Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
1.
iPSCs for Studying Infectious Diseases ; : 31-46, 2021.
Article in English | Scopus | ID: covidwho-1803274

ABSTRACT

Intracranial inoculation of susceptible strains of mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV, a member of the Coronaviridae family of viruses) results in an acute encephalomyelitis characterized by widespread growth of virus in astrocytes, microglia, and oligodendrocytes with relative sparing of neurons. Virus-specific CD4+ and CD8+ T cells infiltrate into the central nervous system in response to infection and control viral replication through secretion of interferon gamma as well as cytolytic activity. Nonetheless, virus persists in white matter tracts, and animals develop an immune-mediated demyelinating disease in which both T cells and macrophages amplify white matter damage. For the past decade, we have explored the therapeutic potential of human neural progenitor cells derived from pluripotent stem cells in promoting clinical recovery associated with remyelination of demyelinated axons following intraspinal transplantation. This chapter highlights recent studies from our laboratories demonstrating that tissue repair is associated with the emergence of regulatory T cells in response to transplantation of NPCs. © 2021 Elsevier Inc. All rights reserved.

2.
Journal of Virology ; 96(4):16, 2022.
Article in English | Web of Science | ID: covidwho-1755961

ABSTRACT

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not ex-hibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited antiviral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, similar to 50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-lambda and Tnf-alpha) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Micro-glia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work dem-onstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. IMPORTANCE Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

3.
PUBMED; 2021.
Preprint in English | PUBMED | ID: ppcovidwho-293060

ABSTRACT

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ~50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine ( Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19 ) and cytokine ( Ifn-lambda and Tnf-alpha ) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease. Importance: Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

6.
American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277106

ABSTRACT

Introduction: Before the COVID-19 pandemic, 20-30% of family members had symptoms of Post-Traumatic Stress Disorder (PTSD) or anxiety, while 15-30% had symptoms of depression. Interventions supporting family members have reduced burden of these symptoms. COVID-19 has resulted in prolonged ICU stays, high morbidity/mortality, and hospital policies severely limiting family presence at the bedside. We hypothesized the combination of prolonged critical illness and the necessary reduction of family presence would lead to high rates of PTSD, anxiety, and depression;likely higher than observed in previous studies. Methods: This was a multicenter study including 12 US hospitals, 8 academic and 4 community-based hospitals. A consecutive sample of family members of all patients with COVID-19 receiving ICU admission during the spring US peak in 2020 were called 3-4 months after the patients' ICU admission, except for New York City hospitals where a random sample was generated given the large number of hospitalizations. Consented participants completed the Impact-of- Events Scale-6 (IES-6;scored 0-30, higher scores indicate more symptoms of PTSD), Hospital-Anxiety- Depression Score (HADS, scored 0-20 for anxiety and 0-20 for depression, higher scores indicate more symptoms), and a subset of questions from Family-Satisfaction in the ICU-27 (FS-ICU27;scored on a Likert scale 1 to 5, with higher scores indicating more positive responses) selected as most likely impacted by restrictive family presence.Results: There were 945 eligible family members during the study period. Of those, 594 were contacted and 269 (45.3%) consented and completed surveys. The mean IES-6 score was 12.6 (95% CI 11.8- 13.4) with 65.4% having a score of 10 or greater, consistent with high levels of symptoms of PTSD. The mean score on the HADS-anxiety was 9.4 (95% CI 8.8-10.1) with 59.5% having a score of 8 or greater, consistent with high levels of symptoms of anxiety. Finally, the mean score for the HADS-depression was 8.0 (95% CI 7.3-8.7) with 47.6% having scores of 8 or greater, consistent with high level of symptoms of depression. The mean response for the FSICU27 questions of “I felt I had control” was 3.5 (95% CI 3.3-3.6), “I felt supported” was 3.8 (95% CI 3.6-4.0), and “I felt included” was 4.3 (95% CI 4.2-4.4).Conclusion: The consequences of a family member admitted to the ICU with COVID-19 infection are significant. We identify rates of PTSD, anxiety, and depression higher than recorded in non-COVID population. Further analysis is warranted to understand modifiable risk factors for developing these symptoms.

7.
American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277046

ABSTRACT

RATIONALE: Currently, there are over 20,000 COVID-19 positive patients requiring intensive care unit (ICU) care in the United States (US). Even prior to the pandemic, up to 30% of family members of ICU patients experience post-traumatic stress disorder and up to 50% sustain potentially prolonged anxiety and/or depression. Although family bedside engagement improves both short-and long-term outcomes for patients and their families, nationwide social distancing recommendations have curtailed hospital visitation, potentially heightening the risk of stress-related disorders in these family members. The goal of this analysis is to explore the experiences of physically distanced family members of COVID-19 ICU patients in order to inform future best practices. Methods: This qualitative analysis is part of a multisite, observational, mixed-methods study of 12 US hospitals. Qualitative interviews were conducted with 75 participants from five sites;14 interviews were analyzed in this preliminary analysis. Adult family members of COVID-19 positive patients admitted to the ICU from March-June 2020 were interviewed three months post-discharge. After sequential screening by site coordinators, participants were contacted by the qualitative team until all interviews (10-15 per site) were completed. Qualitative interviews explored the illness stories, communication perceptions, and explored stressors. Thematic analysis was applied to the verbatim transcripts of the phone interviews. Four coders utilized an iteratively-developed codebook to analyze transcripts using a round-robin method with two analysts per transcript. Discrepant codes were adjudicated by a third analyst to attend to inter-rater reliability. Results: Five preliminary themes and seven subthemes emerged (Table 1). Positive communication experiences were more common than negative ones. Communication themes were: 1) Participants were reassured by proactive and frequent communication, leaving them feeling informed and included in care;and 2) Mixed feelings were expressed about the value of video-conferencing technology. Themes from the emotional and stress experiences were: 3) Profound sadness and distress resulted from isolation from patients, clinicians, and supportive family;4) Stress was amplified by external factors;and 5) Positive experiences centered upon appreciation for healthcare workers and gratitude for compassionate care. Conclusion: Incorporating the voices of family members during the COVID-19 pandemic establishes a foundation to inform family-centered, best practice guidelines to support the unique needs of family members who are physically distant from their critically ill and dying loved ones.

8.
Compend Contin Educ Dent ; 42(6):"298-304, 2021.
Article in English | WHO COVID | ID: covidwho-1250388

ABSTRACT

The advent of the COVID-19 pandemic in the final months of 2019 prompted an extraordinary response on the part of the scientific community, with fundamental research on the biology of the virus and the human immune response, and development of testing, therapeutics, and vaccines occurring on an unprecedentedly short timescale. Within a year after the worldwide outbreak of the disease, more than 40 vaccine candidates had emerged, with 21 candidates in phase 3 trials or already being used on an emergency basis. Many of these vaccines have involved innovative platforms. In this concise review, the authors will summarize the characteristics and performance of the leading vaccines and discuss considerations of virus mutations and asymptomatic spread that may affect the ability of the worldwide community to use these vaccines as a means to defeat the pandemic and restore pre-COVID-19 normality.

SELECTION OF CITATIONS
SEARCH DETAIL