 것이다.

여기에는

영양분 및 수분 공급 변화,

물리적 스트레스,

온도 변화,

생리적 스트레스,

감염 및 악성 종양 등이 포함된다1.

수십억 년에 걸친 진화를 통해

이러한 과제를 가장 성공적으로 해결하는

생명체 형태와 생물학적 과정이 선택되어 왔다.

모든 생물이 직면하는 한 가지 과제는

미생물과 비정상적이거나 손상된 세포 물질의 제거이다.

이상적인 면역 반응은

잠재적 위협을 제거하고 건

강한 세포와 조직에 과도한 손상을 주지 않으면서 항상성을 회복해야 한다.

그러나

감염에 대한 면역 반응은

종종 파괴적이며 현저한 조직 손상을 초래할 수 있다2,3.

이러한 반응은

위협 제거의 이점이 관련된 조직 손상 및 재생 요구의 위험을 능가할 때

진화적으로 유리하다.

그러나

빈번하게 발생하지만

심각한 항상성 교란 위협으로 발전하는 경우는

드문 잠재적 위협에 대해서는 전신적 또는 잠재적으로 파괴적인 면역 반응을 일으키는 것이

바람직하지 않습니다.

또한

뇌처럼 면역 매개 손상에 특히 민감한 장기 및 조직에서는

강력한 면역 반응이 바람직하지 않습니다.

따라서 이상적인 면역 반응은

위협의 본질에 따라 반응의 규모와 지속 시간을 조절할 수 있도록 하는

견제와 균형 장치를 갖추고 있습니다.

The mammalian immune system, as we understand it today, is induced mainly by two types of receptor systems, the germline-encoded pattern recognition receptors (PRRs), which initiate innate immune responses, and the antigen-specific receptors generated through gene rearrangement after antigen encounter, which initiate adaptive immune responses4–6. The immune responses induced by PRRs, such as Toll-like receptors (TLRs), interact with those induced by antigen-specific receptors; this interaction is notably represented by dendritic cells, which rely on PRR-driven cues to initiate dendritic cell maturation for the stimulation of lymphocytes through antigen-specific receptors5. However, the research literature contains numerous reports of host defence activities that occur independently of both PRR-based immunity and antigen-specific receptors7–10, and emerging evidence suggests that several of these mechanisms have non-redundant roles in host defence in humans11,12. Here we review the literature on this topic by focusing on constitutive immune mechanisms. On the basis of this analysis, and by integrating concepts previously reviewed13, we propose that this constitutive layer of innate immunity exerts early host defence activities through specific molecular mechanisms and at the same time limits PRR activation as a specific feature.

오늘날 우리가 이해하는 포유류 면역 체계는

주로 두 가지 유형의 수용체 시스템에 의해 유도됩니다.

선천성 면역 반응을 시작하는

생식세포 유전자에 의해 암호화된 패턴 인식 수용체(PRRs)와

항원 특이적 수용체로,

항원 접촉 후 유전자 재배열을 통해 생성되어 적응성 면역 반응을 시작합니다4–6.

the germline-encoded pattern recognition receptors (PRRs),

which initiate innate immune responses,

and the antigen-specific receptors generated through gene rearrangement

after antigen encounter, which initiate adaptive immune responses

톨 유사 수용체(TLRs)와 같은 PRR에 의해 유도된 면역 반응은

항원 특이적 수용체에 의해 유도된 반응과 상호작용합니다.

이 상호작용은 특히

수지상 세포에서 두드러지게 나타납니다.

수지상 세포는

PRR에 의해 유도된 신호를 통해 성숙을 시작하여

항원 특이적 수용체를 통해 림프구를 자극합니다5.

그러나 연구 문헌에는

PRR 기반 면역과 항원 특이적 수용체 모두와 독립적으로 발생하는

숙주 방어 활동에 대한 수많은 보고가 존재하며7–10,

새롭게 제시되는 증거들은 이러한 메커니즘 중 다수가

인간 숙주 방어에서 중복되지 않는 역할을 수행함을 시사한다11,12.

본고에서는 

구성적 면역 메커니즘에 초점을 맞춰 이 주제에 관한 문헌을 검토한다.

이 분석을 바탕으로, 그리고 이전에 검토된 개념들을 통합하여13,

우리는 이 선천 면역의 구성적 층이 특정 분자적 메커니즘을 통해

초기 숙주 방어 활동을 수행하는 동시에 PRR 활성화를 제한하는 특이적 특징을 지닌다고 제안한다.

Constitutive and inducible mechanisms

The innate immune system uses both constitutive and inducible mechanisms to eliminate infections and damaged self to maintain homeostasis (Fig. 1). Although the constitutive mechanisms have the advantage of providing an immediate response to a danger signal, they lack the potential to amplify the response. In addition, constitutive mechanisms consume energy to remain operative, and there are hence limits to how many of these can be maintained in any one organism. By contrast, inducible mechanisms such as those mediated through PRRs, as well as antigen-specific receptors, are activated only in response to stimuli and have the ability to amplify signals many times. Hence, inducible mechanisms can give rise to very strong and efficient immune responses, but can also lead to excess inflammation and immunopathology. Given their amplification potential, inducible immune mechanisms require tight control and negative regulatory systems.

구성적 및 유도적 기전

선천 면역계는

감염과 손상된 자가 물질을 제거하여 항상성을 유지하기 위해

구성적 기전과 유도적 기전을 모두 활용한다(그림 1).

구성적 기전은

위험 신호에 즉각적으로 반응한다는 장점이 있지만,

반응을 증폭시킬 잠재력은 부족하다.

또한 구성적 기전은 작동 상태를 유지하기 위해 에너지를 소모하므로,

한 유기체 내에서 유지할 수 있는 기전의 수에는 한계가 있다.

반면 PRR 및 항원 특이적 수용체를 매개로 하는 유도성 기전은

자극에 반응하여 활성화되며

신호를 여러 차례 증폭시킬 수 있다.

따라서

유도성 기전은 매우 강력하고 효율적인 면역 반응을 유발할 수 있지만,

과도한 염증 및 면역병리를 초래할 수도 있다.

증폭 잠재력으로 인해 유도성 면역 기전은

엄격한 조절과 음성 조절 시스템이 필요하다.

Fig. 1. Constitutive innate immune responses versus inducible immune responses.

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Illustration of how constitutive and inducible immune responses vary over time during the course of a generalized infection, and their impact on host defence, energy consumption and host fitness. In the case of a sterilizing and resolving immune response, the additional energy consumption required by the inducible immune response is balanced by the re-establishment of homeostasis. By contrast, in the case of an immunopathological response, the energy that is consumed to mount an inducible response does not benefit the host and instead leads to tissue damage and disruption of homeostasis.

그림 1. 구성적 선천 면역 반응 대 유도성 면역 반응.

일반화된 감염 과정 중 시간에 따른

구성적 및 유도성 면역 반응의 변화 양상과

숙주 방어, 에너지 소비, 숙주 적합성에 미치는 영향의 도식화.

살균 및 해결 면역 반응의 경우,

유도성 면역 반응에 필요한 추가 에너지 소비는 항상성 회복으로 상쇄된다.

반면 면역병리학적 반응의 경우,

유도성 반응을 일으키는 데 소모되는 에너지는 숙주에 이롭지 않으며

오히려 조직 손상과 항상성 파괴를 초래한다.

The constitutive immune mechanisms can be divided into the chemical and physical barriers of the body, such as skin, saliva, stomach acid and urine flow, which are not the focus of this Review, and various molecularly defined mechanisms that control microbial infection and/or replication1. Although these mechanisms have been known for many years, they have generally been considered to have only minor roles in the immune system, and evidence has been lacking as to their specific, non-redundant functions in host defence. Consequently, they have not received much attention in front-line immunology research. Here we discuss the constitutive innate immune responses in comparison with the better-described inducible innate responses triggered by PRRs. In addition, we present evidence suggesting that efficient action of constitutive innate immune mechanisms leads to both antimicrobial activity and mitigation of PRR-driven activities (Fig. 2).

구성적 면역 기전은

본 리뷰의 초점이 아닌

피부, 타액, 위산, 요류와 같은 신체의 화학적·물리적 장벽과

미생물 감염 및/또는 복제를 제어하는 다양한 분자적으로 정의된 기전으로 구분될 수 있다1.

이러한 기전들은 수년간 알려져 왔음에도 불구하고

일반적으로 면역 체계에서 사소한 역할만 하는 것으로 간주되어 왔으며,

숙주 방어에서 특정적이고 중복되지 않는 기능에 대한 증거가 부족했다.

결과적으로,

이들은 최전선 면역학 연구에서 큰 주목을 받지 못했다.

본고에서는

PRR에 의해 유발되는 잘 알려진 유도성 선천 면역 반응과 비교하여

구성적 선천 면역 반응을 논의한다.

또한, 구성적 선천 면역 기전의 효율적 작용이

항균 활성과 PRR에 의한 활동의 완화 모두로 이어진다는 증거를 제시한다(그림 2).

그림 2. 구성적 선천 면역

Fig. 2. Constitutive innate immune responses negatively regulate inducible immune responses.

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a | Constitutive innate immune mechanisms eliminate pathogens during the initial stages of an infection, which prevents the accumulation of pathogen-associated molecular patterns (PAMPs) that would otherwise activate an inducible immune response through pattern recognition receptors (PRRs). In addition, many of the constitutive mechanisms are known to directly downregulate PAMP signalling through PRRs. Both of these effects limit PRR-induced expression‎ of type I interferon and IL-1β. b | The relationship between the different proposed layers of the immune response. A first layer of defence is exerted by physical and chemical barriers. Constitutive innate immune mechanisms function as soon as a danger signal is detected and eliminate harmful microorganisms and host molecules by specific non-inflammatory mechanisms that operate independently of PRRs. This prevents establishment of the infection and accumulation of PAMPs, thus limiting the activation of PRR-based inducible innate immune responses. If PRR-based immunity is activated, owing to the level of PAMPs exceeding a certain threshold, this leads to inflammation and promotes activation of the adaptive immune response mediated by T cells and antibodies. IRF, interferon regulatory factor.

그림 2. 구성적 선천 면역 반응은 유도성 면역 반응을 음성적으로 조절한다.

새 탭에서 열기

a | 선천적 면역 메커니즘은 감염 초기 단계에서 병원체를 제거하여, 패턴 인식 수용체(PRRs)를 통해 유도성 면역 반응을 활성화시킬 수 있는 병원체 관련 분자 패턴(PAMPs)의 축적을 방지한다. 또한 많은 선천적 메커니즘이 PRRs를 통한 PAMP 신호전달을 직접적으로 억제하는 것으로 알려져 있다. 이러한 두 가지 효과 모두 PRR에 의한 제1형 인터페론 및 IL-1β 발현을 제한한다.

b | 제안된 면역 반응의 서로 다른 계층 간 관계. 물리적·화학적 장벽이 첫 번째 방어 계층을 형성한다. 선천성 면역 기전은 위험 신호가 감지되는 즉시 작동하며, PRR과 독립적으로 작동하는 특정 비염증성 기전을 통해 유해한 미생물 및 숙주 분자를 제거한다. 이는 감염 확립과 PAMP 축적을 방지하여 PRR 기반 유도성 선천 면역 반응의 활성화를 제한한다. PAMP 수준이 특정 임계값을 초과하여 PRR 기반 면역이 활성화되면, 이는 염증을 유발하고 T 세포 및 항체에 의해 매개되는 적응 면역 반응의 활성화를 촉진한다. IRF, 인터페론 조절 인자.

PRR-activated inducible innate immune responses

PRRs detect pathogen-associated molecular patterns (PAMPs), microorganism-associated molecular patterns14, host-derived danger-associated molecular patterns15 and molecular signatures associated with homeostasis-altering molecular processes16. These molecular patterns activate PRR signalling, which ultimately leads to the transcription of antimicrobial and proinflammatory genes. Downstream activities of PRR signalling include the production of type I interferon (interferon-α (IFNα) and IFNβ), IL-1β and tumour necrosis factor (TNF). These cytokines, in turn, activate antimicrobial and proinflammatory activities, as well as the maturation of antigen-specific adaptive immune responses17,18. PRR-based immune responses can be highly potent, and numerous inflammatory diseases are driven by excessive PRR signalling pathways2,19,20 (Box 1). However, the nature of PRR-based immunity is influenced by many factors, and it is worth mentioning that the gut microbiota and chronic viral infections can induce PRR-based, host-beneficial responses that tend towards tolerance rather than inflammation21,22. Nevertheless, given the potency of PRR-based immunity, full activation of PRR-driven immune responses each time a microorganism is encountered may not be beneficial for an organism in the longer term. Moreover, it is essential to control the activation and duration of PRR signalling-induced activities. This is achieved through multiple mechanisms, including two-step procedures for full PRR activation23,24, the requirement for a threshold PAMP concentration to achieve PRR activation25–28, amplification loops from initial low responses29 and numerous negative-feedback mechanisms30. One way in which the activation of PRR signalling in response to very low levels of PAMPs is avoided at the molecular level is through supramolecular organizing centres. These are higher-order signalling complexes at specific subcellular locations that rely on amplification mechanisms to achieve full activation, thus preventing signalling by subthreshold levels of PAMPs but amplifying signalling by superthreshold levels of PAMPs29. The double-edged sword-like nature of PRR-induced immune responses in terms of their roles in both protection and disease is also supported by evolutionary evidence. This includes the recurring loss of 2′-5′-oligoadenylate synthase 1 (OAS1) in primates31. OAS1 is an interferon-inducible protein that is associated with both antiviral and pathological activities32,33.

PRR 활성화 유도성 선천 면역 반응

PRR은

병원체 관련 분자 패턴(PAMPs),

미생물 관련 분자 패턴14,

숙주 유래 위험 관련 분자 패턴15 및 항상성 변화 분자 과정과 연관된

분자 시그니처16를 감지합니다.

이러한 분자 패턴은

PRR 신호전달을 활성화하여

궁극적으로 항균 및 염증 유발 유전자의 전사를 유도합니다.

PRR 신호전달의 하류 활동에는

제1형 인터페론(인터페론-알파(IFNα) 및 IFNβ), IL-1β 및 종양괴사인자(TNF)의 생산이 포함됩니다.

이러한 사이토카인은

차례로 항균 및 염증 촉진 활성, 그리고

항원 특이적 적응 면역 반응의 성숙을 활성화합니다17,18.

PRR 기반 면역 반응은 매우 강력할 수 있으며,

수많은 염증성 질환은 과도한 PRR 신호 전달 경로에 의해 유발됩니다2,19,20 (박스 1).

그러나 PRR 기반 면역의 특성은 여러 요인의 영향을 받으며, 장내 미생물군과 만성 바이러스 감염이 염증보다는 내성으로 이어지는 PRR 기반의 숙주 유익 반응을 유도할 수 있다는 점은 주목할 만하다21,22. 그럼에도 불구하고 PRR 기반 면역의 강력한 특성상, 미생물이 접촉될 때마다 PRR에 의한 면역 반응이 완전히 활성화되는 것은 장기적으로 유기체에 유익하지 않을 수 있다. 또한 PRR 신호전달에 의해 유도된 활동의 활성화와 지속 시간을 조절하는 것이 필수적이다. 이는 완전한 PRR 활성화를 위한 2단계 절차23,24, PRR 활성화를 위한 임계 PAMP 농도 요구25–28, 초기 낮은 반응으로부터의 증폭 루프29 및 수많은 음성 피드백 메커니즘30 등 다양한 기전을 통해 달성된다. 분자 수준에서 극히 낮은 수준의 PAMP에 대한 PRR 신호 활성화가 회피되는 한 가지 방법은 초분자 조직화 센터를 통해서이다. 이는 특정 세포 내 위치에 존재하는 고차 신호 복합체로, 완전한 활성화를 달성하기 위해 증폭 메커니즘에 의존한다. 따라서 역치 미만 수준의 PAMP에 의한 신호 전달은 차단하지만 역치 초과 수준의 PAMP에 의한 신호 전달은 증폭시킨다29. 보호와 질병 양측에서 역할을 하는 PRR 유도 면역 반응의 양날의 검 같은 특성은 진화적 증거로도 뒷받침된다. 여기에는 영장류에서 반복적으로 관찰되는 2′-5′-올리고아데닐산 합성효소 1(OAS1)의 상실이 포함된다31. OAS1은 항바이러스 및 병리학적 활동과 연관된 인터페론 유도 단백질이다32,33.

Box 1 Diseases induced by excessive production of IL-1 and type I interferon.

Excessive or prolonged activation of pattern recognition receptor (PRR) signalling is associated with a range of human diseases. Several cytokines are involved in PRR-driven diseases, including tumour necrosis factor (TNF), IL-1β, IL-6 and type I interferon169,170. Among these, IL-1β and type I interferon are induced exclusively by PRR signalling. Thus, the existence of human diseases that are mediated by these two classes of cytokines provides strong evidence for the pathological potential of PRR-based immune responses. Here we describe some examples of sterile inflammation involving IL-1β and type I interferon. We now know that diseases such as familial Mediterranean fever, TNF receptor-associated periodic syndrome, hyper-IgD syndrome and cryopyrin-associated periodic syndrome are characterized by increased expression‎ of IL-1β; furthermore, blocking IL-1-induced signalling in these disease can relieve clinical symptoms and improve disease outcome171. Similarly, diseases such as Aicardi–Goutières syndrome, stimulator of interferon gene (STING)-associated vasculopathy with onset in infancy, Sjögren syndrome, proteasome-associated autoinflammatory syndromes and systemic lupus erythematosus are associated with high levels of expression‎ of interferon-stimulated genes (known as an ‘interferon signature’) and are termed ‘interferonopathies’, although the precise contribution of the interferon signature to disease pathogenesis is not completely understood170. For several of these diseases, inhibition of Janus kinase 1 (JAK1) and JAK3, which are involved in interferon-induced signalling, significantly reduces disease activity172. There are marked differences in the pathogenesis of IL-1-driven diseases and interferon-driven diseases. Diseases that depend on IL-1 are generally neutrophilic and associated with fever and increased levels of acute phase reactants, whereas interferon-driven diseases are characterized mainly by lymphopenia, vasculitis, central nervous system manifestations in some diseases, skin manifestations and varying levels of autoantibodies171,173.

박스 1 IL-1 및 제1형 인터페론 과잉 생산으로 유발되는 질환들.

패턴 인식 수용체(PRR) 신호전달의 과도하거나 지속적인 활성화는 다양한 인간 질환과 연관되어 있습니다. 종양괴사인자(TNF), IL-1β, IL-6 및 제1형 인터페론169,170을 비롯한 여러 사이토카인이 PRR에 의해 유발되는 질환에 관여한다. 이들 중 IL-1β와 제1형 인터페론은 PRR 신호전달에 의해 독점적으로 유도된다. 따라서 이 두 종류의 사이토카인에 의해 매개되는 인간 질환의 존재는 PRR 기반 면역 반응의 병리학적 잠재력에 대한 강력한 증거를 제공한다. 여기서는 IL-1β와 제1형 인터페론이 관여하는 무균성 염증의 몇 가지 사례를 설명한다. 현재 우리는 가족성 지중해열, TNF 수용체 관련 주기성 증후군, 고-IgD 증후군, 크라이오피린 관련 주기성 증후군과 같은 질환들이 IL-1β 발현 증가를 특징으로 한다는 사실을 알고 있다. 더욱이, 이러한 질환에서 IL-1 유도 신호전달을 차단하면 임상 증상을 완화하고 질환 예후를 개선할 수 있다171. 마찬가지로 아이카르디-구티에르 증후군, 영아기 발병 STING(인터페론 유전자 자극자) 관련 혈관병증, 쇼그렌 증후군, 프로테아좀 관련 자가염증 증후군 및 전신성 홍반성 루푸스는 인터페론 자극 유전자(‘인터페론 시그니처’로 알려짐)의 높은 발현 수준과 연관되어 있으며 ‘인터페론병증’으로 불리지만, 인터페론 시그니처가 질병 발병 기전에 정확히 어떻게 기여하는지는 완전히 이해되지 않았다170. 이러한 질환 중 일부의 경우, 인터페론 유도 신호 전달에 관여하는 야누스 키나제 1(JAK1) 및 JAK3의 억제가 질환 활성을 현저히 감소시킵니다172. IL-1에 의해 유발되는 질환과 인터페론에 의해 유발되는 질환의 병인에는 현저한 차이가 있습니다. IL-1에 의존하는 질환은 일반적으로 호중구성이고 발열 및 급성기 반응 물질의 증가와 관련이 있는 반면, 인터페론에 의해 유발되는 질환은 주로 림프구 감소증, 혈관염, 일부 질환에서 중추 신경계 증상, 피부 증상 및 다양한 수준의 자가 항체171,173을 특징으로 합니다.

Constitutive innate immune mechanisms

Constitutive innate immune mechanisms respond to microbial activities, cellular stress and metabolic alterations by inducing antimicrobial effector functions. As there is most evidence for constitutive innate immune mechanisms that exert antiviral and antibacterial activities, these are the focus of this Review (Fig. 3). A large range of constitutive mechanisms of innate immunity have been identified, including restriction factors, antimicrobial peptides, basal autophagy and proteasomal degradation (Box 2; Table 1). Here we divide these mechanisms into two classes: those that target specific steps in microbial replication cycles, such as restriction factors34,35, and those that lead to degenerative processes, such as autophagy9,36. The constitutive mechanisms that target specific steps in microbial replication function by blocking molecularly defined events that are essential for the replication of specific microorganisms but are dispensable for cellular fitness. By contrast, those mechanisms that operate through degenerative programmes target microbial or altered host molecules for recycling or degradation. The modes of action of representative examples from each of these mechanistic classes are described in the following sections.

구성적 선천 면역 기전

구성적 선천 면역 기전은

미생물 활동, 세포 스트레스 및 대사 변화에 반응하여 항균 효과기 기능을 유도한다.

항바이러스 및 항균 활성을 발휘하는 구성적 선천 면역 기전에 대한 증거가 가장 많으므로,

본 리뷰에서는 이를 중점적으로 다룬다(그림 3).

제한 인자, 항균 펩타이드, 기초적 자가포식 및 프로테아좀 분해 등

광범위한 선천 면역의 구성적 기전이 확인되었다(박스 2; 표 1).

여기서는 이러한 기전을 두 가지 범주로 구분한다:

제한 인자34,35와 같이 미생물 복제 주기의 특정 단계를 표적으로 하는 기전과,

자가포식9,36과 같이 퇴행성 과정을 유도하는 기전이다.

미생물 복제 과정의 특정 단계를 표적으로 하는 구성적 메커니즘은

특정 미생물의 복제에 필수적이지만 세

포 적합성에는 불필요한 분자적으로 정의된 사건을 차단함으로써 기능한다.

반면 퇴행성 프로그램을 통해 작동하는 메커니즘은

재활용 또는 분해를 위해 미생물 또는 변형된 숙주 분자를 표적으로 한다.

이러한 각 메커니즘 범주의 대표적 사례들의 작용 방식은

다음 섹션에서 설명한다.

Fig. 3. Overview of the regulation of microbial replication by constitutive innate immune mechanisms.

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a | Constitutive innate immune mechanisms and viral infection. The accumulation of specific viral molecular structures (such as double-stranded RNA (dsRNA) or capsids) and cellular stress responses (such as autophagy) activate constitutive–latent mechanisms with direct antiviral activity, independently of pattern recognition receptors. Some of the antiviral effector functions target microbial replication by blocking specific steps in the replication cycles of viruses; these effectors include soluble lectins, antimicrobial peptides, restriction factors, RNA interference (RNAi) and metabolites. Other antiviral effectors of the constitutive response function through the degradation of virus particles; these include nucleases such as TREX1, which degrades viral DNA in the cytoplasm, and RNase L, which degrades viral RNA, as well as autophagy and proteasomal degradation. Viruses can be targeted for proteasomal degradation by the ubiquitin E3 ligase TRIM21, which binds to antibody-attached viral capsids. b | Constitutive innate immune mechanisms and bacterial infection. The presence of bacteria changes the local microenvironment, for example through the accumulation of hydrophobic and charged bacterial surfaces or alteration of cellular metabolism. This activates antibacterial activities independently of pattern recognition receptors, including inactivation by soluble lectins and antimicrobial peptides, nutritional depletion by natural resistance-associated macrophage protein 1 (NRAMP1) and lactoferrin, and bacterial degradation by phagocytosis and basal autophagy. dsDNA, double-stranded DNA; RISC, RNA-induced silencing complex; ROS, reactive oxygen species; viRNA, virus-derived small interfering RNA.

그림 3. 구성적 선천 면역 메커니즘에 의한 미생물 복제 조절 개요.

a | 구성적 선천 면역 기전과 바이러스 감염.

특정 바이러스 분자 구조(이중가닥 RNA(dsRNA) 또는 캡시드 등)의 축적과 세포 스트레스 반응(자가포식 등)은 패턴 인식 수용체와 무관하게 직접적인 항바이러스 활성을 지닌 구성적-잠복 기전을 활성화한다. 일부 항바이러스 효과기 기능은 바이러스 복제 주기의 특정 단계를 차단하여 미생물 복제를 표적으로 합니다. 이러한 효과기에는 용해성 렉틴, 항균 펩타이드, 제한 인자, RNA 간섭(RNAi), 대사 산물이 포함됩니다. 구성적 반응의 다른 항바이러스 효과기는 바이러스 입자의 분해를 통해 기능합니다. 여기에는 세포질에서 바이러스 DNA를 분해하는 TREX1과 같은 뉴클레아제, 바이러스 RNA를 분해하는 RNase L, 그리고 자가포식과 프로테아좀 분해가 포함됩니다. 바이러스는 항체가 부착된 바이러스 캡시드에 결합하는 유비퀴틴 E3 리가아제 TRIM21에 의해 프로테아좀 분해 대상으로 표적화될 수 있습니다.

b | 구성적 선천 면역 기전과 세균 감염.

박테리아의 존재는 소수성 및 전하를 띤 박테리아 표면의 축적이나 세포 대사의 변화 등을 통해 국소 미세환경을 변화시킵니다. 이는 패턴 인식 수용체와 무관하게 항균 활성을 활성화시키며, 여기에는 용해성 렉틴 및 항균 펩타이드에 의한 비활성화, 자연 저항성 관련 대식세포 단백질 1(NRAMP1) 및 락토페린에 의한 영양소 고갈, 식작용 및 기초적 자가포식에 의한 박테리아 분해 등이 포함됩니다. dsDNA, 이중 가닥 DNA; RISC, RNA 유도 침묵 복합체; ROS, 활성산소종; viRNA, 바이러스 유래 소형 간섭 RNA.

Table 1.

Constitutive immune mechanisms in host defence

Type of effectorExamplesTriggerTarget microorganismsEvidence for control of inflammatory responsesRefs

Targeting microbial replication
Restriction factors	BST2, YBX1, IFITMs	Specific viral replication events	HIV-1, HCV, HSV-1, VSV, RSV	Increased IL-6 and IL-1β expression‎ in the lungs of RSV-infected Ifitm1–/– mice; increased constitutive infiltration of monocytes and macrophages in the kidney in Ybx1–/– mice	40,44,154–156
	SAMHD1, APOBEC3	Modulation of nucleic acid availability and/or function	HIV-1, vaccinia virus, HSV-1, murine herpesvirus 68, parvovirus	Increased spontaneous and lentivirus-induced interferon and ISG expression‎ in Samhd1–/– mice; increased IFNβ expression‎ in Apobec3–/– mice infected with murine leukaemia virus	39,41,120,121,157,158
RNAi	RISC	dsRNA	Cucumovirus (plants), Flock House virus (worms), cricket paralysis virus (flies)	Introduction of Drosophila Dicer-2 in mammalian cells reduced dsRNA-induced IFNβ expression‎	50–52,159
Antimicrobial peptides	β-Defensins, cathelicidin	Negatively charged surfaces	Salmonella enterica subsp. enterica serovar Typhimurium, Escherichia coli, Shigella spp., HIV-1	LL37 inhibits DNA-sensing inflammasomes in psoriatic skin; an engineered antimicrobial peptide inhibits TLR4 signalling through the TRIF pathway	58–60,65,129,160
Soluble lectins	Collectins, ficolins, galectins, pentraxins	Glycans	HIV-1, influenza A virus, Streptococcus pneumoniae	SP-A inhibits LPS-induced TLR4 activation by preventing the interaction with LPS-binding protein; SP-D-deficient mice have increased levels of proinflammatory cytokines after influenza virus infection	68–72,161
Metabolites	Lactate, palmitic acid	Metabolic alterations	HIV-1, HSV-1, Zika virus, VSV	Ldha–/– mice express increased levels of type I interferon on infection with RNA viruses	73,74,77,162,163
	NRAMP1, lactoferrin	Iron depletion	Mycobacterium tuberculosis, S. Typhimurium, Leishmania donovani, Streptococcus mutans	Lactoferrin binds CpG DNA and impedes stimulation through TLR9	80,81,84,123
Degenerative mechanisms
Autophagy	–	Viral proteins, organelle dysfunction, protein aggregates	M. tuberculosis, S. Typhimurium, Sindbis virus	Increased interferon expression‎ and inflammasome activation in autophagy-defective cells; excess IL-1β production and lung inflammation in autophagy-deficient mice after infection and sterile challenge	9,89,96,126,164
Phagocytosis	–	Opsonization	Staphylococcus aureus, Salmonella spp., Mycobacteria spp., Aspergillus spp.	Patients with CGD have increased inflammasome activity and IL-1β production	165,166
LC3-associated phagocytosis	–	Not known	S. Typhimurium, Listeria monocytogenes, Burkholderia pseudomallei	LC3-deficient mice fail to clear dead cells and develop lupus-like inflammatory disease	102,123,167,168
Proteasomal degradation	–	Cytosolic capsids and capsid–IgG complexes	Adenovirus, turnip yellow mosaic virus	Patients with PRAAS-associated mutations in proteasome genes have strong interferon signatures	105–107,111,148,149
Nucleic acid degradation	–	Cytosolic RNA and DNA	Endogenous retroviruses, murine coronaviruses	Patients with defective TREX1 have increased interferon expression‎ and develop Aicardi–Goutières syndrome	117,118,137

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APOBEC3, apolipoprotein B mRNA-editing complex 3; BST2, bone marrow stromal antigen 2 (also known as tetherin); CGD, chronic granulomatous disease; dsRNA, double-stranded RNA; HCV, hepatitis C virus; HSV-1, herpes simplex virus type 1; IFITMs, interferon-induced transmembrane proteins; ISG, interferon-stimulated gene; Ldha, lactate dehydrogenase A; LPS, lipopolysaccharide; NRAMP1, natural resistance-associated macrophage protein 1; PRAAS, proteasome-associated autoinflammatory syndromes; RISC, RNA-induced silencing complex; RNAi, RNA interference; RSV, respiratory syncytial virus; SAMHD1, SAM domain and HD domain-containing protein 1; SP, surfactant protein; TLR, Toll-like receptor; VSV, vesicular stomatitis virus; YBX1, Y-box binding protein 1.

Given the ability of constitutive immune mechanisms to exert antimicrobial activity, one consequence of their successful action is decreased levels of PAMPs (Fig. 2a). This, in turn, limits PRR activation and the downstream inflammatory response (Fig. 2b). Thus, constitutive immune mechanisms equip cells and tissues with a layer of defence that can fight infections immediately and hence potentially limit the requirement for inducible immune responses, such as type I interferon, IL-1β and other proinflammatory cytokines.

항균 활성을 발휘하는 상시적 면역 기전의 능력으로 인해, 이들의 성공적인 작용의 한 결과는 PAMP 수준이 감소하는 것이다(그림 2a). 이는 차례로 PRR 활성화와 하류 염증 반응을 제한한다(그림 2b). 따라서 상시적 면역 기전은 세포와 조직에 감염을 즉시 퇴치할 수 있는 방어 계층을 제공함으로써, 제1형 인터페론, IL-1β 및 기타 전염증성 사이토카인과 같은 유도성 면역 반응의 필요성을 잠재적으로 제한할 수 있다.

Box 2 Overlap between constitutive and inducible immune responses.

In most respects, constitutive and inducible immune responses operate through different principles; however, in certain cases, their downstream effector activities may overlap. This is to be expected given that all of these responses use mechanisms from the same ‘evolutionary toolbox’ to achieve optimal protection of the host. For example, autophagy can be activated during infection and upon sterile danger9,174. Similarly, phagocytosis can be activated by both Toll-like receptor (TLR)-dependent and TLR-independent mechanisms175–177. Moreover, many restriction factors are expressed at basal levels to exert immediate antiviral activity, but are also induced transcriptionally in response to stimulation with type I interferon35,40,178. Nevertheless, despite these minor areas of overlap between constitutive immune mechanisms and the pattern recognition receptor (PRR)-induced immune responses, the differences are more pronounced. The key difference between constitutive immune mechanisms and PRR-induced immunity is that the former mechanisms are all activated through pre-existing molecules to directly eliminate danger, whereas the latter system functions mainly through inducible transcription-dependent proinflammatory programmes. In addition, inducible innate responses can amplify adaptive responses, whereas constitutive innate responses do not amplify inducible innate responses.

박스 2 상시적 면역 반응과 유도성 면역 반응의 중첩

대부분의 측면에서 상시적 면역 반응과 유도성 면역 반응은 서로 다른 원리로 작동하지만, 특정 경우 하류 효과기 활동이 중첩될 수 있다. 이는 모든 반응이 숙주의 최적 보호를 달성하기 위해 동일한 '진화적 도구 상자'의 메커니즘을 사용한다는 점을 고려하면 예상되는 현상이다. 예를 들어, 자가포식은 감염 시와 무균성 위험9,174에 의해 활성화될 수 있다. 마찬가지로, 식작용은 Toll-like receptor(TLR) 의존적 및 TLR 비의존적 메커니즘 모두에 의해 활성화될 수 있다175–177. 또한 많은 제한 인자들은 기초 수준에서 발현되어 즉각적인 항바이러스 활성을 발휘하지만, 제1형 인터페론35,40,178에 의한 자극에 반응하여 전사적으로 유도되기도 합니다. 그럼에도 불구하고, 구성적 면역 기전과 패턴 인식 수용체(PRR) 유도 면역 반응 사이의 이러한 사소한 중첩 영역에도 불구하고, 차이점은 더욱 두드러집니다. 구성적 면역 기전과 PRR 유도 면역의 핵심 차이는 전자가 모두 기존 분자를 통해 활성화되어 위험을 직접 제거하는 반면, 후자는 주로 유도 가능한 전사 의존적 전염증성 프로그램을 통해 기능한다는 점이다. 또한 유도 가능한 선천 반응은 적응 반응을 증폭시킬 수 있지만, 구성적 선천 반응은 유도 가능한 선천 반응을 증폭시키지 않는다.

Targeting microbial replication

Direct inhibition of microbial replication is executed by molecules that interfere with specific steps in the replication cycle of a given microorganism. There are at least six mechanisms of action in this category: restriction factors that directly block a specific replication step; restriction factors that deplete molecules essential for replication; RNA interference (RNAi); antimicrobial peptides; soluble lectins; and metabolite-mediated inhibition of microbial replication (Table 1).

미생물 복제 표적화

미생물 복제의 직접적 억제는 특정 미생물의 복제 주기 단계에 간섭하는 분자들에 의해 수행된다. 이 범주에는 최소 여섯 가지 작용 기전이 존재한다: 특정 복제 단계를 직접 차단하는 제한 인자; 복제에 필수적인 분자를 고갈시키는 제한 인자; RNA 간섭(RNAi); 항균 펩타이드; 용해성 렉틴; 그리고 대사산물 매개 미생물 복제 억제(표 1).

Restrictions factors

Restriction factors are antiviral proteins that target viral replication. Extensive studies, particularly of HIV-1 and herpesviruses37,38, have led to the identification of numerous restriction factors that together target nearly all steps in the viral replication cycle (Fig. 4a). For example, APOBEC3 proteins belong to the family of cytidine deaminases, which catalyse the deamination of cytidine to uridine in single-stranded DNA, thus introducing potentially deleterious mutations into the HIV-1 genome39. Likewise, tetherin is a membrane-bound protein that prevents the release of progeny HIV-1 particles from the cell surface40. These two mechanisms provide examples of direct blockade of specific steps in the replication cycle. By contrast, SAM domain and HD domain-containing protein 1 (SAMHD1) blocks HIV-1 replication indirectly, by converting deoxynucleoside triphosphates into inorganic phosphate and 2′-deoxynucleoside, thus depleting essential building blocks for HIV-1 reverse transcription34,41. The aforementioned restriction factors work in the plasma membrane or in the cytoplasm. However, many DNA viruses, including herpesviruses, replicate in the nucleus, where they are also targeted by numerous restriction factors. These include nuclear domain 10 bodies (ND10 bodies) and IFNγ-inducible protein 16 (IFI16), which operate by different mechanisms to epigenetically silence viral genomes35,42. The herpesvirus DNA rapidly associates with ND10 bodies, which restrict viral gene expression‎ by promoting processes that lead to the formation of nucleosome-like structures42. IFI16 restricts viral replication in the nucleus mainly by interfering directly with transcription35. New evidence suggests that this involves the ability of IFI16 to form DNA filaments, which reduces recruitment of RNA polymerase II (ref.43), but also leads to recruitment of ND10 bodies, thus indicating that these two restriction systems might interact. The restriction factors discussed here are all constitutively expressed, although the expression‎ of many of them is further increased by interferons35,44,45. Tonic type I interferon signalling or constitutive activity of interferon regulatory factor 1 (IRF1) drives the basal expression‎ of many constitutive restriction factors8,46,47.

제한 인자

제한 인자는

바이러스 복제를 표적으로 하는 항바이러스 단백질이다.

특히 HIV-1과 헤르페스바이러스에 대한 광범위한 연구37,38을 통해

바이러스 복제 주기의 거의 모든 단계를 함께 표적으로 하는

수많은 제한 인자가 확인되었다(그림 4a).

예를 들어, APOBEC3 단백질은 시티딘 탈아미노효소 계열에 속하며,

단일 가닥 DNA에서 시티딘을 우리딘으로 탈아미노화하여

HIV-1 게놈에 잠재적으로 해로운 돌연변이를 유발한다39.

마찬가지로, 테더린은 세포 표면에서 자손 HIV-1 입자의 방출을 차단하는 막 결합 단백질이다40. 이 두 메커니즘은 복제 주기의 특정 단계를 직접 차단하는 사례를 보여줍니다. 반면, SAM 도메인과 HD 도메인 함유 단백질 1(SAMHD1)은 데옥시뉴클레오사이드 삼인산을 무기 인산염과 2′-데옥시뉴클레오사이드로 전환함으로써 HIV-1 역전사에 필수적인 구성 요소를 고갈시켜 HIV-1 복제를 간접적으로 차단합니다34,41. 앞서 언급한 제한 인자들은 세포막이나 세포질에서 작용한다. 그러나 헤르페스바이러스를 포함한 많은 DNA 바이러스들은 핵 내에서 복제되며, 여기서도 수많은 제한 인자들의 표적이 된다. 여기에는 핵 도메인 10 바디(ND10 바디)와 IFNγ 유도 단백질 16(IFI16)이 포함되며, 이들은 서로 다른 기전을 통해 바이러스 게놈을 후성유전학적으로 침묵시킨다35,42. 헤르페스바이러스 DNA는 신속하게 ND10 바디와 결합하며, 이는 뉴클레오솜 유사 구조체 형성을 촉진하는 과정을 통해 바이러스 유전자 발현을 제한한다42. IFI16은 주로 전사 과정에 직접 간섭함으로써 핵 내 바이러스 복제를 억제한다35. 새로운 증거에 따르면, 이는 IFI16이 DNA 필라멘트를 형성하는 능력과 관련이 있으며, 이는 RNA 중합효소 II의 모집을 감소시키지만(ref.43), 동시에 ND10 바디의 모집을 유도하여 이 두 제한 시스템이 상호작용할 수 있음을 시사한다. 여기서 논의된 제한 인자들은 모두 지속적으로 발현되지만, 그중 다수의 발현은 인터페론에 의해 추가로 증가된다35,44,45. 토닉형 I형 인터페론 신호전달 또는 인터페론 조절 인자 1(IRF1)의 구성적 활성은 많은 구성적 제한 인자의 기초 발현을 주도한다8,46,47.

Fig. 4. Constitutive control of microbial replication by restriction factors and autophagy.

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a | Restriction factors that control herpesvirus and retrovirus infections, including their targets in the viral replication cycle. Restriction factors interfere with viral replication by either blocking a specific and essential step in the viral replication cycle (for example, viral gene transcription or release of progeny virus) or depletion of factors that are essential for replication (such as deoxynucleoside triphosphates). b | Blockade of viral and bacterial replication by autophagy. Various ubiquitin E3 ligases (such as SMURF1, LRSAM1 and TRIM23) and ubiquitin-binding proteins (such as p62, optineurin and NDP52) have been identified to conjugate ubiquitin to microbial surfaces, which targets them for loading into autophagosomes. Also, cytosolic exposure of glycans by pathogen-damaged vesicles can be recognized by galectin 8 for targeting to autophagosomes. APOBEC3, apolipoprotein B mRNA-editing complex 3; BST2, bone marrow stromal antigen 2 (also known as tetherin); DBR1, RNA lariat debranching enzyme 1; IFI16, interferon-γ-inducible protein 16; IFITM, interferon-induced transmembrane protein; MTOC, microtubule-organizing centre; ND10, nuclear domain 10; SAMHD1, SAM domain and HD domain-containing protein 1; SIRT6, sirtuin 6; SNORA31, small nucleolar RNA, H/ACA box 31.

RNA interference

RNAi is another constitutive immune mechanism that directly controls viral replication. RNAi involves the processing of double-stranded RNA molecules by members of the Dicer nuclease family to 20–25-bp fragments, thus leading to the formation of the RNA-induced silencing complex (RISC), which blocks gene expression‎ or translation through binding to target mRNAs48. The ability of RNAi to directly block viral replication was first shown in plants49 and was later also shown in insects and worms50–52. For example, Caenorhabditis elegans and Drosophila melanogaster infected with Flock House virus activate antiviral defence mechanisms that depend on Dicer51,53. This constitutive immune mechanism might have a more important role in lower organisms, but as some mammalian viruses do target the RNAi system, there may be a subdominant role for this primordial antiviral system in host defence in more evolved organisms54. For example, Ebola virus VP35 and VP30 proteins interact with Dicer cofactors, and the hepatitis C virus core protein directly associates with Dicer55,56.

RNA 간섭

RNAi는 바이러스 복제를 직접적으로 제어하는

또 다른 구성적 면역 기전이다.

RNAi는 Dicer 핵산분해효소 계열에 의해 이중가닥 RNA 분자를 20–25-bp 단편으로 처리하는 과정을 포함하며,

이로 인해 RNA 유도 침묵 복합체(RISC)가 형성되어

표적 mRNA에 결합함으로써 유전자 발현 또는 번역을 차단한다48.

RNAi가 바이러스 복제를 직접 차단하는 능력은 식물에서 최초로 확인되었으며49, 이후 곤충과 선충에서도 입증되었다50–52. 예를 들어, Flock House 바이러스에 감염된 Caenorhabditis elegans와 Drosophila melanogaster는 Dicer에 의존하는 항바이러스 방어 기전을 활성화한다51,53. 이러한 구성적 면역 기전은 하등 생물에서 더 중요한 역할을 할 수 있으나, 일부 포유류 바이러스가 RNAi 시스템을 표적으로 삼는다는 점에서, 이 원시적 항바이러스 시스템은 진화한 숙주 방어에서 부차적 역할을 할 수 있다54. 예를 들어, 에볼라 바이러스 VP35 및 VP30 단백질은 Dicer 보조인자와 상호작용하며, C형 간염 바이러스 코어 단백질은 Dicer와 직접 결합한다55,56.

Antimicrobial peptides

Antimicrobial peptides, including defensins and cathelicidins, contribute to the first line of defence against bacteria in the skin and at mucosal surfaces. They work by binding directly to bacterial membranes, thus perturbing membrane integrity and inhibiting microbial growth57–60. These peptides are rich in both cationic and hydrophobic amino acids, and generally form amphiphilic helical structures, although this may not be the case for all antimicrobial peptides61. This enables the peptides to interact with negatively charged bacterial surfaces through electrostatic interactions, thus triggering disruption of the bacterial membranes by pore-forming or non-pore-forming mechanisms62. Many antimicrobial peptides, such as β-defensin 1, are constitutively expressed on epithelial surfaces, thus providing immediate antimicrobial action on infection63. This is illustrated by the increased susceptibility to a broad range of bacterial infections in mice lacking cathelicidin antimicrobial peptide (CAMP)59,64. Beyond their role in antibacterial defence, there is also evidence that antimicrobial peptides can disrupt viral particles, thus exerting antiviral activity65,66. Similarly to the restriction factors, many antimicrobial peptides are expressed in both constitutive and inducible manners. This illustrates the general principle that different branches of the immune system can use overlapping effector functions (Box 2).

Soluble lectins

Many microorganisms have extensive and more complex glycan patterns than mammalian cells, and these sugars can therefore be used as a means to distinguish self from non-self. There are four classes of soluble lectins carrying out this function, namely collectins, ficolins, galectins and pentraxins67. On recognition of non-self glycans, soluble lectins can exert host defence activities indirectly through complement activation and opsonization, as discussed later, or directly through aggregation and neutralization. For example, the collectin surfactant protein D (SP-D) has been reported to bind directly to highly glycosylated viruses such as HIV-1 and influenza A virus and neutralize their infectivity68,69. Similarly, pentraxin 3 directly binds influenza A virus particles and neutralizes virus infectivity70. Importantly, SP-D-deficient mice have impaired clearance of influenza A virus and increased production of proinflammatory cytokines in response to viral challenge71. In addition to viruses, SP-D also binds and agglutinates Streptococcus pneumoniae72, thus suggesting that soluble lectins might also have a role in the immediate inactivation of bacteria.

Metabolite-mediated inhibition

A final example of constitutive immune mechanisms that directly interfere with microbial growth is provided by metabolites that block pathogen replication, and perhaps the best example of which is lactate73,74. Many viral infections are characterized by a shift of host cellular metabolism to aerobic glycolysis, which leads to the production of lactate75,76. Viral infections also induce fatty acid synthesis and intermediate molecules in these pathways. These include palmitic acid and oleic acid, which have been shown to have antiviral activity77,78. The mechanisms by which lactate and other metabolites block viral replication remain to be determined, but the antiviral activity of lactate illustrates a general principle that select molecules accumulating during alterations of cellular homeostasis can interfere with microbial replication.

A second form of metabolite-dependent constitutive host defence is mediated through nutritional depletion and starvation of pathogens. For example, natural resistance-associated macrophage protein 1 (NRAMP1; also known as SLC11A1) is a metal ion transporter that transports divalent cations from vacuoles into the cytoplasm, hence depleting factors from vacuoles that are essential for the growth of intracellular pathogens79. The gene encoding NRAMP1 was shown to contribute to defence against, for example, Mycobacterium tuberculosis, Salmonella enterica subsp. enterica serovar Typhimurium and Leishmania donovani80,81, which was later shown to be mediated by the reduction of metal ion concentrations inside microorganism-containing vacuoles82. A second example of nutritional depletion is provided by lactoferrin, which is present in various secretory fluids. Lactoferrin is a highly cationic molecule that shows antimicrobial activity, in part, by binding and sequestering iron from pathogenic microorganisms83. Lactoferrin contributes to host defence in a non-redundant manner, as lactoferrin-deficient mice have increased susceptibility to Streptococcus mutans-induced dental caries, for example84.

Degenerative mechanisms

The second class of constitutive innate immune mechanisms functions through the degradation of danger molecules and elimination of unwanted cells. This class of mechanisms includes autophagy, phagocytosis, proteasomal degradation and nucleases (Table 1). Collectively, degenerative programmes function to continually limit danger signals, allowing for the rapid elimination of unwanted molecules without the activation of energy-consuming amplificative induced immune responses.

Autophagy and phagocytosis

Autophagy and phagocytosis execute the digestion of intracellular and extracellular microorganisms, respectively, through membrane encapsulation followed by chemical and enzymatic degradation85,86. Pathogens are shunted into these pathways through the recognition of polyubiquitin chains or glycans inside damaged vacuoles in the case of autophagy9,87, and through complement coating of microorganisms in the case of phagocytosis88. In the case of autophagy, a large number of ubiquitin E3 ligases have been identified that coat viral and bacterial surfaces with ubiquitin9,89–92, thus targeting microorganisms for loading into autophagosomes through interaction with the autophagosome-associated protein LC3 (also known as MAP1ALC3)85 (Fig. 4b). This targeting mechanism involves E3 ligases, including SMURF1 and LRSAM1 (refs91,92), as well as the ubiquitin-binding selective autophagy receptors p62 (also known as SQSTM1), optineurin and NDP52 (also known as CALCOCO2)9,89,93. An alternative mechanism for sensing of vesicle-damaging pathogens has been identified that involves damaged vesicles exposing glycans in the cytoplasm for sensing by galactin 8, which links to autophagy via NDP52 (ref.87). This triggers phagophore formation in the vicinity of cytosolic bacteria94. Autophagy has important roles in the control of infection. For example, defective autophagy leads to increased susceptibility to infection with Sindbis virus in mice89. In addition, stimulation of autophagy in primary human macrophages mediated protection against M. tuberculosis infection95,96. However, mice defective in autophagy do not have impaired antimycobacterial defence in vivo, which indicates that the precise role of autophagy requires further investigation97. Third, herpes simplex virus type 1 specifically interferes with autophagy, which is essential for neuropathogenicity of the virus36.

Complement-mediated phagocytosis involves specific recognition of complement components bound to the surface of microorganisms by the corresponding complement receptors on phagocytes. Activation of the complement system, for example after sensing of glycans by the lectin pathway, leads to the formation of C3 convertase, eventually generating C3b, which binds to complement receptors, thus inducing phagocytosis98. Mice devoid of the lectin-based complement pathway have increased susceptibility to Staphylococcus aureus infection and impaired bacterial phagocytosis99. Furthermore, several bacteria, including Streptococcus pyogenes, inhibit complement-mediated phagocytosis100.

A third degenerative mechanism for the degradation of membrane-encapsulated extracellular material is LC3-associated phagocytosis (LAP), which uses components from both the phagocytosis and autophagy pathways101. LAP is involved in the clearance of extracellular pathogens and dead cells102, and LAP-deficient mice fail to clear Aspergillus fumigatus infection103. Thus, autophagy, phagocytosis and LAP are important systems for immediate host defence.

Proteasomal degradation

The proteasome is a cytoplasmic protein complex that degrades proteins by proteolysis104. Proteins to be degraded are tagged by K48-linked polyubiquitylation, attracted to the proteasome, unfolded into polypeptides and then degraded104. The proteasomal degradation pathway also contributes to immediate defence against infecting pathogens. For example, viruses can be detected by the ubiquitin E3 ligase TRIM21 through binding to antibody-bound viral capsids, which links to downstream proteasomal degradation105. This process is involved in the elimination of infecting viral capsids from the cytoplasm and contributes to antiviral defence105–107. Other studies have shown that the viral RNA-dependent RNA polymerase of turnip yellow mosaic virus is degraded by the ubiquitin–proteasome pathway to control infection108. Proteasome activity also contributes to defence against many bacterial infections, including Yersinia spp. infections109, and the ubiquitin–proteasome pathway is targeted by many viruses and bacteria to promote replication110–114. For example, the human cytomegalovirus protein pUL25 inhibits proteasomal degradation of another viral protein, pUL26, to sustain the activity of a pUL26-mediated immune evasion mechanism114. Collectively, these examples show that the conserved proteasome pathway is part of the constitutive immune defence repertoire.

Nucleases

The cytoplasm contains RNAses and DNAses that eliminate unwanted nucleic acid species, including viral nucleic acids, and these enzymes can thereby contribute to sterilization of the cytoplasm. RNase L is a latent cytoplasmic exoribonuclease that is activated by 2′-5′ oligoadenylates produced by OASs115. Although OASs are highly interferon inducible, they are also expressed at a basal level and hence induce basal RNase L activity116. Importantly, this activity has been suggested to contribute to basal restriction of coronaviruses in myeloid cells, and hence to protect other cell types from infection117. TREX1 is a cytoplasmic exodeoxyribonuclease that eliminates DNA from the cytoplasm. Very few microorganisms have free DNA as part of their productive replication cycle, but exogenous and endogenous retroviruses have a cytoplasmic DNA step that is sensitive to degradation by TREX1. Consequently, Trex1–/– mice have increased levels of endogenous retroviral DNA in the cytoplasm118, which indicates that TREX1 has a role in limiting retroviral infection and hence maintaining genome integrity.

Limiting inflammatory responses

Immune responses induced by PRRs and by antigen-specific receptors are often highly potent and sterilizing. However, they may also be relatively disruptive and can be associated with tissue damage and the requirement for significant tissue repair and energy consumption119. Many of the constitutive immune mechanisms discussed here not only interfere with microbial replication but also have negative effects on PRR activity (Table 1). This raises the possibility that an overarching function of the constitutive immune mechanisms is to both eliminate danger and limit the use of PRR-driven activities. At the mechanistic level, this immunoregulatory function of the constitutive mechanisms can be exerted in two qualitatively different ways. The first is through the direct effect of their antimicrobial activity on decreasing levels of PAMPs. The second is through specific inhibition of PRR signalling.

Reduction of PAMP levels

Many studies have shown that PRR activation requires PAMP levels to be above a certain threshold25–28. Above this threshold, PRRs are activated in a concentration-dependent manner until saturation is reached. Therefore, constitutive immune mechanisms that reduce PAMP levels will limit or even prevent PRR activation (Fig. 2a). For example, mice deficient in the restriction factor APOBEC3, which has antiretroviral activity, have higher viral loads after infection with murine leukaemia virus and corresponding higher levels of reverse viral transcripts and downstream interferon induction through the cGAS–STING pathway (cyclic GMP–AMP synthase–stimulator of interferon genes pathway)120. Similarly, SAMHD1 activity in vivo controls lentivirus load and limits virus-induced production of interferons in myeloid cells121. In addition, SAMHD1 deficiency leads to increased expression‎ of costimulatory molecules and T cell activation on lentiviral infection, which suggests that the constitutive reduction of PRR activation by SAMHD1 limits not only the expression‎ of innate immune cytokines but also downstream adaptive immune responses121. A third example is provided by the observation that expression‎ of Drosophila Dicer in mammalian cells leads to decreased induction of IFNβ by double-stranded RNA, most likely owing to the digestion of immunostimulatory RNA into shorter 20–25-bp RNA species that activate PRRs only inefficiently122. Finally, constitutive innate immune mechanisms can also reduce PRR activity by lowering the concentration of PAMPs that have immunostimulatory activity. For example, lactoferrin binds CpG DNAs and inhibits their ability to activate TLR9 (ref.123).

Inhibition of PRR signalling

In addition to reducing the levels of PAMPs, some constitutive mechanisms have been reported to target PRR activity at the signalling level (Fig. 2a). For example, autophagy negatively regulates signalling by the RIG-I–MAVS pathway (retinoic acid-inducible gene I protein–mitochondrial antiviral signalling protein pathway) and by the cGAS–STING pathway; in the former case by limiting reactive oxygen species-mediated amplification of signalling and by LC3-dependent MAVS inactivation124,125, and in the latter case through degradation of STING126. In line with this, defective autophagy as a result of ATG16L deficiency predisposes to STING-dependent intestinal pathology in mice127, and ATG5 deficiency selectively in neutrophils exacerbates M. tuberculosis immunopathology without affecting bacterial load97. As a second example, lactate, which is produced during aerobic glycolysis and has virus-restricting activity73,74, also directly inhibits MAVS activity; thus lactate both reduces levels of viral PAMPs and has a negative regulatory function to inhibit PAMP-driven signalling and interferon expression‎128. Third, an engineered amphipathic-helical antimicrobial peptide was found to block TLR4 signalling through the TRIF pathway129. This occurs by the inhibition of TLR4 endocytosis, which is an essential step for the engagement of TRIF from endosomal compartments.

Collectively, the current literature suggests that constitutive immune mechanisms reduce PRR activation through a range of mechanisms and, therefore, that these constitutive mechanisms impose a threshold and negative regulatory activity on the amplificative innate and adaptive immune responses (Fig. 2b). We propose that rapid, molecularly specific and non-amplificative responses to challenges provided by constitutive immune mechanisms are beneficial for achieving optimal host defence with minimal immunopathology.

Constitutive immunity beyond infection

Our main focus here has been on infections. However, constitutive immune mechanisms are also involved in the elimination of sterile danger. For example, DNA damage in the nucleus and the accumulation of DNA in extranuclear compartments are eliminated by the DNA damage response and specific DNases130, respectively; the accumulation of misfolded proteins leads to the formation of aggresomes, which are cleared by selective autophagy131,132; excessive accumulation of reactive oxygen species leads to death of the oxygen-stressed cells133; and free cholesterol is converted into an ester derivative by lecithin–cholesterol acyltransferase, thus enabling transport to the liver by high-density lipoprotein and eventual degradation134. Defects in these constitutive and latent danger-eliminating mechanisms lead to the accumulation of danger-associated molecular patterns and activation of PRR-based immunity. For example, in cells with defects in either the DNA damage response or extranuclear DNases, the accumulation of DNA induces type I interferon production through the cGAS–STING pathway135–138. Similarly, defective elimination of protein aggregates or cholesterol leads to the induction of IL-1β production through activation of the NLRP3 inflammasome139,140. Common to all of the examples given above is that the accumulated abnormal endogenous molecules are detected and eliminated through molecularly specific mechanisms independently of PRRs. This elimination limits PRR activation and hence inflammatory reactions. Therefore, in addition to eliminating microorganisms and PAMPs, constitutive immune mechanisms also eliminate sterile danger signals in a damage-limiting manner that prevents the activation of excessive inflammation.

Constitutive immunity in human health

We propose that constitutive immune mechanisms enable cells and organisms to fight infections and eliminate endogenous abnormalities in a non-inflammatory manner. Therefore, an important benefit of these mechanisms may be to increase the threshold for development of clinically overt signs of disease on exposure to infections or endogenous danger. Studies of the associations between single-nucleotide polymorphisms and infections have shown that restriction factors, antimicrobial peptides and autophagy have important roles in antimicrobial defence141–144. Constitutive immune mechanisms may be particularly active in the protection of tissues that are frequently exposed to pathogens, such as epithelial cells in the airways and the gut, or tissues that are particularly vulnerable to immunopathology, such as the brain. In favour of this idea, RNA lariat debranching enzyme 1 (DBR1) and small nucleolar RNA, H/ACA box 31 (SNORA31) were recently shown to have non-redundant, interferon-independent roles in the prevention of viral brainstem encephalitis and herpes simplex encephalitis, respectively11,12. The mechanisms through which they exert their antiviral activity remain to be determined. Reports have shown that autophagy is an antiviral mechanism in the brain in mice36,89,145. In addition, some cell populations, including stem cells, seem to use constitutive immune mechanisms to eliminate danger without losing key functions, such as self-renewal and differentiation capacity, that are known to be impaired by PRR-based immunity146,147.

An important question related to human immunology is how individuals with a loss-of-function mutation in a constitutive immune mechanism may present clinically. Deficiency of a mechanism that is expressed in specific organs or cell types might lead to a higher frequency of clinical infections by a subset of microorganisms that are normally controlled by the defective mechanism. This seems to be the case for defects in DBR1, which confer susceptibility to disease caused by infections with herpes simplex virus type 1, influenza virus or norovirus in the brainstem11. The impact of deficiencies in constitutive immune mechanisms might not be limited to acute infections and could also include chronic and latent infections. In support of a link between such defects and increased inflammation, patients with inborn defects in DNA repair, elimination of extranuclear DNA or degradation of misfolded proteins develop autoinflammatory diseases, including Aicardi–Goutières syndrome and proteasome-associated autoinflammatory syndromes, which are characterized by type I interferon-dependent autoinflammation and are termed ‘interferonopathies’137,148–150. Therefore, a loss of function in constitutive immune mechanisms can lead to selective susceptibility to specific infections or to infections in specific organs. Likewise, such deficiency might lead to the accumulation of PAMPs, microorganism-associated molecular patterns, danger-associated molecular patterns and/or homeostasis-altering molecular processes and associated pathological inflammation (Box 1).

Outlook

In this article, we have described the role and mode of action of a large panel of constitutive mechanisms used by the immune system to exert immediate control of infections and endogenous dangers independently of the inducible mechanisms that are activated through PRRs and antigen-specific receptors. Although many such constitutive responses have been known for years, greater understanding of the mechanisms involved and renewed interest in fields such as restriction factor biology and immunometabolism are spurring further work in the area. With the identification of constitutive mechanisms that have non-redundant roles in host defence, we now know that these immune mechanisms are not just redundant, non-specific players in immunology11,12. This should stimulate interest in understanding the roles played by constitutive immune mechanisms in host defence in vivo, which might include the identification of new primary immune disorders. Improved knowledge of the host cell type and tissue specificities of constitutive immune mechanisms in relation to susceptibility to infections could greatly improve our understanding of human immunology. Such work will start to provide answers to the fundamental question of how the immune system determines the degree of threat caused by an infection and balances that with the appropriate strength of the immune reaction.

Finally, as we gain further insights into the various host responses that are activated during immunological challenge, it will be interesting to explore the idea that the immune system has a defensive layer of activities that have been selected to eliminate danger without engaging the PRR system (Box 3). In this respect, it is interesting to note that in addition to the constitutive mechanisms described in this Review, there are various sensing systems that use transcriptional programmes to induce host defence independently of PRRs and with the ability to control inflammation. They include the NRF2–KEAP1, hypoxia-inducible factor 1α and bone morphogenetic protein–SMAD pathways10,151–153. In addition, the constitutive host defence exerted by commensal bacteria through several mechanisms, including niche competition, warrants more attention. With more and more data emerging on the importance of constitutive mechanisms in immunology, there is a need to understand this phenomenon in more detail. Such work may advance our understanding of one of the most interesting questions in immunology, namely how to eliminate danger in a rapid, efficient and specific manner without causing excess damage to the host.

Box 3 A new concept of damage-limiting immune mechanisms?

In addition to the constitutive immune mechanisms described in this Review, several pathways are activated in response to infections and sterile challenge that function independently of pattern recognition receptors (PRRs) and antigen-specific receptors to control infection. These include the NRF2–KEAP1, hypoxia-inducible factor 1α and bone morphogenetic protein–SMAD pathways10,151–153. These pathways differ from the constitutive immune mechanisms by engaging transcriptional programmes to execute their activities10,151–153. Some of these pathways have also been reported to exert negative control of PRR signalling151,152,179,180, which shows that they share both antimicrobial and immunoregulatory functions with the constitutive immune mechanisms. For example, NRF2-deficient mice have increased susceptibility to certain viral infections152, and NRF2 also negatively regulates cyclic GMP–AMP synthase (cGAS)–stimulator of interferon gene (STING) signalling180. As we gain more information about the actions of constitutive immune mechanisms and PRR-independent transcriptional pathways in early host defence, we believe that the immunological community should consider whether these diverse mechanisms share features that distinguish them from other immune pathways. It is possible that the constitutive immune mechanisms described in this Review are part of a larger group of damage-limiting immune mechanisms that can be defined by fulfilling all of the following criteria:

1. Function independently of PRRs and antigen-specific receptors

2. Respond to the presence of specific microbial or host stress-related molecules

3. Eliminate danger in a non-inflammatory manner, and limit PRR activation by removing PRR ligands and/or inhibiting PRR signalling

4. Eliminate danger through specific effector functions that target defined host or microbial structures and activities

Whereas the physical and chemical barrier functions of the immune system fulfil criteria 1 and 3, they do not satisfy criteria 2 and 4. Similarly, PRRs and antigen-specific receptors fulfil criteria 2 and 4, but do not fulfil criteria 1 and 3. Although it is speculative at present, we think that the idea of damage-limiting immune mechanisms may serve as a useful guide for future experimental and clinical research.

Acknowledgements

S.R.P. is funded by the European Research Council (ERC-AdG ENVISION; 786602), the Novo Nordisk Foundation (NNF18OC0030274) and the Lundbeck Foundation (R198-2015-171 and R268-2016-3927). T.P. is funded by the European Research Council (ERC-StG IDEM; 637647). S.L.M. acknowledges funding from a Howard Hughes Medical Institute–Wellcome International Research Scholarship and the Sylvia and Charles Viertel Foundation. T.H.M. received funding from Aarhus University Research Foundation (AUFF-E-215-FLS-8-66), the Danish Council for Independent Research-Medical Sciences (4004-00047B) and the Lundbeck Foundation (R268-2016-3927). The authors thank D. Olagnier for critical reading of the manuscript and comments and suggestions.

Glossary

Pattern recognition receptors

(PRRs). A family of germline-encoded immune receptors, including the Toll-like receptors, that detect immunostimulatory molecules to activate signal transduction and gene expression‎, which induces antimicrobial and inflammatory responses.

Constitutive immune mechanisms

Host mechanisms that are constitutively present in an active or latent form and thus can exert host defence activities immediately, independently of inducible processes.

Inducible mechanisms

Biological processes that depend on the activation of transcriptional programmes and hence require intermediate steps between the trigger stimulus and effector function.

Supramolecular organizing centres

Location-specific higher-order signalling complexes, such as the myddosome in Toll-like receptor signalling, that amplify pattern recognition receptor signalling when pathogen-associated molecular pattern levels exceed specific threshold concentrations.

RNA interference

(RNAi). The use of double-stranded RNA molecules containing sequences that match a given gene to knock down the expression‎ of that gene by inhibiting translation of the targeted mRNA or by directing RNA-degrading enzymes to destroy the encoded mRNA transcript.

Nuclear domain 10 bodies

(ND10 bodies). Membraneless, interchromatin structures in the nucleus of eukaryotic cells. ND10 bodies are made up mainly of proteins and have been described to be involved in a broad range of processes, including gene regulation, cell cycle, apoptosis, DNA repair and antiviral defence.

Aerobic glycolysis

The process by which glucose is converted to lactate in the presence of oxygen to produce energy in the form of ATP.

cGAS–STING pathway

(Cyclic GMP–AMP synthase–stimulator of interferon genes pathway). cGAS is a cytosolic DNA-sensing pattern recognition receptor that signals via STING to induce the expression‎ of type I interferon and inflammatory cytokines.

RIG-I–MAVS pathway

(Retinoic acid-inducible gene I protein–mitochondrial antiviral signalling protein pathway). RIG-I is a cytosolic RNA-sensing pattern recognition receptor that signals via MAVS to induce the expression‎ of type I interferon and inflammatory cytokines.

DNA damage response

Cellular response to DNA damage, including the re-establishment of genome integrity and cell death responses.

NLRP3 inflammasome

The NLRP3 inflammasome is activated by danger-associated molecular patterns and molecular signatures associated with homeostasis-altering molecular processes to execute caspase 1-mediated cleavage of molecules such as pro-IL-1β and gasdermin D.

NRF2–KEAP1

Nuclear factor erythroid 2-related factor 2 (NRF2) senses oxidative stress, whereupon it is released from Kelch-like ECH-associated protein 1 (KEAP1) to translocate to the nucleus and induce gene expression‎.

Hypoxia-inducible factor 1α

A transcription factor that is activated by hypoxia to induce the expression‎ of genes with hypoxia-responsive elements in their promoters.

Bone morphogenetic protein–SMAD

Bone morphogenetic proteins are growth factors that signal through SMAD proteins to induce gene transcription.

Author contributions

S.R.P. conceived the idea and wrote the first version of the manuscript together with T.H.M. All authors together fully developed the work, and drafted, finalized and revised the manuscript.

Competing interests

The authors declare no competing interests.

Footnotes

Peer review information

Nature Reviews Immunology thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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References

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