SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice (original) (raw)
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Frontiers in bioscience, 2022
Background: The recently emerged variants of the severe acute respiratory coronavirus 2 (SARS-CoV-2) pose a threat to public health. Understanding the pathogenicity of these variants is a salient factor in the development of effective SARS-CoV-2 therapeutics. This study aimed to compare the expression patterns of genes involved in immune responses in K18-hACE2 mice infected with the wild-type, Delta, and Omicron SARS-CoV-2 variants. Methods: K18-hACE2 mice were intranasally infected with either wild-type (B.1), Delta (B.1.617.2), or Omicron (B.1.1.529) variants. On day 6 post-infection, lung, brain, and kidney tissues were collected from each variantinfected group. The mRNA expression levels of 39 immune response genes in all three groups were compared by RT-qPCR. Viral titers were measured using the median tissue culture infectious dose (TCID50) assay and expressed as Log10 TCID50/0.1 g. The statistical significance of the differences in gene expression was determined by one-way analysis of variance (ANOVA) (alpha = 0.05). Results: The expression of toll-like receptors (TLRs) was upregulated in the lung and brain tissues of the wild-type-and Delta-infected groups but not in those of the Omicron-infected group. The highest expression of cytokines, including interleukin (IL)-1α, IL-1β, IL-17α, interferon, and tumor necrosis factors, was observed in the lungs of mice infected with the wild-type variant. Additionally, CCL4, CCL11, CXCL9, and CXCL10 were upregulated (>3-fold) in wild-type-infected mice, with markedly higher expressions in the brain than in the lungs. Most of the apoptotic factors were mainly expressed in the brain tissues of Omicron-infected mice (caspase 8, caspase 9, p53, Bax, Bak, BCL-2, and Bcl-XL), whereas neither the lung nor kidney showed more than 3-fold upregulation of these apoptotic factors. Conclusions: Collectively, our findings revealed that the wild-type SARS-CoV-2 variant exhibited the highest pathogenicity, followed by the Delta variant, then the Omicron variant.
There has been a growing body of evidence that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant (B.1.617.2) shows enhanced transmissibility and increased viral loads compared to other variants. A recent study has even suggested that respiratory samples from people infected with the Delta variant can harbor up to 1000 times higher viral loads compared to samples with variants that are more closely related to the original Wuhan strain, although the sample size of this study was very limited. Here, we have compared the viral load in 16,185 samples that were obtained during which non-VOC, the Alpha (B.1.1.7) or Delta variant (B.1.617.2) were dominant as evidenced by genomic surveillance. We found that the Delta variant contained about 4-fold higher viral loads compared to the non-VOC or Alpha variants.
Viruses
Small animal models that accurately model pathogenesis of SARS-CoV-2 variants are required for ongoing research efforts. We modified our human immune system mouse model to support replication of SARS-CoV-2 by implantation of human lung tissue into the mice to create TKO-BLT-Lung (L) mice and compared infection with two different variants in a humanized lung model. Infection of TKO-BLT-L mice with SARS-CoV-2 recapitulated the higher infectivity of the B.1.1.7 variant with more animals becoming infected and higher sustained viral loads compared to mice challenged with an early B lineage (614D) virus. Viral lesions were observed in lung organoids but no differences were detected between the viral variants as expected. Partially overlapping but distinct immune profiles were also observed between the variants with a greater Th1 profile in VIDO-01 and greater Th2 profile in B.1.1.7 infection. Overall, the TKO-BLT-L mouse supported SARS-CoV-2 infection, recapitulated key known similarities...
Nature Communications
SARS-CoV-2 variants of concern (VOC) B.1.1.7 (alpha) and B.1.351 (beta) show increased transmissibility and enhanced antibody neutralization resistance. Here we demonstrate in K18-hACE2 transgenic mice that B.1.1.7 and B.1.351 are 100-fold more lethal than the original SARS-CoV-2 bearing 614D. B.1.1.7 and B.1.351 cause more severe organ lesions in K18-hACE2 mice than early SARS-CoV-2 strains bearing 614D or 614G, with B.1.1.7 and B.1.351 infection resulting in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death. However, K18-hACE2 mice with prior infection of early SARS-CoV-2 strains or intramuscular immunization of viral spike or receptor binding domain are resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC than early strains. Our results thus distinguish pathogenic patterns in K18-hACE2 mice caused by B.1.1.7 and B.1.351...
SARS-CoV-2 Delta Spike Protein Enhances the Viral Fusogenicity and Inflammatory Cytokine Production
SSRN Electronic Journal, 2021
The Delta variant is now the most dominant and virulent SARS-CoV-2 variant of concern 24 (VOC). In this study, we investigated several virological features of Delta spike protein (SP Delta), 25 including protein maturation and its impact on viral entry of cell-free pseudotyped virus, cell-cell 26 fusion ability and its induction of inflammatory cytokine production in human macrophages and 27 dendritic cells. The results showed that SPΔC Delta exhibited enhanced S1/S2 cleavage in cells and 28 pseudotyped virus-like particles (PVLPs). We further showed that SPΔC Delta elevated 29 pseudovirus infection in human lung cell lines and mediated significantly enhanced syncytia 30 formation. Furthermore, we revealed that SPΔC Delta-PVLPs had stronger effects on stimulating 31 NF-κB and AP-1 signaling in human monocytic THP1 cells and induced significantly higher 32 levels of pro-inflammatory cytokine, such as TNF-α, IL-1β and IL-6, released from human 33 macrophages and dendritic cells. Overall, these studies provide evidence to support the important 34 role of SPΔC Delta during virus infection, transmission and pathogenesis.
SARS-CoV-2 Delta Variant Pathogenesis and Host Response in Syrian Hamsters
Viruses
B.1.617 is becoming a dominant Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) lineage worldwide with many sublineages, of which B.1.617.2 is designated as a variant of concern. The pathogenicity of B.1.617.2 (Delta) and B.1.617.3 lineage of SARS-CoV-2 was evaluated and compared with that of B.1, an early virus isolate with D614G mutation in a Syrian hamster model. Viral load, antibody response, and lung disease were studied. There was no significant difference in the virus shedding pattern among these variants. High levels of SARS-CoV-2 sub genomic RNA were detected in the respiratory tract of hamsters infected with the Delta variant for 14 days, which warrants further transmission studies. The Delta variant induced lung disease of moderate severity in about 40% of infected animals, which supports the attributed disease severity of the variant. Cross neutralizing antibodies were detected in animals infected with B.1, Delta, and B.1.617.3 variant, but neutralizing capac...
Influence of the Delta Variant and Vaccination on the SARS-CoV-2 Viral Load
Viruses
Studies comparing SARS-CoV-2 nasopharyngeal (NP) viral load (VL) according to virus variant and host vaccination status have yielded inconsistent results. We conducted a single center prospective study between July and September 2021 at the drive-through testing center of the Toulouse University Hospital. We compared the NP VL of 3775 patients infected by the Delta (n = 3637) and Alpha (n = 138) variants, respectively. Patient’s symptoms and vaccination status (2619 unvaccinated, 636 one dose and 520 two doses) were recorded. SARS-CoV-2 RNA testing and variant screening were assessed by using Thermo Fisher® TaqPath™ COVID-19 and ID solutions® ID™ SARS-CoV-2/VOC evolution Pentaplex assays. Delta SARS-CoV-2 infections were associated with higher VL than Alpha (coef = 0.68; p ≤ 0.01) independently of patient’s vaccination status, symptoms, age and sex. This difference was higher for patients diagnosed late after symptom onset (coef = 0.88; p = 0.01) than for those diagnosed early (coef...
The Delta and Omicron Variants of SARS-CoV-2: What We Know So Far
Vaccines
The world has not yet completely overcome the fear of the havoc brought by SARS-CoV-2. The virus has undergone several mutations since its initial appearance in China in December 2019. Several variations (i.e., B.1.616.1 (Kappa variant), B.1.617.2 (Delta variant), B.1.617.3, and BA.2.75 (Omicron variant)) have emerged throughout the pandemic, altering the virus’s capacity to spread, risk profile, and even symptoms. Humanity faces a serious threat as long as the virus keeps adapting and changing its fundamental function to evade the immune system. The Delta variant has two escape alterations, E484Q and L452R, as well as other mutations; the most notable of these is P681R, which is expected to boost infectivity, whereas the Omicron has about 60 mutations with certain deletions and insertions. The Delta variant is 40–60% more contagious in comparison to the Alpha variant. Additionally, the AY.1 lineage, also known as the “Delta plus” variant, surfaced as a result of a mutation in the D...
K18-hACE2 mice develop respiratory disease resembling severe COVID-19
2020
SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 104 TCID50 or 105 TCID50, the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 105 TCID50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and l...