Re: 치매의 원인들 3. 바이러스 감염 - 2023년 네이처 리뷰

[문형철]

2023년 영향력지수 44점 네이처 리뷰 뉴롤로지 논문

바이러스가 치매를 일으킬 수 있다...

문형철의 세포단위 질병치료 가설 추정

'70억 거의 모든 인류가 인플루엔자 바이러스에 감염이 되는데, 어떤 사람이 인지장애, 치매로 진행하는가? 

장누수 leaky Gut -->뇌혈관벽 누수 leaky BBB 환자에서 치매, 파킨슨, 다발성 경화증으로 진행할 것이다

그러면 어떤 사람이 장누수 leaky Gut -->뇌혈관벽 누수 leaky BBB 환자가 되는가? 

만성염증을 일으키는 음식(예를들어 글루텐, 유당 소화효소가 없는 사람이 지속적으로 이런 음식을 섭취할 경우)이 그 원인이 될 것이다

• News & Views
• Published: 02 March 2023

Neurodegenerative disease

Viral pathogens increase risk of neurodegenerative disease

• Britanie M. Blackhurst & 
• Kristen E. Funk 

Nature Reviews Neurology volume 19, pages259–260 (2023)Cite this article

• 3429 Accesses

• 1 Citations

• 34 Altmetric

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A new study, drawing on data from national biobanks, adds to the growing evidence that exposure to common viral pathogens increases the risk of Alzheimer disease and other neurodegenerative diseases. These findings might provide insights into the initiating factors that lead to neurodegeneration.

국가 바이오뱅크의 데이터를 기반으로 한 새로운 연구에 따르면 일반적인 바이러스 병원체에 노출되면 알츠하이머병 및 기타 신경 퇴행성 질환의 위험이 높아진다는 증거가 늘어나고 있습니다. 이러한 연구 결과는 신경 퇴행으로 이어지는 시작 요인에 대한 통찰력을 제공할 수 있습니다.

REFERS TO Levine, K. S. et al. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron https://doi.org/10.1016/j.neuron.2022.12.029 (2023).

Neurodegenerative diseases, which include conditions such as Alzheimer disease (AD) Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), vascular dementia and multiple sclerosis (MS), are a class of progressive disorders defined by neuronal death. Each of these disorders is characterized by degeneration of distinct brain areas, and they present with overlapping but discrete symptoms that can include motor impairment, cognitive dysfunction, affective changes and/or dementia. With the exception of rare familial cases, the aetiopathogenic origins of these diseases are poorly understood; however, two common factors seem to be neuroinflammation and epidemiological links to viral infections1.

알츠하이머병(AD) 파킨슨병(PD), 근위축성 측삭 경화증(ALS), 혈관성 치매, 다발성 경화증(MS) 등의 질환을 포함하는 신경 퇴행성 질환은 신경세포의 죽음으로 정의되는 진행성 장애의 한 종류입니다. 이러한 각 질환은 서로 다른 뇌 영역의 퇴행이 특징이며, 운동 장애, 인지 기능 장애, 정서 변화 및/또는 치매를 포함하여 중복되지만 개별적인 증상을 나타냅니다. 드문 가족성 사례를 제외하고는 이러한 질환의 발병 기전에 대해 잘 알려져 있지 않지만, 두 가지 공통적인 요인은 신경 염증과 바이러스 감염과의 역학적 연관성인 것으로 보입니다1.

Neuroinflammation was originally thought to be a consequence of neurodegeneration; however, subsequent research indicated that neuroinflammation can drive the onset and progression of neurodegenerative diseases. The idea of neuroinflammation as a driver of neurodegeneration was advanced by genome-wide association studies (GWAS) that identified immune-related genes, including CD33 and TREM2, as risk factors for AD2. In addition, the ε4 allele of the apolipoprotein E gene (APOE ε4), which is the strongest known genetic risk factor for AD and accounts for approximately 10–20% of the risk of late-onset disease, has been hypothesized to exert its effects partially through neuroinflammatory processes3. These genetic factors increase the risk of developing neurodegenerative disease but are not sufficient to cause disease on their own. Instead, genetic risk factors are likely to work with environmental factors that underlie sporadic forms of neurodegenerative disease.

신경염증은 원래 신경 퇴화의 결과로 생각되었지만, 후속 연구에 따르면 신경염증이 신경 퇴행성 질환의 발병과 진행을 촉진할 수 있는 것으로 나타났습니다. 신경염증이 신경 퇴행의 원인이라는 생각은 CD33 및 TREM2를 포함한 면역 관련 유전자를 AD2의 위험 요인으로 확인한 게놈 전체 연관성 연구(GWAS)를 통해 더욱 발전했습니다. 또한, 아포지단백 E 유전자(APOE ε4)의 ε4 대립 유전자는 알츠하이머병의 가장 강력한 유전적 위험 인자이며 후기 발병 위험의 약 10~20%를 차지하는데, 이는 부분적으로 신경 염증 과정을 통해 그 효과를 발휘한다는 가설이 제기되었습니다3. 이러한 유전적 요인은 신경 퇴행성 질환의 발병 위험을 증가시키지만 그 자체로는 질병을 유발하기에 충분하지 않습니다. 대신, 유전적 위험 요인은 산발적인 형태의 신경 퇴행성 질환의 근간이 되는 환경적 요인과 함께 작용할 가능성이 높습니다.

In a recent study, Kristin Levine and colleagues mined medical record data and found that viral infections were associated with an increased risk of several neurodegenerative diseases4 (Table 1). This study is the most expansive of its nature, eval‎uating various viral agents and several neurodegenerative diseases from two different datasets: a nationwide Finnish biobank including over 300,000 individuals and a second biobank from the UK with data from nearly 500,000 individuals. Whereas previous studies generally focused on one disease and/or a single viral pathogen, Levine et al. probed medical records for associations between six neurodegenerative diseases — AD, ALS, generalized dementia, MS, PD and vascular dementia — and multiple viral pathogens. The strongest association found was between AD and viral encephalitis, although the exact virus was not identified. Influenza and pneumonia together showed significant associations with all the diseases examined except for MS. A previously reported association between Epstein–Barr virus (EBV) infection and MS5 was replicated using the Finnish but not the UK dataset. This discrepancy might be attributable to differences between countries in how illnesses are reported in medical records4.

크리스틴 레빈과 동료들은 최근 연구에서 의료 기록 데이터를 마이닝하여 바이러스 감염이 여러 신경 퇴행성 질환의 위험 증가와 관련이 있다는 사실을 발견했습니다4(표 1). 이 연구는 30만 명 이상의 개인이 포함된 핀란드의 전국적인 바이오뱅크와 약 50만 명의 데이터가 포함된 영국의 두 번째 바이오뱅크 등 두 개의 서로 다른 데이터 세트에서 다양한 바이러스와 여러 신경 퇴행성 질환을 평가한 가장 광범위한 연구입니다. 이전 연구는 일반적으로 한 가지 질병 및/또는 단일 바이러스 병원체에 초점을 맞춘 반면, 레빈 등은 6가지 신경 퇴행성 질환(AD, ALS, 전신성 치매, MS, PD, 혈관성 치매)과 여러 바이러스 병원체 간의 연관성을 의료 기록을 통해 조사했습니다. 정확한 바이러스는 밝혀지지 않았지만 알츠하이머병과 바이러스성 뇌염 사이에 가장 강력한 연관성이 발견되었습니다. 인플루엔자와 폐렴은 다발성 경화증을 제외한 모든 조사 대상 질환과 유의미한 연관성을 보였습니다. 이전에 보고된 엡스타인-바 바이러스(EBV) 감염과 MS5 사이의 연관성은 영국 데이터셋이 아닌 핀란드 데이터셋을 사용하여 복제되었습니다. 이러한 불일치는 의료 기록에 질병이 보고되는 방식에서 국가 간 차이가 있기 때문일 수 있습니다4.

Table 1 Viral infections linked to neurodegenerative diseases

Full size table

“The strongest association found was between AD and viral encephalitis”

알츠하이머 치매 - 인플루엔자, 폐렴, intestinal 감염, 수막염, viral encephalitis

루게릭병 - human papilloma virus

generalized 치매 - 인플루엔자, 폐렴, viral encephalitis

다발성 경화증 - 앱스테인바 바이러스, herpes simplex virus, 바리셀라 조스터 바이러스

파킨슨 병 - c형 간염바이러스, 인플루엔자, 폐렴

The hypothesis that viral pathogens are an environmental risk factor for neurodegenerative diseases is not new, but it has gained support in recent years. Adding to the aforementioned GWAS data highlighting the role of immune genes in AD risk2, a multiomic study identified increased levels of genomic DNA from human herpesvirus 6A and 7 in the brains of patients with AD compared with cognitively healthy controls, and viral abundance correlated with transcriptomic signatures linked to amyloid-β (Aβ) processing6. Another study published at the same time showed that, in a mouse model that developed Aβ pathology, infection with herpes simplex virus 1 (HSV1) directly incited and accelerated Aβ deposition7. Together, these data reinvigorated the microbial aetiology hypothesis of AD.

바이러스성 병원체가 신경 퇴행성 질환의 환경적 위험 요인이라는 가설은 새로운 것은 아니지만, 최근 몇 년 동안 지지를 얻고 있습니다. 앞서 언급한 알츠하이머병 위험에서 면역 유전자의 역할을 강조하는 GWAS 데이터에 더해2, 한 다중 유전체 연구에서 인지적으로 건강한 대조군에 비해 알츠하이머병 환자의 뇌에서 인간 헤르페스 바이러스 6A 및 7의 유전체 DNA 수준이 증가하고, 바이러스 풍부도가 아밀로이드-β(Aβ) 처리와 관련된 전사체 시그니처와 상관관계가 있는 것으로 확인되었습니다6. 같은 시기에 발표된 또 다른 연구에서는 Aβ 병리가 발생한 마우스 모델에서 단순포진 바이러스 1(HSV1)에 감염되면 Aβ 침착이 직접적으로 유발되고 가속화된다는 사실이 밝혀졌습니다7. 이러한 데이터를 통해 알츠하이머병의 미생물 병인 가설이 다시 힘을 얻게 되었습니다.

In 2021, we reviewed the evidence that microbial pathogens are a risk factor for neurodegenerative diseases1, and several studies have since been published that support this hypothesis. Following on from the preclinical study highlighted above7, HSV1 has been an important focus of clinical research into the link between viral infections and AD. A large population-based cohort study in northern Sweden8, in which the patient population was selected on the basis of positive HSV1 carrier status and matched for sex and APOE ε4 status, found that treatment with an antiviral drug reduced the relative risk of developing AD by approximately 70%.

2021년에는 미생물 병원체가 신경 퇴행성 질환의 위험 인자라는 증거를 검토했으며1, 이후 이 가설을 뒷받침하는 여러 연구가 발표되었습니다. 위에서 살펴본 전임상 연구7에 이어, 바이러스 감염과 알츠하이머병의 연관성에 대한 임상 연구의 중요한 초점이 되고 있는 것은 HSV1입니다. 스웨덴 북부에서 실시된 대규모 인구 기반 코호트 연구8에서는 HSV1 보균자 양성 여부에 따라 환자군을 선정하고 성별과 APOE ε4 상태를 일치시킨 결과, 항바이러스제 치료가 AD 발병의 상대적 위험을 약 70% 감소시킨다는 사실이 밝혀졌습니다.

Another nested case–control study of several national registries in Sweden analysed the incidence of hospital-treated infections in individuals newly diagnosed with AD, PD or ALS9. To reduce the influence of surveillance bias, this study excluded infections experienced in the 5 years preceding diagnosis with a neurodegenerative disease. The results showed an increased risk of AD and PD, but not ALS, in individuals who experienced a hospital-treated infection 5 years or more earlier, and these associations persisted with infections treated 10 years or more before diagnosis. Multiple infections before the age of 40 years conveyed the greatest risk of AD and PD. This study found similar associations for bacterial, viral and other infections, but did not classify the data on the basis of specific infectious pathogens.

스웨덴의 여러 국가 레지스트리를 대상으로 한 또 다른 중첩 사례 관리 연구에서는 새로 루게릭병, 파킨슨병 또는 ALS 진단을 받은 개인의 병원 치료 감염 발생률을 분석했습니다9. 이 연구에서는 감시 편향의 영향을 줄이기 위해 신경 퇴행성 질환 진단 전 5년 동안 경험한 감염은 제외했습니다. 연구 결과, 5년 이상 이전에 병원 치료를 받은 감염을 경험한 사람에서 루게릭병은 아니지만 AD와 PD의 위험이 증가했으며, 이러한 연관성은 진단 전 10년 이상 치료받은 감염에서도 지속되었습니다. 40세 이전에 여러 번 감염된 경우 루게릭병과 파킨슨병의 위험이 가장 컸습니다. 이 연구에서는 박테리아, 바이러스 및 기타 감염에 대해서도 유사한 연관성을 발견했지만 특정 감염 병원체를 기준으로 데이터를 분류하지는 않았습니다.

In a cohort study of more than 10 million US military personnel on active duty, infection with EBV, but not other viruses including cytomegalovirus, significantly increased the risk of MS5. Another study identified clonally expanded CD8+ T cells specific for EBV antigens in the cerebrospinal fluid of patients with AD, although this study did not speculate on a causative link between EBV infection and AD incidence10.

현역 미군 천만 명 이상을 대상으로 한 코호트 연구에서 거대세포바이러스를 포함한 다른 바이러스는 아니지만 EBV에 감염되면 MS5의 위험이 크게 증가했습니다. 또 다른 연구에서는 알츠하이머병 환자의 뇌척수액에서 EBV 항원에 특이적인 클론적으로 확장된 CD8+ T 세포를 확인했지만, 이 연구에서는 EBV 감염과 알츠하이머병 발병 사이의 인과 관계를 추측하지는 못했습니다10.

The brain is protected from most viral pathogens by the blood–brain barrier, but neurotropic viruses can subvert these protective measures to infect cells of the nervous system. Interestingly, the majority of associations identified in the study by Levine et al.4 involved viruses that are considered to be neurotropic, including HSV, varicella zoster virus (VZV), some strains of influenza virus, and viruses that cause encephalitis or meningitis. The most common causes of viral encephalitis are HSV, VZV and West Nile virus, and although neurotropic viruses have long been recognized to cause post-infectious cognitive dysfunction, it is less clear whether these viruses cause classic neurodegenerative diseases.

뇌는 혈액-뇌 장벽에 의해 대부분의 바이러스 병원체로부터 보호되지만, 신경성 바이러스는 이러한 보호 조치를 무력화하여 신경계 세포를 감염시킬 수 있습니다. 흥미롭게도 Levine 등의 연구에서 확인된 대부분의 연관성은 HSV, 수두 대상포진 바이러스(VZV), 일부 인플루엔자 바이러스 균주, 뇌염 또는 수막염을 유발하는 바이러스 등 신경성 바이러스로 간주되는 바이러스와 관련이 있습니다. 바이러스성 뇌염의 가장 흔한 원인은 HSV, VZV 및 웨스트 나일 바이러스이며, 신경 영양성 바이러스가 감염 후 인지 기능 장애를 유발하는 것으로 오랫동안 알려져 왔지만 이러한 바이러스가 전형적인 신경 퇴행성 질환을 유발하는지 여부는 명확하지 않습니다.

“the majority of associations identified […] involved viruses that are considered to be neurotropic”

Emerging infections should also be monitored for possible relationships with neurodegenerative disease. For example, SARS-CoV-2, the viral cause of COVID-19, primarily manifests as a respiratory infection but is also linked to cognitive dysfunction. Whether this dysfunction is attributable to viral entry into the brain or to widespread inflammation that affects brain function is not fully understood. Considering the strong association between influenza and pneumonia and several neurodegenerative diseases, future studies should examine the potential links between SARS-CoV-2 and these diseases and explore the molecular and cellular mechanisms that underlie these associations.

신종 감염도 신경 퇴행성 질환과의 연관성이 있는지 모니터링해야 합니다. 예를 들어, COVID-19의 바이러스 원인인 SARS-CoV-2는 주로 호흡기 감염으로 나타나지만 인지 기능 장애와도 관련이 있습니다. 이러한 기능 장애가 바이러스가 뇌에 침투하기 때문인지, 아니면 뇌 기능에 영향을 미치는 광범위한 염증 때문인지는 아직 완전히 밝혀지지 않았습니다. 인플루엔자 및 폐렴과 여러 신경 퇴행성 질환 사이의 강력한 연관성을 고려할 때, 향후 연구에서는 SARS-CoV-2와 이러한 질환 사이의 잠재적 연관성을 조사하고 이러한 연관성의 기초가 되는 분자 및 세포 메커니즘을 탐구해야 합니다.

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