Delayed Mucosal Antiviral Responses Despite Robust Peripheral Inflammation in Fatal COVID-19
Sidhu JK., Siggins MK., Liew F., Russell CD., Uruchurtu ASS., Davis C., Turtle L., Moore SC., Hardwick HE., Oosthuyzen W., Thomson EC., Semple MG., Baillie JK., Openshaw PJM., Thwaites RS., Baillie JK., Openshaw PJM., Semple MG., Alex B., Andrikopoulos P., Bach B., Barclay WS., Bogaert D., Chand M., Chechi K., Cooke GS., Filipe ADS., de Silva T., Docherty AB., Correia GDS., Dumas M-E., Dunning J., Fletcher T., Green CA., Greenhalf W., Griffin JL., Gupta RK., Harrison EM., Ho AYW., Holden K., Horby PW., Ijaz S., Khoo S., Klenerman P., Law A., Lewis MR., Liggi S., Lim WS., Maslen L., Mentzer AJ., Merson L., Meynert AM., Moore SC., Noursadeghi M., Olanipekun M., Osagie A., Palmarini M., Palmieri C., Paxton WA., Pollakis G., Price N., Rambaut A., Robertson DL., Russell CD., Sancho-Shimizu V., Sands CJ., Scott JT., Sigfrid L., Solomon T., Sriskandan S., Stuart D., Summers C., Swann OV., Takats Z., Takis P., Tedder RS., Thompson AAR., Thomson EC., Thwaites RS., Turtle LCW., Zambon M., Drake TM., Fairfield CJ., Knight SR., Mclean KA., Murphy D., Norman L., Pius R., Shaw CA., Connor M., Dalton J., Gamble C., Girvan M., Halpin S., Harrison J., Jackson C., Lee J., Marsh L., Plotkin D., Roberts S., Saviciute E., Clohisey S., Hendry R., Knight S., Lahnsteiner E., Law A., Leeming G., Norris L., Scott-Brown J., Tait S., Wham M., Carson G., Clark R., Coutts A., Donnelly L., Fawkes A., Gilchrist T., Hafezi K., MacGillivray L., Maclean A., McCafferty S., Morrice K., Murphy L., Wrobel N., Adeniji K., Agranoff D., Agwuh K., Ail D., Aldera EL., Alegria A., Allen S., Angus B., Ashish A., Atkinson D., Bari S., Barlow G., Barnass S., Barrett N., Bassford C., Basude S., Baxter D., Beadsworth M., Bernatoniene J., Berridge J., Berry C., Best N., Bothma P., Brittain-Long R., Bulteel N., Burden T., Burtenshaw A., Caruth V., Chadwick D., Chadwick D., Chambler D., Chee N., Child J., Chukkambotla S., Clark T., Collini P., Cosgrove C., Cupitt J., Cutino-Moguel M-T., Dark P., Dawson C., Dervisevic S., Donnison P., Douthwaite S., Drummond A., DuRand I., Dushianthan A., Dyer T., Evans C., Eziefula C., Fegan C., Finn A., Fullerton D., Garg S., Garg A., Gkrania-Klotsas E., Godden J., Goldsmith A., Graham C., Grammatikopoulos T., Hardy E., Hartshorn S., Harvey D., Havalda P., Hawcutt DB., Hobrok M., Hodgson L., Hormis A., Howard J., Jacobs M., Jain S., Jennings P., Kaliappan A., Kasipandian V., Kegg S., Kelsey M., Kendall J., Kerrison C., Kerslake I., Koch O., Koduri G., Koshy G., Laha S., Laird S., Larkin S., Leiner T., Lillie P., Limb J., Linnett V., Little J., Lyttle M., MacMahon M., MacNaughton E., Mankregod R., Masson H., Matovu E., McCullough K., McEwen R., Meda M., Mills G., Minton J., Mohandas K., Mok Q., Moon J., Moore E., Morgan P., Morris C., Mortimore K., Moses S., Mpenge M., Mulla R., Murphy M., Nagarajan T., Nagel M., Nelson M., Norris L., O'Shea MK., Ostermann M., Otahal I., Pais M., Palmieri C., Panchatsharam S., Papakonstantinou D., Papineni P., Paraiso H., Patel B., Pattison N., Pepperell J., Peters M., Phull M., Pintus S., Planche T., Post F., Price D., Prout R., Rae N., Reschreiter H., Reynolds T., Richardson N., Roberts M., Roberts D., Rose A., Rousseau G., Ruge B., Ryan B., Saluja T., Cole S., Schmid ML., Shah A., Shankar-Hari M., Shanmuga P., Sharma A., Shawcross A., Pooni JS., Sizer J., Smith R., Snelson C., Spittle N., Staines N., Stambach T., Stewart R., Subudhi P., Szakmany T., Tatham K., Thomas J., Thompson C., Thompson R., Tridente A., Tupper-Carey D., Twagira M., Vallotton N., Vancheeswaran R., Vincent R., Vincent-Smith L., Visuvanathan S., Vuylsteke A., Waddy S., Wake R., Walden A., Welters I., Whitehouse T., Whittaker P., Whittington A., Wijesinghe M., Williams M., Wilson L., Winchester S., Wiselka M., Wolverson A., Wootton DG., Workman A., Yates B., Young P., McDonald SE., Shaw V., Ahmed KA., Armstrong JA., Ashworth M., Asiimwe IG., Bakshi S., Barlow SL., Booth L., Brennan B., Bullock K., Carlucci N., Cass E., Catterall BWA., Clark JJ., Clarke EA., Cole S., Cooper L., Cox H., Davis C., Dincarslan O., Carracedo AD., Dunn C., Dyer P., Elliott A., Evans A., Finch L., Fisher LWS., Flaherty L., Foster T., Garcia-Dorival I., Gunning P., Hartley C., Holmes A., Jensen RL., Jones CB., Jones TR., Khandaker S., King K., Kiy RT., Koukorava C., Lake A., Lant S., Latawiec D., Lavelle-Langham L., Lefteri D., Lett L., Livoti LA., Mancini M., Massey H., Maziere N., McDonald S., McEvoy L., McLauchlan J., Metelmann S., Miah NS., Middleton J., Mitchell J., Moore SC., Murphy EG., Penrice-Randal R., Pilgrim J., Prince T., Reynolds W., Ridley PM., Sales D., Shaw VE., Shears RK., Small B., Subramaniam KS., Szemiel A., Taggart A., Tanianis-Hughes J., Thomas J., Trochu E., van Tonder L., Wilcock E., Zhang JE., Keating S., Donegan C., Spencer RG., Chikowore P., Donohue C., Griffiths F., Hardwick H., Oosthuyzen W.
Abstract Background While inflammatory and immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished coronavirus disease 2019 (COVID-19) severity categories, and relate these to disease progression and peripheral inflammation. Methods We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalized with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0–5 days after symptom onset) or late (6–20 days after symptom onset) phase. Results Patients that survived severe COVID-19 showed interferon (IFN)-dominated mucosal immune responses (IFN-γ, CXCL10, and CXCL13) early in infection. These early mucosal responses were absent in patients who would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by interleukin 2 (IL-2), IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions Defective early mucosal antiviral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19.