COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds

Abstract

Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.

COVID-19-associated pulmonary aspergillosis in immunocompetent patients: A virtual patient cohort study

“…Tappe, B et al . 2022 [20] found that neutrophils of COVID-19 patients had reduced ROS production qualitatively similar to the reduction in neutrophils’ killing ability in simulated CAPA patients in our model (Figure A4). At the same time, Grunwell, JR et al .…”

“…Our model suggests that both reducing neutrophil activity and increasing fungal intrinsic growth rate might be necessary for CAPA to emerge (Figures 4 and 5). Tappe, B et al 2022 [20] found that neutrophils of COVID-19 patients had reduced ROS production qualitatively similar to the reduction in neutrophils' killing ability in simulated CAPA patients in our model (Figure A4). At the same time, Grunwell, JR et al 2018 [21] found that neutrophils treated with airway supernatant of patients with acute respiratory failure due to lower respiratory tract viral infection had altered surface markers.…”

“…A4 Immune system inhibition by SARS-CoV-2. A: decrease in ROS production in patients with SARS-CoV-2 [20]. B: decrease in neutrophil killing ability in virtual patients with CAPA relative to patients without CAPA (Scenario 1).

Fig.

…”

Defective antifungal immunity in patients with COVID-19

“…A functional analysis to determine the connection between immune cells from COVID-19 patients and fungal pathogens demonstrated an impaired immune response to fungal infection ( 87 ). Challenging T cells from COVID-19 patients with antigens from A. fumigatus and Rhizopus arrhizus revealed impaired cytokine expression and increased expression of the exhaustion marker PD-1 ( 87 ).…”

“…A functional analysis to determine the connection between immune cells from COVID-19 patients and fungal pathogens demonstrated an impaired immune response to fungal infection ( 87 ). Challenging T cells from COVID-19 patients with antigens from A. fumigatus and Rhizopus arrhizus revealed impaired cytokine expression and increased expression of the exhaustion marker PD-1 ( 87 ). A significant finding in this study was impaired fungicidal activity by neutrophils, neutropenia is a significant risk factor for IFD and neutrophils are the most important innate immune cells in antifungal immunity ( 88 ).…”