Neuroinvasion and encephalitis following intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice

Kumari, Pratima; Rothan, Hussin A.; Natekar, Janhavi P; Stone, Shannon; Pathak, Heather; Strate, Philip G; Arora, Komal; Brinton, Margo A.; Kumar, Mukesh

doi:10.1101/2020.12.14.422714

Cited by 92 publications

(77 citation statements)

References 46 publications

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“…Virus titer in hACE2-lentivirus transduced mice lung were comparable to other studies using mice transduced with Ad5 or AAV expressing hACE2 (10, 17, 18). These transduction methodologies avoid the fulminant brain infection seen in K18-hACE2 mice, with infection of this organ the major contributor to mortality in the K18-hACE2 model (78, 79). The key advantage of lentiviral over adenoviral systems is the integration of the lentiviral payload into the host cell genome, thereby providing long-term stable expression.…”

Section: Discussionmentioning

confidence: 99%

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

Rawle

Dumenil

et al. 2021

Preprint

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SARS-CoV-2 uses the human ACE2 receptor (hACE2), with mouse ACE2 (mACE2) unable to support infection. Herein we describe an ACE2-lentivirus system and illustrate its utility in vitro and in vivo. Transduction of non-permissive cell lines with hACE2 imparted replication competence, and transduction with mACE2 containing N30D, N31K, F83Y and H353K mutations, to match hACE2, rescued SARS-CoV-2 replication. hACE2-lentivirus transduction of C57BL/6J, IFNAR-/- and IL-28RA-/- mice lungs indicated type I and III IFN receptor knockout had minimal effect on virus replication. However, RNA-Seq illustrated that they were required for inflammatory responses in C57BL/6J mice, which were similar to those seen in COVID-19 patients. Finally, we illustrate the utility of hACE2 transduction for vaccine evaluation in C57BL/6J mice. The hACE2-lentivirus system thus has broad application in SARS-CoV-2 research, in particular allowing access to GM mice, while also offering the inherent advantages of lentiviral transduction such as stable genomic integration.

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Section: Discussionmentioning

confidence: 99%

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

Rawle

Dumenil

et al. 2021

Preprint

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“…Початок тяжкого захворювання в інфікованих мишей корелював з піковими рівнями вірусу в головному мозку, при цьому вони були приблизно в 1000 разів вище, ніж пікові титри в легенях, що свідчить про високий реплікативний потенціал SARS-CoV-2 у мозку. Відносна регуляція мРНК цитокінів і хемокінів була приблизно в 10-50 разів вище в мозку порівняно з легенями, що переконливо свідчить про те, що велике нейрозапалення, яке супроводжується інфільтрацією лейкоцитів, кровотечею і загибеллю нейрональних клітин, сприяло клінічному захворюванню в цих мишей [12].…”

Section: пряме пошкодження вірусом а нейрогенний шляхunclassified

“…Тривалі дослідження продемонстрували, що вплив SARS-CoV-2 на головний, спинний мозок і периферичні нерви може бути особливо руйнівним і сприяти порушенням жит-тєдіяльності організму навіть після елімінації вірусу. У проведених експериментальних дослідженнях виявлено тривале персистування вірусу в центральній нервовій системі (ЦНС) [12].…”

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Дзяк¹,

Tsurkalenko²,

Chekha³

et al. 2021

INJ

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Coronavirus infection is a systemic pathology resulting in impairment of the nervous system. The involvement of the central nervous system in COVID-19 is diverse by clinical manifestations and main mechanisms. The mechanisms of interrelations between SARS-CoV-2 and the nervous system include a direct virus-induced lesion of the central nervous system, inflammatory-mediated impairment, thrombus burden, and impairment caused by hypoxia and homeostasis. Due to the multi-factor mechanisms (viral, immune, hypoxic, hypercoagulation), the SARS-CoV-2 infection can cause a wide range of neurological disorders involving both the central and peripheral nervous system and end organs. Dizziness, headache, altered level of consciousness, acute cerebrovascular diseases, hypogeusia, hyposmia, peripheral neuropathies, sleep disorders, delirium, neuralgia, myalgia are the most common signs. The structural and functional changes in various organs and systems and many neurological symptoms are determined to persist after COVID-19. Regardless of the numerous clinical reports about the neurological and psychiatric symptoms of COVID-19 as before it is difficult to determine if they are associated with the direct or indirect impact of viral infection or they are secondary to hypoxia, sepsis, cytokine reaction, and multiple organ failure. Penetrated the brain, COVID-19 can impact the other organs and systems and the body in general. Given the mechanisms of impairment, the survivors after COVID-19 with the infection penetrated the brain are more susceptible to more serious diseases such as Parkinson’s disease, cognitive decline, multiple sclerosis, and other autoimmune diseases. Given the multi-factor pathogenesis of COVID-19 resulting in long-term persistence of the clinical symptoms due to impaired neuroplasticity and neurogenesis followed by cholinergic deficiency, the usage of Neuroxon® 1000 mg a day with twice-day dosing for 30 days. Also, a long-term follow-up and control over the COVID-19 patients are recommended for the prophylaxis, timely determination, and correction of long-term complications.

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“…To circumvent the missing sensitivity of conventional mice, some groups studying SARS-CoV-2-related immune mechanisms take advantage of K18-hACE2 transgenic mice, which express human ACE2 under the epithelial cytokeratin-18 (K18) promoter (Winkler et al, 2020). However, K18-hACE2 mice are overly susceptible as they develop deadly SARS-CoV-2 encephalitis (in addition to pneumonia) in response to low infection doses, due to nonphysiological and broad (over)expression of hACE2 (Kumari et al, 2021). Recently, four mouseadapted SARS-CoV-2 strains have been generated by either genetic engineering (Dinnon et al, 2020) and/or serial passaging (Gu et al, 2020;Huang et al, 2021;Leist et al, 2020).…”

mentioning

confidence: 99%

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

Gawish

Starkl

Pimenov

et al. 2021

Preprint

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Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modelling revealed how Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNγ and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

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Neuroinvasion and encephalitis following intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice

Cited by 92 publications

References 46 publications

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

1

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

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