The trinity of COVID-19: immunity, inflammation and intervention

Tay, Matthew Zirui; Poh, Chek Meng; Rénia, Laurent; MacAry, Paul A.; Ng, Lisa F. P.

doi:10.1038/s41577-020-0311-8

Cited by 3,739 publications

(4,681 citation statements)

References 132 publications

(149 reference statements)

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“…This is in line with previous reports that obese patients may present shifted testosterone-to-estradiol levels due to high-level aromatase activity, an enzyme expressed in adipose tissues 20 . Interestingly, elevated estradiol levels in male patients correlated with elevated IL-6 levels that is a poor prognostic marker in COVID-19 patients 14 . This is in line with reports on the inflammatory role of estrogens in men 21,22 .…”

Section: Discussionmentioning

confidence: 92%

“…Avian H7N9 influenza also shows a strong male bias and is a known strong inducer of inflammatory cytokines defined as "cytokine storm" comparable to SARS-CoV-2 infection. In both infections, high IL-6 levels present a poor prognostic marker 14 . Indeed, it was reported before that "cytokine storm", including high TNF-α levels may suppresses steroidogenesis in the testis by inhibiting defined pathways 29,30 .…”

Section: Discussionmentioning

confidence: 99%

“…Several independent studies reported that cytokine storm is a major hallmark of severe COVID-19 in humans 14 . Therefore, we sought to analyze whether the severe testosterone deficiency detected in male COVID-19 patients might be associated with altered cytokine and chemokine levels.…”

Section: In Male Covid-19 Patients Level Of Inflammation Correlatesmentioning

confidence: 99%

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Sex hormone and metabolic dysregulations are associated with critical illness in male Covid-19 patients

Schroeder

Schaumburg

Mueller

et al. 2020

Preprint

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Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide and pose a major public health burden. There is increasing evidence that men are more likely to die from SARS-CoV-2 infection than women. However, underlying factors that mediate the observed sex bias in coronavirus disease 2019 (COVID-19) remain unknown. Methods. In this retrospective cohort, we included COVID-19 patients who were admitted to an Intensive Care Unit at the University Hospital Hamburg-Eppendorf, Germany. We obtained demographic data of all patients who were discharged or had died by 29th April 2020. We systematically analyzed sex hormones as well as cytokine and chemokine responses in male and female patients with laboratory-confirmed SARS-CoV-2 infections upon hospital admission. We used uni- and multivariable linear regression methods to identify potential risk factors for disease severity in males and females. Findings. All enrolled patients (n=45; n=35 males and n=10 females) presented comorbidities with hypertension being the most common (45.7% in males; 40% in females), followed by cancer (35% in males; 40% in females), obesity (34.3% in males and 30% in females), type II diabetes (25.7% in males and 20% in females) and chronic heart diseases (8.6% in males and 0% in females). We detected that the vast majority of male COVID-19 patients present low testosterone (68.6%) and low dihydrotestosterone (48.6%) levels. In contrast, most female COVID-19 patients have elevated testosterone levels (60%) without alterations in dihydrotestosterone levels. Both, female and male COVID-19 patients may present elevated estradiol levels (45.7% in males and 40% in females). Disease severity defined by SOFA score correlates with elevated cytokine responses (e.g. IL-6) in males and IL-2 in females. In male COVID-19 patients, testosterone levels negatively correlate with inflammatory IL-2 and IFN-γ, whereas estradiol levels positively correlate with the inflammatory cytokine IL-6. Vice versa, in female COVID-19 patients, testosterone levels positively correlate with inflammatory cytokines (e.g. IL-6). Interpretation. We here show that critically ill male COVID-19 patients suffer from severe testosterone and dihydrotestosterone deficiencies. Both androgens are required to mount antiviral immune responses to combat infection in males.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Sex hormone and metabolic dysregulations are associated with critical illness in male Covid-19 patients

Schroeder

Schaumburg

Mueller

et al. 2020

Preprint

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“…Lung is one of the main target organ of SARS-CoV-2 20 and pneumonia is the typical symptom of COVID-19 21 . To evaluate the detailed expression patterns of ACE2 and TMPRSS2 in lung cells for various species, we generated single nuclei libraries for livestock (pig, goat), poultry (chicken, pigeon, goose, duck), pets (cat, dog, hamster, lizard) and wildlife (pangolin), resulting in a total of 123,445 cells passing quality control ( Supplementary Table 1).…”

Section: Construction Of the Single-cell Atlas For Lungs Of Livestockmentioning

confidence: 99%

Single-cell screening of SARS-CoV-2 target cells in pets, livestock, poultry and wildlife

Chen

Sun

Zhu

et al. 2020

Preprint

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“…The activated T cells can migrate to the site of infection, where they facilitate viral clearance, but can also contribute to immune pathogenesis. There is mounting evidence that the latter is the major reason for critical COVID-19 disease manifestations 3,4 .…”

Section: Main Textmentioning

confidence: 99%

The SARS-CoV-2 T-cell immunity is directed against the spike, membrane, and nucleocapsid protein and associated with COVID 19 severity

Thieme

Anft

Paniskaki

et al. 2020

Preprint

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Identification of immunogenic targets of SARS-CoV-2 is crucial for monitoring of antiviral immunity and vaccine design. Currently, mainly anti-spike (S)-protein adaptive immunity is investigated. However, also the nucleocapsid (N)-and membrane (M)-proteins should be considered as diagnostic and prophylactic targets.The aim of our study was to explore and compare the immunogenicity of SARS-CoV-2 S-, Mand N-proteins in context of different COVID-19 manifestations. Analyzing a cohort of COVID-19 patients with moderate, severe, and critical disease severity, we show that overlapping peptide pools (OPP) of all three proteins can activate SARS-CoV-2-reactive T-cells with a stronger response of CD4 + compared to CD8 + T-cells. Although interindividual variations for the three proteins were observed, M-protein induced the highest frequencies of CD4 + T-cells, suggesting its relevance as diagnostic and vaccination target. Importantly, patients with critical COVID-19 demonstrated the strongest T-cell response, including the highest frequencies of cytokine-producing bi-and trifunctional T-cells, for all three proteins. Although the higher magnitude and superior functionality of SARS-CoV-2-reactive T-cells in critical patients can also be a result of a stronger immunogenicity provided by severe infection, it disproves the hypothesis of insufficient SARS-CoV-2-reactive immunity in critical COVID-19. To this end, activation of effector T-cells with differentiated memory phenotype found in our study could cause hyper-reactive response in critical cases leading to immunopathogenesis. Conclusively, since the S-, M-, and N-proteins induce T-cell responses with individualdifferences, all three proteins should be evaluated for diagnostics and therapeutic strategies to avoid underestimation of cellular immunity and to deepen our understanding of COVID-19 immunity.

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The trinity of COVID-19: immunity, inflammation and intervention

Cited by 3,739 publications

References 132 publications

Sex hormone and metabolic dysregulations are associated with critical illness in male Covid-19 patients

Sex hormone and metabolic dysregulations are associated with critical illness in male Covid-19 patients

Single-cell screening of SARS-CoV-2 target cells in pets, livestock, poultry and wildlife

The SARS-CoV-2 T-cell immunity is directed against the spike, membrane, and nucleocapsid protein and associated with COVID 19 severity

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