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1.
Alzheimer's and Dementia ; 18(S4) (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2172414

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may impact neurological function acutely or chronically, even in the absence of severe respiratory illness. Developing clinically relevant laboratory models to understand the neuropathogenesis of SARS-CoV-2 infection is an important step towards unravelling this neurologic consequence. We hypothesize that mouse adapted SARS-CoV-2 viral infection will induce neuroinflammation in immuno-competent C57BL/6J (10 weeks old male) as well as immunodeficient RAG2-/- (10 weeks old male) and BALB/c (1 year old female) mice. Method(s): All three mouse strains were inoculated intranasally with a dose of 1x103 PFU/mouse (50 microL) of either mock or the mouse-adapted (MA)10 strain of SARS-CoV-2 (BEI resource, NR-55329). Mice were euthanized on day 2, 3, 7, 15 or 30 post infection and brain samples processed for qRT-PCR, immunofluorescence, and H&E analysis. Result(s): SARS-CoV-2 MA10 resulted in a significantly higher (p < 0.05) mRNA expression for chemokine ligand 2 (CCL2) and lower (p < 0.05) mRNA expression for the blood-brain barrier component Claudin-5 in RAG2-/- and WT mice when compared to mock infection. Also, SARS-CoV-2 MA10 infection increased microglial expression in 1 year old female BALB/c mice after 2 days of infection, compared to mock infected group. At 30 days post infection, MA10 infected BALB/c mice had a higher perivascular lymphocyte cuffing in the brain. Conclusion(s): This study demonstrates that the mouse-adapted MA10 strain of SARS-CoV-2 can induce a neuroinflammatory state in the brain and more so in immunodeficient and aging mouse models. These mouse models will enable the investigation of the long-term neurological effects of SARS-CoV-2 infection. Copyright © 2022 the Alzheimer's Association.

2.
American Journal of Respiratory and Critical Care Medicine ; 205:1, 2022.
Article in English | English Web of Science | ID: covidwho-1880771
6.
National Technical Information Service; 2021.
Non-conventional in English | National Technical Information Service | ID: grc-753724

ABSTRACT

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.

7.
American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277575

ABSTRACT

RATIONALE While SARS-CoV-2 viral infection, acute lung injury, and inflammation resolve in a timely manner in most individuals, there is growing clinical evidence of long-term sequelae of COVID-19 in some patients, particularly in vulnerable populations. We established a mouse model of SARS-CoV-2 infection using a mouseadapted virus and a standard laboratory strain of mice that displays age-dependent disease severity. In comparison to young BALB/c mice, old BALB/c mice display increased morbidity and mortality when infected with SARS-CoV-2 MA-10, and most succumb to acute infection or reach the criteria for humane euthanasia within 7 days of infection. We examined the lung pathology of older BALB/c mice that survive acute infection to determine the potential long-term pulmonary manifestations of COVID-19 in vulnerable populations such as the elderly.METHODS Mice were randomized and assigned to specific harvest days spanning 30 days prior to the start of the experiment. BALB/cAnNHsd mice were intranasally infected with SARS-CoV-2 MA-10 and clinical signs of disease were monitored, including weight loss and lung function via whole body plethysmography. At each time point, animals were sacrificed and lung lobes were collected for viral titer and histopathological analyses. Lung viral titers of the caudal right lobe were determined by plaque assay. Histopathology of the left lobe was assessed utilizing formalin-fixed, paraffin-embedded specimens.RESULTSIn comparison to 10-week-old BALB/c mice, 1-year-old BALB/c mice were highly susceptible to SARS-CoV-2 MA-10, displaying high morbidity and mortality, even requiring a lower viral dose than young BALB/c mice to yield similar kinetics of weight loss and clinical signs. In some experiments, survival of older mice was low as ∼15% at day 7. For older mice surviving to days 15 and 30 post infection, acute lung injury resolved but there were regionally extensive consolidated areas containing proliferative smooth muscle actin-positive fibroblasts, collagen accumulation, and admixed immune cells with formation of tertiary lymphoid organs. Mice displaying this pulmonary fibroproliferative response did not have detectable levels of virus in the lung.CONCLUSIONSThis mouse adapted SARS-CoV-2 model reveals a response in older mice surviving acute lung injury with robust chronic inflammation and tissue remodeling resulting in pulmonary fibrosis despite viral clearance of the tissue. This offers a model to investigate mediators driving the fibroproliferative and inflammatory responses that may be a COVID-19 sequela and cause persistent pulmonary dysfunction in some vulnerable patients such as the elderly.

8.
Epidemiol Infect ; 148: e267, 2020 08 14.
Article in English | MEDLINE | ID: covidwho-912841

ABSTRACT

Previous research on respiratory infection transmission among university students has primarily focused on influenza. In this study, we explore potential transmission events for multiple respiratory pathogens in a social contact network of university students. University students residing in on-campus housing (n = 590) were followed for the development of influenza-like illness for 10-weeks during the 2012-13 influenza season. A contact network was built using weekly self-reported contacts, class schedules, and housing information. We considered a transmission event to have occurred if students were positive for the same pathogen and had a network connection within a 14-day period. Transmitters were individuals who had onset date prior to their infected social contact. Throat and nasal samples were analysed for multiple viruses by RT-PCR. Five viruses were involved in 18 transmission events (influenza A, parainfluenza virus 3, rhinovirus, coronavirus NL63, respiratory syncytial virus). Transmitters had higher numbers of co-infections (67%). Identified transmission events had contacts reported in small classes (33%), dormitory common areas (22%) and dormitory rooms (17%). These results suggest that targeting person-to-person interactions, through measures such as isolation and quarantine, could reduce transmission of respiratory infections on campus.


Subject(s)
Respiratory Tract Infections/virology , Social Networking , Students , Virus Diseases/transmission , Coinfection/virology , Female , Housing , Humans , Male , Michigan , Respiratory Tract Infections/transmission , Universities
9.
Journal of Immunology ; 204(1), 2020.
Article in English | EMBASE | ID: covidwho-881910

ABSTRACT

Immune homeostasis is the state where the immune system maintains stability in the absence of insult. Much of the analysis of immune homeostasis has focused on systemic immunity, but it is also likely to be important in an organ specific manner. There is evidence that homeostatic immunity can affect subsequent responses to infection or vaccination. Since the lungs are a major site of infection, we used the Collaborative Cross (CC) mouse genetic reference population to study the genetic regulation of the breadth of baseline immune cell populations in the lung and identify loci regulating these cells at the steady state. We found that all immune cell populations measured showed strong genetic (i.e. strain-specific) variation in cell type abundances. We identified 12 quantitative trait loci (QTL) associated with variation in 12 immune cell populations or the relationships between cell populations. Given the role of various immune cells in the lungs during respiratory virus pathogenesis, we asked whether any of the mapped QTL correlated with influenza A virus (IAV) or Severe acute respiratory syndrome associated coronavirus (SARS-CoV) disease following infection in the same strains of mice. Notably, a locus we mapped for baseline abundance of CD8+ T cells in the lungs was associated with peak weight loss following IAV infection. Additionally, a locus mapped for variation in Ly6C+ monocyte/macrophage abundance was associated with SARS-CoV titer at days 2 and 4 post-infection. These data suggest that abundance of lung leukocyte populations prior to infection could serve as predictors of immune responses to respiratory viruses.

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