SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways

Rothan, Hussin A.; Kumari, Pratima; Stone, Shannon; Natekar, Janhavi P; Arora, Komal; Auroni, Tabassum Tasnim; Kumar, Mukesh

doi:10.3390/pathogens11020257

Cited by 26 publications

(22 citation statements)

References 53 publications

(106 reference statements)

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“…In another hACE2 mouse study, with prominent microglial activation, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7 weeks post-infection, a feature also reported in human patients with long COVID syndrome [ 68 ]. Moreover, in vitro neuronal cell cultures of K18-hACE2 mouse neurons showed an upregulation of the expression of genes involved in innate immunity and inflammation [ 69 ]. An astrocytic SARS-CoV-2 infection, which was described in human brains and cultured astrocytes [ 36 ], could not be detected in any mouse brain with any virus variant in our study.…”

Section: Discussionmentioning

confidence: 99%

Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse

Seehusen

Clark

Sharma

et al. 2022

Viruses

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2), we investigated the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with SARS-CoV-2 variants, as well as after prior influenza A virus infection. Apart from Omicron, we found all variants to frequently spread to and within the CNS. Infection was restricted to neurons and appeared to spread from the olfactory bulb mainly in basally oriented regions in the brain and into the spinal cord, independent of ACE2 expression and without evidence of neuronal cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed, accompanied by apoptotic death of endothelial, microglial and immune cells, without their apparent infection. Microgliosis and immune cell apoptosis indicate a potential role of microglia for pathogenesis and viral effect in COVID-19 and the possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates and broadly support the investigation of agents with adequate penetration into relevant regions of the CNS.

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Section: Discussionmentioning

confidence: 99%

Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse

Seehusen

Clark

Sharma

et al. 2022

Viruses

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“…For instance, ZBP1-dependent PANoptosis restrict the viral loads of IAV and SARS-CoV-2 but caused severe inflammation and lung dysfunction in critical patients [ 23 , 95 ]. ZBP1-mediated brain cell death may be a key cause of the neuropathology during HSV-1 or SARS-CoV-2 infection [ 104 , 125 ]. In addition, the endogenous activation of ZBP1 causes multiple auto-inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

“…High dose infection or late infection with SARS-CoV-2 induce IFN-α/γ responses and the expression of ZBP1 [ 95 , 124 ]. In SARS-CoV-2 infected mice or BMDMs, the additional IFN-β inducing ZBP1 provokes PANoptosis via CASP1/3/7/8, GSDMD, GSDME, MLKL [ 75 , 95 , 125 ], and deletion of ZBP1 (ZBP1 −/− ) or Zα2 deficiency of ZBP1 (ZBP1 ΔZα2 ) substantially alleviated the inflammatory cell death and lethality of mice upon treatment with IFN and SARS-CoV-2 infection [ 95 ]. The ZBP1-mediated PANoptosis explains why non-early IFN treatment is not clinically helpful in treating SARS-CoV-2 infection [ 126 , 127 ].…”

Section: Zbp1 Signaling In Microbial Infectionmentioning

confidence: 99%

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

Hao

Yang

et al. 2022

IJMS

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Z-conformation nucleic acid binding protein 1 (ZBP1), a powerful innate immune sensor, has been identified as the important signaling initiation factor in innate immune response and the multiple inflammatory cell death known as PANoptosis. The initiation of ZBP1 signaling requires recognition of left-handed double-helix Z-nucleic acid (includes Z-DNA and Z-RNA) and subsequent signaling transduction depends on the interaction between ZBP1 and its adapter proteins, such as TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), and RIPK3. ZBP1 activated innate immunity, including type-I interferon (IFN-I) response and NF-κB signaling, constitutes an important line of defense against pathogenic infection. In addition, ZBP1-mediated PANoptosis is a double-edged sword in anti-infection, auto-inflammatory diseases, and tumor immunity. ZBP1-mediated PANoptosis is beneficial for eliminating infected cells and tumor cells, but abnormal or excessive PANoptosis can lead to a strong inflammatory response that is harmful to the host. Thus, pathogens and host have each developed multiplex tactics targeting ZBP1 signaling to maintain strong virulence or immune homeostasis. In this paper, we reviewed the mechanisms of ZBP1 signaling, the effects of ZBP1 signaling on host immunity and pathogen infection, and various antagonistic strategies of host and pathogen against ZBP1. We also discuss existent gaps regarding ZBP1 signaling and forecast potential directions for future research.

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“…In another hACE2 mouse study, with prominent microglial activation, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7 weeks post infection, a feature also reported in human patients with long COVID syndrome [68]. Also in vitro neuronal cell cultures of K18-hACE2 mouse neurons showed an upregulation of the expression of genes involved in innate immunity and inflammation [69]. An astrocytic SARS-CoV-2 infection which was described in human brains and cultured astrocytes [36] could not be detected in any mouse brain with any virus variant in our study.…”

Section: Discussionmentioning

confidence: 88%

Neuroinvasion and neurotropism by SARS-CoV-2 variants in the K18-hACE2 mouse

Seehusen

Clark

Sharma

et al. 2021

Preprint

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Coronavirus disease 2019 (COVID-19) is a primarily respiratory disease with variable clinical courses for which animal models are needed to gather insights into the pathogenesis of its causative virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), in human patients. SARS-CoV-2 not only affects the respiratory tract but also the central nervous system (CNS), leading to neurological symptoms such as loss of smell and taste, headache, fatigue or severe complications like cerebrovascular diseases. Transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) under the cytokeratin 18 promoter (K18-hACE2) represent a well-known model of SARS-CoV-2 infection. In the present study, it served to investigate the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with relatively low SARS-CoV-2 doses and after prior influenza A virus infection. In K18-hACE2 mice, SARS-CoV-2 was found to frequently spread to and within the CNS during the later phase (day 7) of infection. Infection was restricted to neurons and appeared to first affect the olfactory bulb and spread from there mainly in basally orientated regions in the brain and into the spinal cord, in a dose dependent manner and independent of ACE2 expression. Neuronal infection was not associated with cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed. This was accompanied by apoptotic death of endothelial, microglial and immune cells, without evidence of viral infection of glial cells, endothelial cells and leukocytes. Taken together, microgliosis and immune cell apoptosis indicate a potential important role of microglial cells for the pathogenesis and viral effect in COVID-19 and possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates, and broadly support investigation of agents with adequate penetration into relevant regions of the CNS.

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SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways

Cited by 26 publications

References 53 publications

Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse

Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

Neuroinvasion and neurotropism by SARS-CoV-2 variants in the K18-hACE2 mouse

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