Sex-biased response to and brain cell infection by SARS-CoV-2 in a highly susceptible human ACE2 transgenic model

Tsai, Ching-Yen; Chou, Yu‐Chi; Chen, Chiung-Ya; Jan, Jia-Tsrong; Chang, Mei‐Ling; Lu, Lu-A; Huang, Pau-Yi; Chu, Mandy F.-C.; Hsu, Tsan-Ting; Hsueh, Yi‐Ping

doi:10.1101/2021.05.04.441029

Cited by 4 publications

(9 citation statements)

References 28 publications

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“…The lung tissue of K18‐hACE2 mice showed mildly focal inflammation 23,27–29 . Lung and brain are the main target organs of SARS‐CoV‐2 in CAG promoter‐hACE2 transgenic mice (CAG‐hACE2) inoculated intranasally, and acute lung injury occurs in early infection due to dramatically elevated cytokine and chemokine levels, although with untypical histopathological features 30,31 . A proportion of HFH4‐hACE2 mice, in which the disease is regulated by the lung ciliary epithelial cell‐specific HFH4/FOXJ1 promoter, experienced significant weight loss and death after SARS‐CoV‐2 infection.…”

Section: Establishment and Characteristics Of Animal Models For Covid‐19mentioning

confidence: 99%

“…23,[27][28][29] Lung and brain are the main target organs of SARS-CoV-2 in CAG promoter-hACE2 transgenic mice (CAG-hACE2) inoculated intranasally, and acute lung injury occurs in early infection due to dramatically elevated cytokine and chemokine levels, although with untypical histopathological features. 30,31 A proportion of HFH4-hACE2 mice, in which the disease is regulated by the lung ciliary epithelial cell-specific HFH4/FOXJ1 promoter, experienced significant weight loss and death after SARS-CoV-2 infection. Although the lung tissue of these mice showed typical interstitial pneumonia, the complementary metrics of pulmonary obstruction and bronchoconstriction, including PenH and Rpef, were maintained at normal levels.…”

Section: Genetically Modified Mice Models With Intranasal Infectionmentioning

confidence: 99%

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Characteristics of animal models for COVID‐19

Qin

2022

Anim Models and Exp Med

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of coronavirus disease 2019 (COVID‐19), the most consequential pandemic of this century, threatening human health and public safety. SARS‐CoV‐2 has been continuously evolving through mutation of its genome and variants of concern have emerged. The World Health Organization R&D Blueprint plan convened a range of expert groups to develop animal models for COVID‐19, a core requirement for the prevention and control of SARS‐CoV‐2 pandemic. The animal model construction techniques developed during the SARS‐CoV and MERS‐CoV pandemics were rapidly deployed and applied in the establishment of COVID‐19 animal models. To date, a large number of animal models for COVID‐19, including mice, hamsters, minks and nonhuman primates, have been established. Infectious diseases produce unique manifestations according to the characteristics of the pathogen and modes of infection. Here we classified animal model resources around the infection route of SARS‐CoV‐2, and summarized the characteristics of the animal models constructed via transnasal, localized, and simulated transmission routes of infection.

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Section: Establishment and Characteristics Of Animal Models For Covid‐19mentioning

confidence: 99%

Section: Genetically Modified Mice Models With Intranasal Infectionmentioning

confidence: 99%

Characteristics of animal models for COVID‐19

Qin

2022

Anim Models and Exp Med

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Section: N-linked Glycosylation Profile On Sars-cov-2 S Protein By Mass Spectrometry 20 μG Of Sars-mentioning

confidence: 99%

“…12). Since hamsters only showed mild-to-moderate sickness upon SARS-CoV-2 infection, we also conducted vaccination experiments in the severe-disease model using highly susceptible CAG-hACE2 transgenic mice 30 (n = 3) (Fig. 3b).…”

Section: Vaccination With Monoglycosylated S Protein (Smg) Provides Better Protection Against Sars-cov-2 Infection In Vivomentioning

confidence: 99%

“…For transgenic mice vaccination and virus challenge study, male 8-week-old CAG-hACE2 transgenic mice (n= 3) were immunized intramuscularly with 10 ug of purified Sfg or Smg proteins mixed with aluminum hydroxide (50 ug) at day 0 and day 14. 30 Blood was collected 28 days and 42 days after first immunization, and serum samples were collected from each transgenic mouse. Transgenic mice were challenged at 6 weeks after second vaccination with 1 x 10 3 TCID50 of SARS-CoV-2 TCDC#4 (hCoV-19/Taiwan/4/2020, GISAID accession ID: EPI_ISL_411927) intranasally in a volume of 50 μL per mice.…”

Section: Cpe-based Neutralization Assaymentioning

confidence: 99%

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Impact of glycosylation on a broad-spectrum vaccine against SARS-CoV-2

Huang

Liao

Chen

et al. 2021

Preprint

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Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 167 million confirmed cases and over 3 million deaths so far. This global pandemic has led to great efforts directed toward the study of this virus and its infection mechanism as well as development of effective means to control this devastating infectious disease. Like many other viral surface proteins, the trimeric SARS-CoV-2 spike (S) protein is heavily glycosylated with 22 N- and 2 O-glycosites per monomer which are likely to influence S protein folding and evade host immune response. More than one million S protein sequences with over 1,000 sites of mutation in its 1,273 amino acids have been reported to the GISAID database, including the highly transmissible variant strains found in the UK and South Africa. This high frequency of transmission and mutation is a major challenge in the development of broadly protective vaccines to control the pandemic. We have studied the impact of glycosylation on receptor-ligand interaction through evaluation of ACE2 and S protein expressed in different cell lines. Of different S protein glycoforms, the one expressed from lung epithelial cells, the primary cells for infection, has more complex-type glycans and higher binding avidity to the receptor as compared with the S protein from HEK293T cells which have more high-mannose or hybrid-type glycoforms. We also found that most of the S protein glycosites are highly conserved and the glycosites at positions 801 and 1194 are essential for viral entry. In addition, the RBD of S1 and the HR regions of S2 contain most of highly conserved sequences, and removal of each glycosite on pseudotyped SARS-CoV-2 virus for evaluation of the impact on structure and function provides insights into the design of broadly protective vaccines. In an effort to develop such universal vaccines, we found that mice immunized with monoglycosylated S protein (Smg) elicited better antibody responses capable of neutralizing not only the wild type but also the variants from the UK and South Africa than those with the fully-glycosylated S protein (Sfg), and strikingly, Smg vaccination provides better survival for hACE2 transgenic mice when challenged with lethal dose of SARS-CoV-2. Moreover, using single B cell technology, we isolated a monoclonal antibody from Smg immunized mice which was also able to neutralize the wild type and variants, suggesting that removal of unnecessary glycans from S protein to better expose the highly conserved sequences is an effective approach to developing broadly protective vaccines against SARS-CoV-2 and variants.

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Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

Halabian,

Monteiro,

et al. 2023

Preprint

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Viral infection severity often varies with host factors such as age and sex. The pathogenesis of infections caused by a broad range of viruses, from neurotropic viruses like Rabies and Zika to respiratory viruses such as influenza and SARS-CoV-2, differ between the sexes and across the lifespan. Typically, older males are more susceptible to severe acute outcomes, while females are more vulnerable to the post-acute sequelae of infections. All of these complications can include neuroinflammation, stroke, cognitive dysfunction, and delirium. While these symptoms can be secondary to infection, recent studies suggest that even peripheral infections can lead to neuropathological changes in the brain. However, few studies have characterized the expression of viral receptors in the human brain or examined age- or sex-related differences in such expression. In this study, we used a publicly accessible transcriptomic database to assess the impact of age and sex on the expression of 67 viral host factor genes, associated with ten virus families. Analyzing data from 15 brain areas (n=33, F=14, M=19, age:4 mo-80 yrs), we determined the lifespan trajectory for each gene in each area via LOESS regressions. We used unsupervised hierarchical clustering to determine if a brain-wide pattern or virus family pattern can be detected. Using Dense-tSNE, a dimension-reduction and visualization technique, we discovered four distinct developmental trajectories, clustering the areas into two mixed-sex subcortical clusters and one each of male and female cortical clusters. Applying Differential Expression Sliding Window Analysis (DeSWAN), we identified the genes driving these age- and sex-related differences. Many sex differences were noted in childhood, potentially impacting the brain’s susceptibility to viral infections and underscoring a broader dimorphic organization of male and female brains. These insights contribute to our understanding of sex-specific responses to viral infections, offering the potential for more personalized treatment strategies.

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Sex-biased response to and brain cell infection by SARS-CoV-2 in a highly susceptible human ACE2 transgenic model

Cited by 4 publications

References 28 publications

Characteristics of animal models for COVID‐19

Characteristics of animal models for COVID‐19

Impact of glycosylation on a broad-spectrum vaccine against SARS-CoV-2

Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

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