47 Matching Annotations
  1. Apr 2021
    1. Some studies suggest a preferential reduction in circulating NK cells and reduced NK functionality are associated with severe COVID-19

      Reduced innate lymphoid cells with age and in males may account for increased risk of severe COVID-19 https://doi.org/10.1101/2021.01.14.21249839

      In addition, a study has shown that a combined reduction in circulating NK cells in the blood (as well as T cells) alongside increased IL-6 and IL-10 was observed in non-survivors of COVID-19 until death https://doi.org/10.1186/s12879-021-05792-7

    2. Table 1:Potential treatments

      Blockade of NFkB/TLR4 pathway may also be beneficial due to the SARS-CoV-2 activation of TLR4 https://doi.org/10.1101/2020.12.18.423427

      Anti-viral neuraminidase inhibitors such as Oseltamivir or Zanamivir reduced neutrophil hyper-activation (via inhibition of host neuraminidase) and may present a new targeted therapeutic strategy https://doi.org/10.1101/2020.11.12.379115

      IL-18 blockade may represent a therapeutic option for COVID-19 as it may participate in hyperinflammation and tissue damage https://doi.org/10.1002/jcp.30008

      Increasing evidence that NK cells could be used as therapies for COVID-19 https://doi.org/10.1186/s40164-021-00199-1 as well as evidence for targeting specific mutants of COVID-19 with ‘off-the shelf’ CAR-NK cells https://doi.org/10.1101/2021.01.14.426742

    3. Ecluzimab C5a 

      An ongoing clinical trial (NCT04371367) investigating Avdoralimab, an antibody for C5a receptors, which may disrupt C5a engagement with NK cells in COVID-19 https://doi.org/10.3389/fimmu.2020.586765

    4. NK cell death

      As NK cells do not express the COVID-19 host entry receptor ACE2 the authors suggest NK cell loss unlikely due to infection induced apoptosis that is observed in influenza infection https://doi.org/10.1038/s41586-020-2922-4 https://doi.org/10.3389/fimmu.2020.586765

    5. CXCR3-dependent mechanism for NK cells recruitment to the lung as described in influenza A infection

      Further evidence for functionally competent CXCR3+, CXCR6+ and/or CCR5+ NK cell migration to the lungs in moderate COVID-19. Lung homing receptor expression is biased towards phenotypically activated NK cells. https://doi.org/10.1101/2021.01.13.426553

    6. persistent elevation of IL-6 in COVID-19 patients

      In Healthy donor NK cells, in vitro stimulation of the soluble IL-6 receptor by IL-6 reduced NK cell degranulation markers perforin and granzyme https://doi.org/10.1002/art.39295 which suggests that IL-6 may hasten the downregulation of granzyme expression on NK cells reported in COVID-19 https://doi.org/10.1016/j.ajpath.2020.08.009

    7. which may highlight the importance of the NKG2C–HLA-E axis on antiviral activity

      HLA-C, the dominant ligand for KIR receptors on NK cells, has also been observed as a novel genetic predictor of clinical course in COVID-19 https://doi.org/10.1101/2020.12.21.20248121

      HLA-A/B types, which bind T cells, are correlated with population responses to COVID-19 https://doi.org/10.3389/fimmu.2020.586765 https://doi.org/10.3389/fimmu.2020.565730

      In addition, another study shows the genetic variants associated with NKG2C loss were significantly overrepresented in hospitalised patients with COVID-19, particularly those requiring intensive care compared to those with mild symptoms https://doi.org/10.1038/s41436-020-01077-7

    8. suggesting that NK cell regulation is abandoned for cytotoxicity, perhaps further promoting tissue damage

      The uniform reduction in CD56bright NK cells suggests that peripheral NK cells do not directly contribute to cytokine storm in COVID-19 https://doi.org/10.1016/j.ajpath.2020.08.009

    9. However, overall, while NK cell dysregulation has been described in SARS-CoV-2 patients there is still lack of understanding of early NK cell-mediated responses and the balance between pathological versus protective NK cell responses at the sites of infection

      In addition, crosstalk with monocytes and macrophages via cytokines which may mediate NK cell dysfunction and impair SARS-CoV-2 clearance https://doi.org/10.1016/j.ajpath.2020.08.009

    10. high neutrophil to lymphocyte ratio

      Neutrophil to lymphocyte ratio as a cost-effective biomarker of COVID-19 severity https://10.1016/j.ajem.2021.01.006

  2. Mar 2021
    1. Antoine R , Valadão Ana Luiza C , Marine T  et al.   PREPRINT: SARS-CoV-2 replication triggers an MDA-5-dependent interferon production which is unable to efficiently control replication. bioRxiv  2020:2020.10.28.358945. doi:10.1101/2020.10.28.358945.

      Rebendenne A, Valadão ALC, Tauziet M, Maarifi G, Bonaventure B, McKellar J, Planès R, Nisole S, Arnaud-Arnould M, Moncorgé O, Goujon C. SARS-CoV-2 triggers an MDA-5-dependent interferon response which is unable to control replication in lung epithelial cells. J Virol. 2021 Jan 29:JVI.02415-20 https://doi.org/10.1128/JVI.02415-20

    2. Bayati A , Kumar R , Francis V  et al.   PREPRINT: SARS-CoV-2 uses clathrin-mediated endocytosis to gain access into cells. bioRxiv  2020:2020.07.13.201509. doi:10.1101/2020.07.13.201509.

      Bayati A, Kumar R, Francis V, McPherson PS. SARS-CoV-2 infects cells following viral entry via clathrin-mediated endocytosis. J Biol Chem. 2021 Jan 18;296:100306 https://doi.org/10.1016/j.jbc.2021.100306

    3. Zhou Q , Wei X-S , Xiang X  et al.   PREPRINT: Interferon-a2b treatment for COVID-19. medRxiv  2020:2020.04.06.20042580. doi:10.1101/2020.04.06.20042580.

      Zhou, Q., Chen, V., Shannon, C. P., Wei, X.-S., Xiang, X., Wang, X., Wang, Z.-H., Tebbutt, S. J., Kollmann, T. R., & Fish, E. N. (2020). Interferon-α2b Treatment for COVID-19. Front Immunol, 11(1061) https://doi.org/10.3389/fimmu.2020.01061

    4. Baker SA , Kowk S , Berry GJ  et al.   PREPRINT: Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation. medRxiv  2020:2020.07.05.20140467. doi:10.1101/2020.07.05.20140467.

      Baker SA, Kwok S, Berry GJ, Montine TJ. Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation. PLoS One. 2021 Feb 16;16(2):e0247060 https://doi.org/10.1371/journal.pone.0247060

    5. impairing IFN signalling

      A M58R mutation in ORF6 inhibited the binding of orf6 to the nuclear core protein Nup98-Rae1 complex, abolishing its IFN antagonistic function https://doi.org/10.1073/pnas.2016650117

    6. The dominant mutant D614G

      D614G mutation not associated with higher mortality, but is associated with a higher viral load and affecting younger patients https://doi.org/10.1016/j.cell.2020.11.020 . D614G mutation proposed to allow increased epitope exposure and greater neutralisation, thus should not affect vaccine efficacy https://doi.org/10.1016/j.chom.2020.11.012

      Additionally a N501Y mutation in the S1 has been reported. This mutation is already present in the UK SARS-CoV-2 variant (20B/501Y.V1, B1.1.7 lineage), and is associated with high higher rates of transmission through increased receptor binding https://doi.org/10.1101/2021.01.04.425316 and potentially higher viral loads https://doi.org/10.1101/2021.01.12.20249080 . However, post vaccination sera can neutralise this variant and thus current vaccines in circulation should protect against this strain https://doi.org/10.1101/2021.01.19.21249592 .

      Interestingly, examination of the global effects of the N501Y mutation revealed that MHCII presentation was poorer than wild type controls. This implicates the N501Y mutation in hindering immune cell cooperation, resulting in immune escape https://doi.org/10.1101/2021.02.02.429431

    7. possibly via reduced shedding of the S1 domain

      and also possibly by enhancing the lysosomal trafficking of the SARS-CoV-2 spike protein https://doi.org/10.1101/2020.12.08.417022

    8. S1 mediates receptor binding

      Another mutation in the receptor binding domain of the S protein, E484K, has been found in the South African and Brazilian variants of the virus. The glutamate to lysine substitution switches the charge on the flexible loop region of the RBD resulting in the formation of novel favourable contacts https://doi.org/10.1101/2021.01.13.426558 . Early studies indicate that higher antibody titres will be required post vaccination to neutralise the variant https://doi.org/10.1101/2021.01.26.21250543

    9. ACE2 expression varies by age and ethnicity and has been associated with comorbidities and severe COVID-19

      Indeed, a recent study indicates that diversity of ACE2 expression amongst those of different ethnicities impacts selection pressures for mutations in SARS-CoV-2, for example, the D614G mutation has become dominant in North America, Europe and Africa where ACE2 expression amongst the population is low in comparison with those from China, where D614G is not the dominant form https://doi.org/10.3390/genes12010016

    10. Part I: viral entry, sensing and evasion

      Ester Gea-Mallorquí is co-corresponding author, email: ester.gea-mallorqui@ndm.ox.ac.uk

    11. Part II
    12. Viral Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK

      Corresponding email: ester.gea-mallorqui@ndm.ox.ac.uk

    13. ,

      Corresponding author: ester.gea-mallorqui@ndm.ox.ac.uk

    14. Meng Z , Wang T , Li C  et al.   PREPRINT: An experimental trial of recombinant human interferon alpha nasal drops to prevent coronavirus disease 2019 in medical staff in an epidemic area. medRxiv  2020:2020.04.11.20061473. doi:10.1101/2020.04.11.20061473.
    15. Wang K , Chen W , Zhou Y-S  et al.   PREPRINT: SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv  2020:2020.03.14.988345. doi:10.1101/2020.03.14.988345.

      Wang, K., Chen, W., Zhang, Z. et al. CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells. Sig Transduct Target Ther 5, 283 (2020). https://doi.org/10.1038/s41392-020-00426-x

    16. Zhang L , Jackson CB , Mou H  et al.   PREPRINT: The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity. bioRxiv  2020:2020.06.12.148726. doi:10.1101/2020.06.12.148726.

      Zhang, L., Jackson, C.B., Mou, H. et al. SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity. Nat Commun 11, 6013 (2020). https://doi.org/10.1038/s41467-020-19808-4

    17. Lee IT , Nakayama T , Wu C-T  et al.   PREPRINT: Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers. medRxiv  2020:2020.05.08.20092866. doi:10.1101/2020.05.08.20092866.

      Lee, I.T., Nakayama, T., Wu, CT. et al. ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. Nat Commun 11, 5453 (2020). https://doi.org/10.1038/s41467-020-19145-6

    1. This overactivation could also be attributed to the phenotype of the neutrophils themselves

      Studies have shown that neutrophils taken from severe COVID-19 patients are immunosuppressed, with a lack of ability to phagocytose and kill bacteria https://doi.org/10.21203/rs.3.rs-142927/v1 , https://doi.org/10.1101/2020.12.01.406306

      It is unclear at this stage whether this defect is programmed into the cells (inherent) or whether it is a result of the in-situ environment – i.e. already activated cells are likely to have a refractory loss of function. This activation has been heavily reported and shown again here with neutrophil elastase deposition in the blood of severe COVID-19 patients, which can predict organ damage https://doi.org/10.1111/all.14746

      However, what is clear is that these cells are not as functional against new threats and this may explain the reported secondary bacterial infections in COVID-19. (Note: this will be covered in a future update)

    2. Innate immunology in COVID-19—a living review. Part II
    3. COVID-19

      Increased antibody dependent complement deposition and lower antibody dependent phagocytosis has been observed in hospitalised COVID-19 patients associated with higher inflammation https://doi.org/10.1101/2021.01.11.426209 . This is intriguing as perhaps the type of antibody produced against SARS-CoV-2 has a role in promoting disease severity (via complement activation). This could also potentially involve auto-antibodies.

    4. IFN signalling

      Another study was unable to find a correlation between severe COVID-19 and polymorphisms that result in loss-of-function in type-1 IFN signalling (TLR3- and IRF7-dependent) https://doi.org/10.1101/2020.12.18.20248226

    5. NETs are also associated with thrombotic events in COVID-19, consisting of platelets, complement (C3) and tissue factor in blood

      Monocyte and neutrophil aggregates with platelets have been identified in COVID-19 patients and correlate with disease severity https://doi.org/10.1055/s-0040-1718732

      Von Willebrand’s factor and ADAMTS13 are also implicated in NET-associated immunothrombosis https://doi.org/10.3389/fimmu.2020.610696 , https://doi.org/10.1002/ctm2.268

      Additionally, NETs have been shown to accumulate and persist in the lungs of severe COVID-19 patients https://doi.org/10.1093/infdis/jiab053 and recruits coagulation Factor XII to promote clotting https://doi.org/10.1101/2020.12.29.424644 .

      This persistence is attributed to poor DNase clearance of NETs https://doi.org/10.1111/all.14746

    6. autoantibody observations

      A range of autoantibodies is now thought to be promoted in severe COVID-19 https://doi.org/10.1101/2020.12.10.20247205

    7. SARS-CoV-2 spike protein can induce IL-8, IL-6 and TNF-α secretion in monocyte-derived macrophages (MDMs)

      Suggested mechanism for this is via Spike protein binding TLR4, this can be blocked with NFkB and TLR4 inhibitors potentially offering a therapeutic strategy https://doi.org/10.1101/2020.12.18.423427

      Additionally SARS-CoV-2 nucleocaspid can drive IL-6 in macrophages https://doi.org/10.3390/vaccines9010054

    8. As macrophages express ACE-2, direct infection with SARS-CoV-2 could prevent IFN I production (a viral evasion mechanism discussed in Part 1 of this review) impairing viral control and causing hyperinflammation [67].

      It is not thought that circulating immune cells (i.e. monocytes) become infected with SARS-CoV-2 to a large extent https://doi.org/10.1101/2021.01.19.427282

      Additionally, a study showed that SARS-CoV-2 does not readily infect human monocyte derived macrophages nor drive significant cytokine production https://doi.org/10.1101/2020.12.22.423940

      However, this is not seen in other studies and the cells primarily thought to be infected would rather be lung alveolar macrophages. These have different receptors, origins (i.e. embryonic vs monocyte perhaps), and are in an in situ setting unlike studies with in vitro-derived monocytic macrophages (6-day culture with only one growth factor). Therefore, this is still unclear.

    9. elevated plasma C5a and sC5b-9

      In contrast low C3 and C4 have been observed, though it is unclear whether this is decreased production or increased utilisation https://doi.org/10.21203/rs.3.rs-127493/v1

    10. mannose-binding lectin

      SARS-CoV-2 N protein is thought to bind MASP-2 as part of the lectin pathway.

      The lectin pathway is thought to be generally increased in COVID-19 https://doi.org/10.1016/j.trsl.2020.11.008

    11. Cerda P , Ribas J , Iriarte A , et al. ; PREPRINT: D-dimer dynamics in hospitalized COVID-19 patients: potential utility for diagnosis of pulmonary embolism. medRxiv  2020:2020.09.21.20193953. doi: 10.1101/2020.09.21.20193953.

      Cerdà P, Ribas J, Iriarte A, Mora-Luján JM, Torres R, Del Río B, Jofre HI, Ruiz Y, Huguet M, Fuset MP, Martínez-Yélamos S, Santos S, Llecha N, Corbella X, Riera-Mestre A. Blood test dynamics in hospitalized COVID-19 patients: Potential utility of D-dimer for pulmonary embolism diagnosis. PLoS One. 2020 Dec 28;15(12):e0243533. https://doi.org/10.1371/journal.pone.0243533

    12. Meizlish ML , Pine AB , Bishai JD  et al.   PREPRINT: a neutrophil activation signature predicts critical illness and mortality in COVID-19. medRxiv  2020. doi:10.1101/2020.09.01.20183897.

      Meizlish ML, Pine AB, Bishai JD, Goshua G, Nadelmann ER, Simonov M, Chang CH, Zhang H, Shallow M, Bahel P, Owusu K, Yamamoto Y, Arora T, Atri DS, Patel A, Gbyli R, Kwan J, Won CH, Dela Cruz C, Price C, Koff J, King BA, Rinder HM, Wilson FP, Hwa J, Halene S, Damsky W, van Dijk D, Lee AI, Chun HJ. A neutrophil activation signature predicts critical illness and mortality in COVID-19. Blood Adv. 2021 Mar 9;5(5):1164-1177. https://doi.org/10.1182/bloodadvances.2020003568

    13. Aschenbrenner AC , Mouktaroudi M , Kraemer B  et al.   PREPRINT: disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients. medRxiv  2020. doi:10.1101/2020.07.07.20148395.

      Aschenbrenner AC, Mouktaroudi M, Krämer B, Oestreich M, Antonakos N, Nuesch-Germano M, Gkizeli K, Bonaguro L, Reusch N, Baßler K, Saridaki M, Knoll R, Pecht T, Kapellos TS, Doulou S, Kröger C, Herbert M, Holsten L, Horne A, Gemünd ID, Rovina N, Agrawal S, Dahm K, van Uelft M, Drews A, Lenkeit L, Bruse N, Gerretsen J, Gierlich J, Becker M, Händler K, Kraut M, Theis H, Mengiste S, De Domenico E, Schulte-Schrepping J, Seep L, Raabe J, Hoffmeister C, ToVinh M, Keitel V, Rieke G, Talevi V, Skowasch D, Aziz NA, Pickkers P, van de Veerdonk FL, Netea MG, Schultze JL, Kox M, Breteler MMB, Nattermann J, Koutsoukou A, Giamarellos-Bourboulis EJ, Ulas T; German COVID-19 Omics Initiative (DeCOI). Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients. Genome Med. 2021 Jan 13;13(1):7. https://doi.org/10.1186/s13073-020-00823-5.

    14. Falck-Jones S , Vangeti S , Yu M  et al.   PREPRINT: functional myeloid-derived suppressor cells expand in blood but not airways of COVID-19 patients and predict disease severity. medRxiv  2020. doi:10.1101/2020.09.08.20190272.

      Falck-Jones S, Vangeti S, Yu M, Falck-Jones R, Cagigi A, Badolati I, Österberg B, Lautenbach MJ, Ahlberg E, Lin A, Lepzien R, Szurgot I, Lenart K, Hellgren F, Maecker HT, Sälde J, Albert J, Johansson N, Bell M, Lore K, Färnert A, Smed-Sörensen A. Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity. J Clin Invest. 2021 Jan 25:144734. https://doi.org/10.1172/JCI144734

    15. Lombardi A , Trombetta E , Cattaneo A  et al.   PREPRINT: early phases of COVID-19 are characterized by a reduction of lymphocyte populations and the presence of atypical monocytes. medRxiv  2020. doi:10.1101/2020.05.01.20087080.

      Lombardi A, Trombetta E, Cattaneo A, Castelli V, Palomba E, Tirone M, Mangioni D, Lamorte G, Manunta M, Prati D, Ceriotti F, Gualtierotti R, Costantino G, Aliberti S, Scaravilli V, Grasselli G, Gori A, Porretti L and Bandera A (2020) Early Phases of COVID-19 Are Characterized by a Reduction in Lymphocyte Populations and the Presence of Atypical Monocytes . Front. Immunol. 11:560330. https://doi.org/10.3389/fimmu.2020.560330

    16. Vietzen H , Zoufaly A , Traugott M  et al.   PREPRINT: NK cell receptor NKG2C deletion and HLA-E variants are risk factors for severe COVID-19. Res Square  2020. doi:10.21203/rs.3.rs-34505/v1.

      Vietzen H, Zoufaly A, Traugott M, Aberle J, Aberle SW, Puchhammer-Stöckl E. Deletion of the NKG2C receptor encoding KLRC2 gene and HLA-E variants are risk factors for severe COVID-19. Genet Med. 2021 Jan 26:1–5. https://doi.org/10.1038/s41436-020-01077-7

    17. Zhou Q , Wei X-S , Xiang X  et al.   PREPRINT: Interferon-a2b treatment for COVID-19. medRxiv  2020:2020.04.06.20042580.

      Zhou Q, Chen V, Shannon CP, Wei X-S, Xiang X, Wang X, Wang Z-H, Tebbutt SJ, Kollmann TR and Fish EN (2020) Interferon-α2b Treatment for COVID-19. Front. Immunol. 11:1061. https://doi.org/10.3389/fimmu.2020.01061

    18. Meng Z , Wang T , Li C  et al.   PREPRINT: An experimental trial of recombinant human interferon alpha nasal drops to prevent coronavirus disease 2019 in medical staff in an epidemic area. medRxiv  2020:2020.04.11.20061473.
    19. Simadibrata DM , Calvin J , Wijaya AD  et al.   PREPRINT: neutrophil-to-lymphocyte ratio on admission to predict the severity and mortality of COVID-19 patients: a meta-analysis. medRxiv  2020. doi:10.1101/2020.09.14.20191098.

      Simadibrata DM, Calvin J, Wijaya AD, Ibrahim NAA. Neutrophil-to-lymphocyte ratio on admission to predict the severity and mortality of COVID-19 patients: A meta-analysis. The American Journal of Emergency Medicine. 2021; 42: 60– 69. https://doi.org/10.1016/j.ajem.2021.01.006.

    20. Zhang D , Guo R , Lei L  et al.   PREPRINT: COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome. medRxiv  2020. doi:10.1101/2020.03.24.20042655.

      Zhang, D, Guo, R, Lei, L, et al. COVID‐19 infection induces readily detectable morphological and inflammation‐related phenotypic changes in peripheral blood monocytes. J Leukoc Biol. 2021; 109: 13– 22. https://doi.org/10.1002/JLB.4HI0720-470R