The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE
, are critical molecules in the initiation and ...resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE
levels and is highly expressed at sites of inflammation. PGE
is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4
regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1
CD4
cells showed impaired IL-17A, IFN-γ, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE
by cocultured APCs synergized with that of Ag-experienced CD4
T cells, with mPGES1 competence in the APC compartment enhancing CD4
IL-17A and IFN-γ responses. However, in contrast with CD4
cells that were Ag primed in vivo, exogenous PGE
inhibited proliferation and skewed IL-17A to IFN-γ production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE
production that impacts effector T cell IL-17A and IFN-γ responses.
Abstract
The COVID-19 pandemic has caused a global public health crisis of unprecedented proportions. SARS-CoV-2, the etiological agent of COVID-19, primarily infects the respiratory tract, leading ...to a range of symptoms including dry cough, fever, and shortness of breath. While many cases remain mild or asymptomatic, a subset progress to acute respiratory distress syndrome (ARDS) requiring ICU admission and ventilation support. Rapid progress has been made to understand the pathogenesis and immune response to SARS-CoV-2 infection; however, there remain a number of unanswered questions.
Recent evidence has indicated that mild cases of COVID-19 are controlled by an effective innate immune response. However, in moderate and severe cases, the immune response to infection appears to be dysfunctional leading to low levels of interferon and high inflammatory responses.
Here, we examined a cohort of patients admitted to the Emory University Hospital with severe COVID-19. Patients had variable neutralization titers measured by FRNT assay, which did not correlate age or disease severity. Flow cytometry immune subset analysis, cytokine and chemokine quantification, and single cell RNA sequencing (scRNAseq) revealed an inflammatory phenotype including a significant shift in the myeloid compartment compared to healthy donors. Numbers of pDCs and non-classical (CD14−CD16+) monocytes in the blood were decreased, while intermediate monocytes (CD14+CD16+) cells were increased. Additionally, stimulated CD14+ cells from healthy donors were able to limit SARS-CoV-2 infection in a human airway epithelial culture system. This suggests a role for monocytes to combat infection by SARS-CoV-2 that may be dysregulated in severe patients.
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