Does Infection-Induced Immune Activation Contribute to Dementia?

Barichello, Tatiana; Generoso, Jaqueline S.; Goularte, Jéssica A.; Collodel, Allan; Pitcher, Meagan R.; Simões, Lutiana R.; Quevedo, João; Dal‐Pizzol, Felipe

doi:10.14336/ad.2015.0521

Cited by 36 publications

(25 citation statements)

References 102 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is a significant increase in the expression of anti-viral defense genes related to interferon signaling (IFI and IFIT families). Toll-like receptor signaling and NF-κB signaling were also upregulated indicating activation of innate immune response, increased inflammation and immune cell regulation, as host defense mechanisms [78][79][80][81]. Transcriptomic profiles of the brains of HIV infected patients and SIV infection macaques also displayed significant upregulation of interferon signaling and inflammation related pathways [24,[82][83][84][85].…”

Section: Discussionmentioning

confidence: 99%

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Mathews

Woods

Katano

et al. 2019

Mol Neurodegeneration

View full text Add to dashboard Cite

Background: Microglia are the principal innate immune defense cells of the centeral nervous system (CNS) and the target of the human immunodeficiency virus type one (HIV-1). A complete understanding of human microglial biology and function requires the cell's presence in a brain microenvironment. Lack of relevant animal models thus far has also precluded studies of HIV-1 infection. Productive viral infection in brain occurs only in human myeloid linage microglia and perivascular macrophages and requires cells present throughout the brain. Once infected, however, microglia become immune competent serving as sources of cellular neurotoxic factors leading to disrupted brain homeostasis and neurodegeneration.Methods: Herein, we created a humanized bone-marrow chimera producing human "microglia like" cells in NOD. Cg-Prkdc scid Il2rg tm1Sug Tg(CMV-IL34)1/Jic mice. Newborn mice were engrafted intrahepatically with umbilical cord blood derived CD34+ hematopoietic stem progenitor cells (HSPC). After 3 months of stable engraftment, animals were infected with HIV-1 ADA , a myeloid-specific tropic viral isolate. Virologic, immune and brain immunohistology were performed on blood, peripheral lymphoid tissues, and brain.Results: Human interleukin-34 under the control of the cytomegalovirus promoter inserted in NSG mouse strain drove brain reconstitution of HSPC derived peripheral macrophages into microglial-like cells. These human cells expressed canonical human microglial cell markers that included CD14, CD68, CD163, CD11b, ITGB2, CX3CR1, CSFR1, TREM2 and P2RY12. Prior restriction to HIV-1 infection in the rodent brain rested on an inability to reconstitute human microglia. Thus, the natural emergence of these cells from ingressed peripheral macrophages to the brain could allow, for the first time, the study of a CNS viral reservoir. To this end we monitored HIV-1 infection in a rodent brain. Viral RNA and HIV-1p24 antigens were readily observed in infected brain tissues. Deep RNA sequencing of these infected mice and differential expression analysis revealed human-specific molecular signatures representative of antiviral and neuroinflammatory responses.Conclusions: This humanized microglia mouse reflected human HIV-1 infection in its known principal reservoir and showed the development of disease-specific innate immune inflammatory and neurotoxic responses mirroring what can occur in an infected human brain.

show abstract

Section: Discussionmentioning

confidence: 99%

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Mathews

Woods

Katano

et al. 2019

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

“…Within mammalian cells, TLRs are known to be expressed on a variety of cell types including numerous immune cell types (Gay et al, 2014;Achek et al, 2016). However, it is now known that TLRs are expressed in cells of the central nervous system (CNS) with expression initially proposed to be in astrocytes, microglia and oligodendrocytes but it is now established that neurons and neuronal progenitor cells also express TLRs (Okun et al, 2011;Barichello et al, 2015). TLRs have been proposed to play a role in CNS diseases including Alzheimer's disease, Parkinson's disease and multiple sclerosis (Lucas et al, 2006) implicating TLRs as therapeutic targets in these diseases (Gambuzza et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…TLRs have been proposed to play a role in CNS diseases including Alzheimer's disease, Parkinson's disease and multiple sclerosis (Lucas et al, 2006) implicating TLRs as therapeutic targets in these diseases (Gambuzza et al, 2014). In addition, TLRs have been implicated in neurodevelopment including modulating neural precursor cell proliferation and fate, adult neurogenesis and neurite outgrowth (Bsibi et al, 2010;Barichello et al, 2015, Vontell et al, 2015. Indeed, one TLR that has been implicated in both neuronal development and CNS disease is TLR3.…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons

et al. 2018

View full text Add to dashboard Cite

Toll like receptor 3 (TLR3) belongs to a family of pattern recognition receptors that recognise molecules found on pathogens referred to as pathogen associated molecular patterns (PAMPs). Its involvement in innate immunity is well known but despite its presence in the central nervous system (CNS), our knowledge of its function is limited. Here, we have investigated whether TLR3 activation modulates synaptic activity in primary hippocampal cultures and induced pluripotent stem cell (iPSC)-derived neurons. Synaptically driven spontaneous action potential (AP) firing was significantly reduced by the TLR3 specific activator, poly I:C, in a concentration-dependent manner following both short (5 min) and long exposures (1h) in rat hippocampal cultures. Notably, the consequence of TLR3 activation on neuronal function was reproduced in iPSC-derived cortical neurons, with poly I:C (25 μg/ml, 1h) significantly inhibiting sAP firing. We examined the mechanisms underlying these effects, with poly I:C significantly reducing peak sodium current, an effect dependent on the MyD88-independent TRIF dependent pathway. Furthermore, poly I:C (25 μg/ml, 1h) resulted in a significant reduction in miniature excitatory postsynaptic potential (mEPSC) frequency and amplitude and significantly reduced surface AMPAR expression. These novel findings reveal that TLR3 activation inhibits neuronal excitability and synaptic activity through multiple mechanisms, with this being observed in both rat and human iPSC-derived neurons. These data might provide further insight into how TLR3 activation may contribute to neurodevelopmental disorders following maternal infection and in patients with increased susceptibility to herpes simplex encephalitis.

show abstract

“…While many other functions are recognised, for example relating to beta-amyloid, cholesterol, lipid and glucose metabolism or diabetes, inter alia [1][2][3][4], the properties isolated in this table focus specifically on immune and pathogen-related effects. The relationship between AD genes, the immune system and inflammation has also previously emphasised [5] and in a recent study from the Alzheimer's Disease Neuroimaging Initiative, another subset of Alzheimer's disease genes showed genetic overlap between Alzheimer's disease and immune-mediated diseases [6] .…”

Section: Supplementary Tablementioning

confidence: 99%

Genetic, transcriptome, proteomic and epidemiological evidence for blood brain barrier disruption and polymicrobial brain invasion as determinant factors in Alzheimer’s disease

Carter

2016

Preprint

View full text Add to dashboard Cite

Multiple pathogens have been detected in Alzheimer’s disease (AD) brains. A bioinformatics approach was used to assess relationships between pathogens and AD genes (GWAS), the AD hippocampal transcriptome and plaque or tangle proteins. Host/pathogen interactomes (C.albicans, C.Neoformans, Bornavirus, B.Burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, C.Pneumoniae, P.Gingivalis, H.Pylori, T.Gondii, T.Cruzi) significantly overlap with misregulated AD hippocampal genes, with plaque and tangle proteins and, except Bornavirus, Ebola and HERV-W, with AD genes. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi or protozoa in immunocompetent blood cells. AD genes are enriched in bone marrow and immune locations and in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance. The age of AD patients implies resistance to infections afflicting the younger. APOE4 protects against malaria and hepatitis C, and immune/inflammatory gain of function applies to APOE4, CR1, TREM2 and presenilin variants. 30/78 AD genes are expressed in the blood brain barrier (BBB), which is disrupted by AD risk factors (ageing, alcohol, aluminium, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolaemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption and smoking). The BBB and AD benefit from statins, NSAIDs, oestrogen, melatonin and the Mediterranean diet. Polymicrobial involvement is supported by the upregulation of pathogen sensors/defenders (bacterial, fungal, viral) in the AD brain, blood or CSF. Cerebral pathogen invasion permitted by BBB inadequacy, activating a hyper-efficient immune/inflammatory system, betaamyloid and other antimicrobial defence may be responsible for AD which may respond to antibiotic, antifungal or antiviral therapy.

show abstract

Does Infection-Induced Immune Activation Contribute to Dementia?

Cited by 36 publications

References 102 publications

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons

Genetic, transcriptome, proteomic and epidemiological evidence for blood brain barrier disruption and polymicrobial brain invasion as determinant factors in Alzheimer’s disease

Contact Info

Product

Resources

About