T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses

Garber, Charise; Soung, Allison; Vollmer, Lauren L.; Kanmogne, Marlene; Brown, Jasmine; Klein, Robyn S.

doi:10.1038/s41593-019-0427-y

Cited by 189 publications

(218 citation statements)

References 50 publications

Supporting

Mentioning

209

Contrasting

Order By: Relevance

“…This was also reported in fetal human brains, where an infiltration of T and B cells was observed in the perivascular space during ZIKV infection (Figure 2) (113). Lymphocytic infiltrates are observed in neonatal and adult mouse models of ZIKV infections (143,148), however an infiltration of monocytes or granulocytes could not be observed in infected human brain parenchyma or animal models. In the perivascular space of infected human fetuses, lymphocytic and monocytic accumulations were described and summarized as signs of meningitis.…”

Section: Zika Virus (Zikv)supporting

confidence: 68%

“…This specific location together with a resulting reduced Homer-1 expression in synapses let to the speculation that ZIKV infection of hippocampal NPCs leads to cognitive decline in infected adult A variety of pathogens responsible for congenital and postnatal CNS infection, the time in which most of the CNS infections occur, the routes of infection and the CNS pathology is shown. individuals (143). As already mentioned above, microglia were shown to have an activated phenotype in histological sections of human fetal brains and microglial nodules are described throughout the gray and white matter of the infected fetal CNS (Figure 2) (113).…”

Section: Zika Virus (Zikv)mentioning

confidence: 61%

See 1 more Smart Citation

CNS Macrophages and Infant Infections

et al. 2020

View full text Add to dashboard Cite

The central nervous system (CNS) harbors its own immune system composed of microglia in the parenchyma and CNS-associated macrophages (CAMs) in the perivascular space, leptomeninges, dura mater, and choroid plexus. Recent advances in understanding the CNS resident immune cells gave new insights into development, maturation and function of its immune guard. Microglia and CAMs undergo essential steps of differentiation and maturation triggered by environmental factors as well as intrinsic transcriptional programs throughout embryonic and postnatal development. These shaping steps allow the macrophages to adapt to their specific physiological function as first line of defense of the CNS and its interfaces. During infancy, the CNS might be targeted by a plethora of different pathogens which can cause severe tissue damage with potentially long reaching defects. Therefore, an efficient immune response of infant CNS macrophages is required even at these early stages to clear the infections but may also lead to detrimental consequences for the developing CNS. Here, we highlight the recent knowledge of the infant CNS immune system during embryonic and postnatal infections and the consequences for the developing CNS.

show abstract

Section: Zika Virus (Zikv)supporting

confidence: 68%

Section: Zika Virus (Zikv)mentioning

confidence: 61%

CNS Macrophages and Infant Infections

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A detailed analysis of the temporal course of microglia activation could bring further evidence for such a hypothesis. Microglia and astrocytes interact in formation and elimination of synaptic connection [ 57 , 58 ], and in WNV infection, T cells promoted microglia-mediated synaptic elimination and cognitive dysfunction [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs

Cornelius

Hosseini

Schreier

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background Tick-borne encephalitis virus (TBEV) is an important human pathogen that can cause the serious illness tick-borne encephalitis (TBE). Patients with clinical symptoms can suffer from severe meningoencephalitis with sequelae that include cognitive disorders and paralysis. While less than 30% of patients with clinical symptoms develop meningoencephalitis, the number of seropositive individuals in some regions indicates a much higher prevalence of TBEV infections, either with no or subclinical symptoms. The functional relevance of these subclinical TBEV infections and their influence on brain functions, such as learning and memory, has not been investigated so far. Methods To compare the effect of low and high viral replication in the brain, wildtype and Irf-7−/− mice were infected with Langat virus (LGTV), which belongs to the TBEV-serogroup. The viral burden was analyzed in the olfactory bulb and the hippocampus. Open field, elevated plus maze, and Morris water maze experiments were performed to determine the impact on anxiety-like behavior, learning, and memory formation. Spine density of hippocampal neurons and activation of microglia and astrocytes were analyzed. Results In contrast to susceptible Irf-7−/− mice, wildtype mice showed no disease signs upon LGTV infection. Detection of viral RNA in the olfactory bulb revealed CNS infections in wildtype and Irf-7−/− mice. Very low levels of viral replication were detectable in the hippocampus of wildtype mice. Although wildtype mice develop no disease signs, they showed reduced anxiety-like behavior and impaired memory formation, whereas Irf-7−/− mice were not affected. This impairment was associated with a significant decrease in spine density of neurons in the hippocampal CA1 region of wildtype mice. Microglia activation and astrogliosis were detected in the hippocampus. Conclusion In this study, we demonstrate that subclinical infections by viruses from the TBEV-serogroup affected anxiety-like behavior. Virus replication in the olfactory bulb induced far-reaching effects on hippocampal neuron morphology and impaired hippocampus-dependent learning and memory formation.

show abstract

“…Abnormalities in synaptic pruning have been reported in many neurological disorders, brain injury, and viral infection (Garber et al, 2019;Gunner et al, 2019;Hong et al, 2016;Sellgren et al, 2019). To examine whether ZIKV exposure alters human microglial synaptic pruning function, we infected day 75 organoids, in which synapses have formed.…”

Section: Microglia Respond To Zika Virus (Zikv) Infection In Brain Ormentioning

confidence: 99%

Developing Human Pluripotent Stem Cell-Based Cerebral Organoids with a Controllable Microglia Ratio for Modeling Brain Development and Pathology

Boreland

et al. 2020

Preprint

View full text Add to dashboard Cite

Microglia, as the brain-resident macrophages, play critical roles in brain development, homeostasis, and disease. Microglia in animal models cannot accurately model the properties of human microglia, because there are due to notable transcriptomic and functional differences between human and other animal microglia at transcriptomic and functional levels. Efficient generation of microglia from human pluripotent stem cells (hPSCs) provides unprecedented opportunities to study the function and behavior of human microglia. Particularly, incorporating hPSCs-derived microglia into brain organoids facilitates their development in a 3-dimensional context, mimicking the brain environment. However, an optimized method that integrates an appropriate amount of microglia into brain organoids at a proper time point, similar to what is seen in vivo, is still needed. Here, we report the development of a new brain region-specific, microglia-containing organoid model by co-culturing hPSCs-derived primitive neural progenitor cells (pNPCs) and primitive macrophage progenitors (PMPs). In these organoids, hPSCs-derived pNPCs and PMPs interact with each other and develop into functional neurons, astroglia, and microglia, respectively. Importantly, the numbers of human microglia population in the organoids can be controlled, resulting in a cell type at a ratio similar to that seen in the human brain. Importantly, uUsing super-resolution microscopy, we demonstrate that these human microglia are able to phagocytize neural progenitor cells (NPCs) and dead cells, as well as to prune synapses at different developmental stages of the organoids. Furthermore, these human microglia respond to Zika virus infection in of the organoids, as indicated by exhibiting amoeboid-like morphology, an increased expression of gene transcripts encoding inflammatory cytokines, and excessive pruning of synaptic materials. ThusTogether, our findings establish a new microglia-containing brain organoid model that will serve to study human microglial function in a variety of neurological disorders.

show abstract

T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses

Cited by 189 publications

References 50 publications

CNS Macrophages and Infant Infections

CNS Macrophages and Infant Infections

Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs

Developing Human Pluripotent Stem Cell-Based Cerebral Organoids with a Controllable Microglia Ratio for Modeling Brain Development and Pathology

Contact Info

Product

Resources

About