Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2

Agrawal, Sudhanshu; Salazar, Jon; Tran, Thu Michelle; Agrawal, Anshu

doi:10.3389/fimmu.2021.739757

Cited by 12 publications

(6 citation statements)

References 61 publications

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“…To investigate innate immune cell activation, we stimulated PBMCs from different age groups with irradiated SARS-CoV-2 virus for 24 h as described [ 30 ]. Since SARS-CoV-2 does not infect and multiply in DCs and monocytes, inactivated virus was used for stimulation [ 35 – 38 ].…”

Section: Resultsmentioning

confidence: 99%

“…Since SARS-CoV-2 does not infect and multiply in DCs and monocytes, inactivated virus was used for stimulation [ 35 – 38 ]. We previously compared irradiated and heat-inactivated SARS-CoV-2 virus and demonstrated that irradiated virus is a better stimulator of the immune response [ 30 ]. Supernatants were collected and stored at -70 °C for cytokine and chemokine analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of volunteers by density gradient centrifugation using lymphocyte separation media (Mediatech, Fisher Scientific, USA). Fresh 5 × 10 6 PBMCs/2 ml were stimulated with 10 µg of irradiated SARS-CoV-2 virus in RPMI 1640 containing 10% fetal bovine serum (Gibco, Thermo Fisher Scientific, USA) as described previously [ 30 ]. After 24 h, half of the cells and supernatants were collected.…”

Section: Methodsmentioning

confidence: 99%

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Changes in the innate immune response to SARS-CoV-2 with advancing age in humans

Agrawal,

Tran,

Jennings

et al. 2024

Immun Ageing

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Background Advancing age is a major risk factor for respiratory viral infections. The infections are often prolonged and difficult to resolve resulting hospitalizations and mortality. The recent COVID-19 pandemic has highlighted this as elderly subjects have emerged as vulnerable populations that display increased susceptibility and severity to SARS-CoV-2. There is an urgent need to identify the probable mechanisms underlying this to protect against future outbreaks of such nature. Innate immunity is the first line of defense against viruses and its decline impacts downstream immune responses. This is because dendritic cells (DCs) and macrophages are key cellular elements of the innate immune system that can sense and respond to viruses by producing inflammatory mediators and priming CD4 and CD8 T-cell responses. Results We investigated the changes in innate immune responses to SARS-CoV-2 as a function of age. Our results using human PBMCs from aged, middle-aged, and young subjects indicate that the activation of DCs and monocytes in response to SARS-CoV-2 is compromised with age. The impairment is most apparent in pDCs where both aged and middle-aged display reduced responses. The secretion of IL-29 that confers protection against respiratory viruses is also decreased in both aged and middle-aged subjects. In contrast, inflammatory mediators associated with severe COVID-19 including CXCL-8, TREM-1 are increased with age. This is also apparent in the gene expression data where pathways related host defense display an age dependent decrease with a concomitant increase in inflammatory pathways. Not only are the inflammatory pathways and mediators increased after stimulation with SARS-CoV-2 but also at homeostasis. In keeping with reduced DC activation, the induction of cytotoxic CD8 T cells is also impaired in aged subjects. However, the CD8 T cells from aged subjects display increased baseline activation in accordance with the enhanced baseline inflammation. Conclusions Our results demonstrate a decline in protective anti-viral immune responses and increase in damaging inflammatory responses with age indicating that dysregulated innate immune responses play a significant role in the increased susceptibility of aged subjects to COVID-19. Furthermore, the dysregulation in immune responses develops early on as middle-aged demonstrate several of these changes. Graphical abstract

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Changes in the innate immune response to SARS-CoV-2 with advancing age in humans

Agrawal,

Tran,

Jennings

et al. 2024

Immun Ageing

Self Cite

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“…In preclinical models, pharmacological inhibitors of IDO1 have therapeutic utility in various diseases, including cancer, HIV and influenza ( Yang et al, 2020b ; Chang et al, 2020 ; Chi et al, 2020 ). Interestingly, IDO1 inhibitors suppress the COVID-19-induced pro-inflammatory cytokine release, including TNF-α, IL-6, IL-1α and IL-1β in isolated PBMCs derived from COVID-19-infected rhesus macaques and lower mortality among critically ill patients with COVID-19 ( Song et al, 2020 ; Agrawal et al, 2021 ). This confirms the critical role of the IDO1 gene network in COVID-19-exaggerated cytokine release.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics insights into the genes and pathways on severe COVID-19 pathology in patients with comorbidities

et al. 2022

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Background: Coronavirus disease (COVID-19) infection is known for its severe clinical pathogenesis among individuals with pre-existing comorbidities. However, the molecular basis of this observation remains elusive. Thus, this study aimed to map key genes and pathway alterations in patients with COVID-19 and comorbidities using robust systems biology approaches.Methods: The publicly available genome-wide transcriptomic datasets from 120 COVID-19 patients, 281 patients suffering from different comorbidities (like cardiovascular diseases, atherosclerosis, diabetes, and obesity), and 252 patients with different infectious diseases of the lung (respiratory syncytial virus, influenza, and MERS) were studied using a range of systems biology approaches like differential gene expression, gene ontology (GO), pathway enrichment, functional similarity, mouse phenotypic analysis and drug target identification.Results: By cross-mapping the differentially expressed genes (DEGs) across different datasets, we mapped 274 shared genes to severe symptoms of COVID-19 patients or with comorbidities alone. GO terms and functional pathway analysis highlighted genes in dysregulated pathways of immune response, interleukin signaling, FCGR activation, regulation of cytokines, chemokines secretion, and leukocyte migration. Using network topology parameters, phenotype associations, and functional similarity analysis with ACE2 and TMPRSS2—two key receptors for this virus-we identified 17 genes with high connectivity (CXCL10, IDO1, LEPR, MME, PTAFR, PTGS2, MAOB, PDE4B, PLA2G2A, COL5A1, ICAM1, SERPINE1, ABCB1, IL1R1, ITGAL, NCAM1 and PRKD1) potentially contributing to the clinical severity of COVID-19 infection in patients with comorbidities. These genes are predicted to be tractable and/or with many existing approved inhibitors, modulators, and enzymes as drugs.Conclusion: By systemic implementation of computational methods, this study identified potential candidate genes and pathways likely to confer disease severity in COVID-19 patients with pre-existing comorbidities. Our findings pave the way to develop targeted repurposed therapies in COVID-19 patients.

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“…Poor T-cell response to SARS-CoV-2 correlates with worse disease progression in female patients. Higher innate immune activation in men leads to higher plasma levels of the inflammatory cytokines IFN-α [ 368 ], IL-8 and IL-18 [ 363 ], driving hyperinflammation and more pronounced lymphopenia in males.…”

Section: Factors Modulating Covid-19: a Mechanistic Understanding Via...mentioning

confidence: 99%

Factors Modulating COVID-19: A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework

Clerbaux

Albertini

Amigó

et al. 2022

JCM

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Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues.

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Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2

Cited by 12 publications

References 61 publications

Changes in the innate immune response to SARS-CoV-2 with advancing age in humans

Changes in the innate immune response to SARS-CoV-2 with advancing age in humans

Bioinformatics insights into the genes and pathways on severe COVID-19 pathology in patients with comorbidities

Factors Modulating COVID-19: A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework

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