Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients

Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in Wuhan in December 2019 and has since spread across the world. Even though the majority of patients remain completely asymptomatic, some develop severe systemic complications. In this prospective study we compared the immunological profile of 101 COVID-19 patients with either mild, moderate or severe form of the disease according to the WHO classification, as well as of 50 healthy subjects, in order to identify functional immune factors independently associated with severe forms of COVID-19. Plasma cytokine levels, and cytokine levels upon in vitro non-specific stimulation of innate and adaptive immune cells, were measured at several time points during the course of the disease. As described previously, inflammatory cytokines IL1β, IL6, IL8, and TNFα associated with cytokine storm were significantly increased in the plasma of moderate and severe COVID-19 patients (p < 0.0001 for all cytokines). During follow-up, plasma IL6 levels decreased between the moment of admission to the hospital and at the last observation carried forward for patients with favorable outcome (p = 0.02148). After in vitro stimulation of immune cells from COVID-19 patients, reduced levels of both type I and type II interferons (IFNs) upon in vitro stimulation were correlated with increased disease severity [type I IFN (IFNα): p > 0.0001 mild vs. moderate and severe; type II IFN (IFNγ): p = 0.0002 mild vs. moderate and p < 0.0001 mild vs. severe] suggesting a functional exhaustion of IFNs production. Stimulated IFNα levels lower than 2.1 pg/ml and IFNγ levels lower than 15 IU/mL at admission to the hospital were associated with more complications during hospitalization (p = 0.0098 and p =0.0002, respectively). A low IFNγ level was also confirmed by multivariable analysis [p = 0.0349 OR = 0.98 (0.962; 0.999)] as an independent factor of complications. In vitro treatment with type IFNα restored type IFNγ secretion in COVID-19 patients while the secretion of pro-inflammatory cytokines IL6 and IL1β remained stable or decreased, respectively. These results (a) demonstrate a functional exhaustion of both innate and adaptive immune response in severe forms of COVID-19; (b) identify IFNα and IFNγ as new potential biomarkers of severity; and (c) highlight the importance of targeting IFNs when considering COVID-19 treatment in order to re-establish a normal balance between inflammatory and Th1 effector cytokines.

Proteinuria as a Biomarker for COVID-19 Severity

“…These facts can support the relation with proteinuria and cytokine storm in SARS-CoV-2 infection. As described previously, inflammatory cytokines IL1β, IL6, IL8, and TNFα increased in the plasma of moderate and severe COVID-19 patients (Ruetsch et al, 2021). Cytokine storm may contribute to COVID-19 AKI by cooperating with renal resident cells and promoting tubular and endothelial dysfunction.…”

“…Cytokine storm may contribute to COVID-19 AKI by cooperating with renal resident cells and promoting tubular and endothelial dysfunction. Previous studies described a relevant role for IL6 (Ruetsch et al, 2021). Interleukin-6 can lead renal endothelial cells to produce proinflammatory cytokines and chemokines, and can induce kidney vascular permeability, acting in microcirculatory dysfunction.…”

“…Even if a case of collapsing glomerulopathy has been reported in COVID-19 (Gaillard et al, 2020), acute tubular necrosis (ATN) with interstitial component probably remains the main cause of kidney injury. Other factors may contribute to kidney involvement: systemic inflammation and cytokine storm (Burton and Harris, 1996;Coletta et al, 2000;Gohda et al, 2001;D'Amico and Bazzi, 2003;Imai, 2003;Thorevska et al, 2003;Mäkelä et al, 2004;Wassmann et al, 2004;Kielar et al, 2005;Abbate et al, 2006;Liu et al, 2007;Delvaeye and Conway, 2009;Murugan et al, 2010;Ranganathan et al, 2013;Darmon et al, 2014Darmon et al, , 2017Su et al, 2017;Sarhan et al, 2018;Meissner et al, 2019;Cremoni et al, 2020;Mehta et al, 2020;Pan et al, 2020;Rossi et al, 2020;Siddiqi and Mehra, 2020;Tang et al, 2020;Vaninov, 2020;Zhang et al, 2020;Ruetsch et al, 2021), release of pathogenassociated molecular patterns (PAMPs), high levels of damageassociated molecular proteins (DAMPS) from lung injury and severe hypoxemic respiratory failure (Burton and Harris, 1996;Coletta et al, 2000;Gohda et al, 2001;D'Amico and Bazzi, 2003;Thorevska et al, 2003;Mäkelä et al, 2004;Wassmann et al, 2004;Kielar et al, 2005;…”

“…Pro-inflammatory cytokines can also induce capillary leak syndrome and the production of thrombosis. Interestingly, IL6 could be produced by renal resident cells, including podocytes (Burton and Harris, 1996;Coletta et al, 2000;Gohda et al, 2001;Mäkelä et al, 2004;Wassmann et al, 2004;Kielar et al, 2005;Abbate et al, 2006;Ranganathan et al, 2013;Su et al, 2017;Cremoni et al, 2020;Pan et al, 2020;Ruetsch et al, 2021), mesangial cells (Coletta et al, 2000;Gohda et al, 2001), endothelial cells (Wassmann et al, 2004) and tubular epithelial cells (Kielar et al, 2005;Ranganathan et al, 2013). All these cells would actively respond to IL6 (Su et al, 2017).…”

A Retrospective Cohort Study on the Clinical Course of Patients With Moderate-Type COVID-19

“…Ali A Ghweil and his colleagues reported that reduced leucocytes count was more likely to appear in patients with severe COVID-19 (30). Functional exhaustion of both innate and adaptive immune response was positively related to the severity of COVID-19 (31). The World Health Organization (WHO) has published guidance recommending no corticosteroids for those with non-severe COVID-19 (32), which seemed to prove our speculation to some extent.…”