TREM2 Protects the Brain From Herpes. The Virus Fights Back.

Retroviruses lurking in the human genome aren’t the only potential troublemakers in neurodegenerative diseases (see Part 5 of this series). Herpes simplex virus type 1 (HSV-1) integrates into the genome of trigeminal ganglia nerves, can lie dormant for decades, and flare up as cold sores throughout a person’s life. Infection with this virus has been epidemiologically tied to a higher risk of developing Alzheimer’s disease. As more laboratories around the world are investigating the herpes virus hypothesis in search of mechanistic explanations for AD, one lab is now implicating TREM2 signaling.

  • More epidemiological evidence links herpes infection to AD risk.
  • HSV turns down the TREM2 pathway in microglia, hobbling the innate antiviral defense.
  • Carriers of a C21ORF91 variant who get frequent cold sores are at higher risk of AD.
  • ApoE4 helps HSV particles bud from host cells.

The microglial receptor helps the cells fend off HSV-1 infection, while the virus quiets the antiviral signaling triggered by TREM2 post-infection, according to Stefanie Fruhwürth and Søren Paludan, University of Gothenburg, Sweden. At the International Conference on Alzheimer’s and Parkinson’s Diseases, held March 28 to April 1 in Gothenburg, Fruhwürth reported that TREM2 deficiency made mice and cultured human microglia more susceptible to herpes infection. In turn, herpes-infected microglia downregulated genes in the TREM2 pathway and in a downstream antiviral sensing pathway; this reduced the cells’ ability to detect and prune infected neurons.

Other AD/PD presentations associated genetic susceptibility to developing cold sores with increased AD risk, and ApoE4 with newly formed viral particle budding on cell membranes.

“These presentations provided important new insights into the mechanistic interplay between HSV1 and TREM2 and APOE, respectively, and thereby contributed to our understanding of the mechanisms by which HSV1 could drive AD processes,” wrote Hugo Lövheim of Umeå University, Sweden. “Direct mechanistic links to known AD risk-associated genes/proteins strengthen the HSV1-AD hypothesis.”

People infected with HSV1 have been reported to have a 1.5- to 2.7-fold higher risk of developing dementia, yet an 11 percent lower risk if they have taken an HSV antiviral drug (Feb 2021 news; Apr 2021 news). At AD/PD, Erika Vestin in Bodil Weidung’s lab at Sweden’s Uppsala University added to this data. She showed that, among 1,002 cognitively normal septuagenarians from Uppsala’s PIVUS longitudinal population-based cohort, those who were seropositive for HSV1 were twice as likely to develop dementia over 15 years, but those who took anti-herpes medication were not at greater risk. Separately, a pilot trial in 33 people with early AD who took valacyclovir for a month saw their Mini-Mental State Exam scores rise one point (Weidung et al., 2022).

But what are the mechanisms by which HSV can set the stage for dementia? Researchers have seen virus trigger amyloidosis, tauopathy, and neuron death in three-dimensional human neuron cultures and mouse models (May 2020 news; Jun 2018 news). Some think Aβ may be antiviral, forming sticky nets to ensnare HSV particles.

At AD/PD, Fruhwürth added TREM2 modulation to HSV’s hit list. To study the role of human microglia during HSV1 infection, she analyzed RNA sequencing data from infected iPSC-derived microglia. The most upregulated genes were antiviral and proinflammatory, including IL-6, IFN-β, and TNF-α.

Among the most downregulated genes were APOE, TREM2, DAP12, and SYK. They caught Fruhwürth’s eye because loss-of-function mutations in TREM2 increase AD risk. DAP12 and SYK are part of the receptor’s signaling pathway. Fruhwürth then discovered that, once infected with HSV, microglia expressed almost no Trem2 protein, and that stimulating the receptor with the agonistic antibody AF1828 boosted the microglia’s antiviral response by ramping up their expression of IL-6, IFN-β, and TNF-α. In contrast, blocking SYK, a protein kinase downstream of TREM2, with the selective inhibitor ER 27319 decreased expression of those antiviral genes.

HSV Halts Antiviral Cascade. When HSV infects neurons (left), microglia sense the virus and spew interferons and cytokines. Within microglia (right), the DNA sensor cGAS detects HSV DNA, activating the antiviral STING pathway to increase transcription of interferon-β, interleukin-6, and tumor necrosis factor-α. But HSV turns down TREM2 signaling, hobbling both the STING cascade and phagocytosis of infected neurons. [Courtesy of Fruhwürth et al., bioRxiv, 2022.]

SYK also functions in the cGAS-STING innate antiviral signaling pathway. Within microglia, the DNA sensor cyclic GMP-AMP synthase (cGAS) lies in wait of viral DNA, churning out cGAMP upon binding HSV DNA. This activates the stimulator of interferon genes (STING) pathway that, as its name suggests, ups transcription of antiviral interferons and inflammatory cytokines, such as IFN-β, IL-6, and TNF-α (see image above). Therefore, tamping down TREM2 signaling stunts both SYK activation and antiviral sensing.

Indeed, knocking down TREM2 by RNA interference rendered the microglia more prone to HSV1 infection. These microglia had abnormally low expression of the antiviral IL-6, IFN-β, and TNF-α genes and double the HSV titers as infected wild-type cells. What’s more, TREM2 knockdown microglia barely nibbled at infected neurons, engulfing 60 percent fewer fluorescently labeled human iPSC-derived neurons infected with HSV1 than did wild-type microglia (see image below).

Less TREM2, Less Appetite. Compared to wild-type human microglia (top), TREM2 knockdown cells (bottom) phagocytosed fewer HSV1-infected neurons (red). [Courtesy of Fruhwürth et al., bioRxiv, 2022.]

What about in vivo? Fruhwürth infected the brainstems of wild-type mice by injecting HSV1 into their eyes; four days later, TREM2 expression was halved. When she infected TREM2 knockout mice, they had twice as much virus in their brainstems as did infected wild-type mice.

Fruhwürth believes TREM2 loss-of-function variants that increase AD risk, such as R47H, may predispose a person to HSV1 infection. This could explain the higher prevalence of HSV1 seropositivity in people with AD. She is now studying how HSV1 infection affects iPSC-derived microglia engineered to carry R47H TREM2.

To learn if TREM2 downregulation is a broader phenomenon, Fruhwürth is investigating if other neurotropic viruses, such as varicella-zoster and cytomegalovirus, interfere with its expression.

It’s Not All About TREM2
Could susceptibility to HSV infection via other gene variants also fuel AD pathogeneis? People who carry a certain variant of C21ORF91 frequently get cold sores (Kriesel et al., 2011). Karin Lopatko Lindman in Lövheim’s lab analyzed blood samples and medical records from 1,244 cognitively normal adults and 331 with AD diagnosed at an average age of 71. She showed on an AD/PD poster that C21ORF91 variant carriers were twice as likely to get AD over a decade as were people without this variant. Curiously, she only saw this for APOE4 noncarriers. Lindman wasn’t sure what to make of this. “Our findings may reflect the complex genetics of AD,” she wrote to Alzforum. Lövheim agreed that this could be due to APOE4 being such a strong risk allele that minor variants show no effect in this type of study among E4 carriers.

APOE genotype has been linked to HSV susceptibility. For example, APOE4 transgenic mice have higher brain viral burdens than E3 mice (Jan 2021 news). At AD/PD, Lifeng Liu in Marta Bally’s group, also at Umeå U, found much the same in green monkey kidney (GMK) cells, commonly used to study HSV (Liu et al., 2023). Adding human ApoE3 or E4, but not E2, proteins to HSV1-infected GMK cells boosted HSV1 titers and accelerated how quickly titers rose. Liu thinks this is because ApoE3 and E4 bind to, and become incorporated into, virus particles budding on the outer membrane of GMK cells, enabling their release. This could explain the higher viral burden seen in the APOE4 mice, and could be explored in human cells, as well.

Even as the circle of scientists who are studying common neurotropic viruses in Alzheimer’s is widening (e.g., Wennberg et al., 2023), the idea that the viruses play an important role in this disease is far from generally accepted. Some research groups find little to no evidence of higher AD risk, of elevated viral loads in the brains of people who had AD, or, indeed, of the proposed antiviral effect proposed for Aβ (Jan 2021 news; Jan 2020 news; Bocharova et al., 2023).—Chelsea Weidman Burke

News Citations

  1. Attack From Within: How Ancient Viruses Resurface to Spread Tau
  2. Herpes Update—Virus Increases Dementia Risk in Sweden
  3. More Data on Herpes and Alzheimer’s Disease
  4. Herpes Simplex Virus Triggers Amyloidosis in 3D Neural Cultures
  5. Herpes Triggers Amyloid—Could This Virus Fuel Alzheimer’s?
  6. APOE Tied to Increased Susceptibility to SARS-CoV-2
  7. New Data Questions Herpes-Alzheimer’s Connection
  8. Herpes Viruses and Alzheimer’s—The Debate Continues

Therapeutics Citations

  1. Valacyclovir

Mutation Interactive Images Citations

  1. TREM2

Mutations Citations

  1. TREM2 R47H

Paper Citations

  1. .
    VALZ-Pilot: High-dose valacyclovir treatment in patients with early-stage Alzheimer’s disease.
    Alzheimers Dement (N Y). 2022;8(1):e12264. Epub 2022 Mar 14
    PubMed.
  2. .
    C21orf91 genotypes correlate with herpes simplex labialis (cold sore) frequency: description of a cold sore susceptibility gene.
    J Infect Dis. 2011 Dec 1;204(11):1654-62.
    PubMed.
  3. .
    Recruitment of apolipoprotein E facilitates Herpes simplex virus 1 release.
    2023 Feb 10 10.1101/2023.02.10.526562
    (version 1)
    bioRxiv.
  4. .
    Association of common infections with cognitive performance in the Baltimore Epidemiologic Catchment Area study follow-up.
    Alzheimers Dement. 2023 Apr 7;
    PubMed.
  5. .
    Aβ plaques do not protect against HSV-1 infection in a mouse model of familial Alzheimer’s disease, and HSV-1 does not induce Aβ pathology in a model of late onset Alzheimer’s disease.
    Brain Pathol. 2023 Jan;33(1):e13116. Epub 2022 Sep 5
    PubMed.

No Available Further Reading

Read more here: Source link

Join us at CRISPR workshops in Koper, Slovenia in 2024. Erasmus+ funds available!
This is default text for notification bar