SARS-CoV-2 variants induce distinct disease and impact in the bone marrow and thymus of mice

Gonçalves, Rute; Couto, Joana; Ferreirinha, Pedro; Costa, J. Pinto da; Silvério, Diogo; Silva, Marta L.; Fernandes, Ana; Madureira, Pedro; Alves, Nuno L.; Lamas, Sofia; Saraiva, Margarida

doi:10.1016/j.isci.2023.105972

Cited by 8 publications

(5 citation statements)

References 74 publications

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“…Moreover, there was infection-induced apoptosis of thymocytes leading to increased cell death. This corroborates with the recently published report showing that K18-hACE2 transgenic mice infection leads to dysregulation of DP and DN cells [58]. Furthermore, it was also shown in another study that SARS-CoV-2 could infect primary human thymic epithelial cells in culture leading to loss of function of thymic epithelial cells [59].…”

Section: Discussionsupporting

confidence: 92%

SARS‐CoV‐2 infection induces thymic atrophy mediated by IFN‐γ in hACE2 transgenic mice

Rizvi,

Sadhu,

Dandotiya

et al. 2024

Eur J Immunol

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Pathogenic infections cause thymic atrophy, perturb thymic T‐cell development, and alter immunological response. Previous studies reported dysregulated T‐cell function and lymphopenia in coronavirus disease‐19 (COVID‐19). However, immunopathological changes in the thymus associated with severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection have not been elucidated. Here, we report that SARS‐CoV‐2 infects thymocytes, and induces CD4+CD8+ (double positive; DP) T‐cell apoptosis leading to thymic atrophy and loss of peripheral TCR repertoire in K18‐hACE2 transgenic mice. Infected thymus led to increased CD44+CD25− T‐cells, indicating an early arrest in the T‐cell maturation pathway. Thymic atrophy was notably higher in male hACE2‐Tg mice than in females and involved an upregulated de‐novo synthesis pathway of thymic glucocorticoid. Further, IFN‐γ was crucial for thymic atrophy, as anti‐IFN‐γ ‐antibody neutralization blunted thymic involution. Therapeutic use of Remdesivir also rescued thymic atrophy. While the Omicron variant and its sub‐lineage BA.5 variant caused marginal thymic atrophy, the delta variant of SARS‐CoV‐2 exhibited severe thymic atrophy characterized by severely depleted DP T‐cells. Recently characterized broadly SARS‐CoV‐2 neutralizing monoclonal antibody P4A2 was able to rescue thymic atrophy and restore the thymic maturation pathway of T‐cells. Together, we report SARS‐CoV‐2‐associated thymic atrophy resulting from impaired T‐cell maturation pathway which may contribute to dyregulated T cell response during COVID‐19.

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Section: Discussionsupporting

confidence: 92%

SARS‐CoV‐2 infection induces thymic atrophy mediated by IFN‐γ in hACE2 transgenic mice

Rizvi,

Sadhu,

Dandotiya

et al. 2024

Eur J Immunol

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“…Delta‐12 was much more lethal, as intranasal exposure to even 1 pfu caused 100% mortality (Supporting Information Figure S2). In a previous study, infection of K18‐hACE mice with SARS‐CoV‐2 Delta resulted in severe histological changes and immune responses and produced viral titers of 10 4 pfu in the lungs 35 . To compare the pathogenicity of SARS‐CoV‐2 Delta, Delta‐10, and Delta‐12, we exposed K18‐hACE2 mice intranasally to 630 pfu of each virus, which corresponds to 10 times the LD 50 of SARS‐CoV‐2 Delta.…”

Section: Resultsmentioning

confidence: 94%

“…In a previous study, infection of K18-hACE mice with SARS-CoV-2 Delta resulted in severe histological changes and immune responses and produced viral titers of 10 4 pfu in the lungs. 35 To compare the pathogenicity of SARS-CoV-2 Delta, Delta-10, and Delta-12, we exposed K18-hACE2 mice intranasally to 630 pfu of each virus, which corresponds to 10 times the LD 50 of SARS-CoV-2 Delta. PBS-exposed control mice remained healthy throughout the experimental period, whereas mice exposed to the viruses displayed loss of body weight (Figure 5A) and mortality (Figure 5B).…”

Section: Differential Pathogenicity Of Sars-cov-2 Delta and Its Mutan...mentioning

confidence: 99%

A mouse xenograft long‐term replication yields a SARS‐CoV‐2 Delta mutant with increased lethality

Kim,

Kim

et al. 2024

Journal of Medical Virology

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We recently established a long‐term SARS‐CoV‐2 infection model using lung‐cancer xenograft mice and identified mutations that arose in the SARS‐CoV‐2 genome during long‐term propagation. Here, we applied our model to the SARS‐CoV‐2 Delta variant, which has increased transmissibility and immune escape compared with ancestral SARS‐CoV‐2. We observed limited mutations in SARS‐CoV‐2 Delta during long‐term propagation, including two predominant mutations: R682W in the spike protein and L330W in the nucleocapsid protein. We analyzed two representative isolates, Delta‐10 and Delta‐12, with both predominant mutations and some additional mutations. Delta‐10 and Delta‐12 showed lower replication capacity compared with SARS‐CoV‐2 Delta in cultured cells; however, Delta‐12 was more lethal in K18‐hACE2 mice compared with SARS‐CoV‐2 Delta and Delta‐10. Mice infected with Delta‐12 had higher viral titers, more severe histopathology in the lungs, higher chemokine expression, increased astrocyte and microglia activation, and extensive neutrophil infiltration in the brain. Brain tissue hemorrhage and mild vacuolation were also observed, suggesting that the high lethality of Delta‐12 was associated with lung and brain pathology. Our long‐term infection model can provide mutant viruses derived from SARS‐CoV‐2 Delta and knowledge about the possible contributions of emergent mutations to the properties of new variants.

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“…Oral medications, including molnupiravir, fluvoxamine, and Paxlovid, are effective in reducing mortality and hospitalization rates in COVID-19 patients [ 37 ]. Omicron Variants BQ.1.1 and XBB.1 have escaped neutralizing antibodies and are surpassing previous VOCs with antibodies generated post-monovalent or bivalent mRNA boosters [ 38 ], and these are now dominant strains in circulation [ 39 ]. Mathematical modeling predicts continued surges of new strains which are not hindered by acquired immunity, and which may have new distinct pathobiology and target systems rendering the previous immunomodulatory treatments ineffective [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

In Silico Binding of 2-Aminocyclobutanones to SARS-CoV-2 Nsp13 Helicase and Demonstration of Antiviral Activity

Mohammad

Gupta

Reidl

et al. 2023

IJMS

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The landscape of viral strains and lineages of SARS-CoV-2 keeps changing and is currently dominated by Delta and Omicron variants. Members of the latest Omicron variants, including BA.1, are showing a high level of immune evasion, and Omicron has become a prominent variant circulating globally. In our search for versatile medicinal chemistry scaffolds, we prepared a library of substituted ɑ-aminocyclobutanones from an ɑ-aminocyclobutanone synthon (11). We performed an in silico screen of this actual chemical library as well as other virtual 2-aminocyclobutanone analogs against seven SARS-CoV-2 nonstructural proteins to identify potential drug leads against SARS-CoV-2, and more broadly against coronavirus antiviral targets. Several of these analogs were initially identified as in silico hits against SARS-CoV-2 nonstructural protein 13 (Nsp13) helicase through molecular docking and dynamics simulations. Antiviral activity of the original hits as well as ɑ-aminocyclobutanone analogs that were predicted to bind more tightly to SARS-CoV-2 Nsp13 helicase are reported. We now report cyclobutanone derivatives that exhibit anti-SARS-CoV-2 activity. Furthermore, the Nsp13 helicase enzyme has been the target of relatively few target-based drug discovery efforts, in part due to a very late release of a high-resolution structure accompanied by a limited understanding of its protein biochemistry. In general, antiviral agents initially efficacious against wild-type SARS-CoV-2 strains have lower activities against variants due to heavy viral loads and greater turnover rates, but the inhibitors we are reporting have higher activities against the later variants than the wild-type (10–20X). We speculate this could be due to Nsp13 helicase being a critical bottleneck in faster replication rates of the new variants, so targeting this enzyme affects these variants to an even greater extent. This work calls attention to cyclobutanones as a useful medicinal chemistry scaffold, and the need for additional focus on the discovery of Nsp13 helicase inhibitors to combat the aggressive and immune-evading variants of concern (VOCs).

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SARS-CoV-2 variants induce distinct disease and impact in the bone marrow and thymus of mice

Cited by 8 publications

References 74 publications

SARS‐CoV‐2 infection induces thymic atrophy mediated by IFN‐γ in hACE2 transgenic mice

SARS‐CoV‐2 infection induces thymic atrophy mediated by IFN‐γ in hACE2 transgenic mice

A mouse xenograft long‐term replication yields a SARS‐CoV‐2 Delta mutant with increased lethality

In Silico Binding of 2-Aminocyclobutanones to SARS-CoV-2 Nsp13 Helicase and Demonstration of Antiviral Activity

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