ABSTRACT
RationaleSevere viral respiratory infections are often characterized by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain elusive. ObjectivesTo identify the mechanisms that drive immune cell recruitment in the lung during viral respiratory infections and identify novel drug targets to reduce inflammation and disease severity. MethodsPreclinical murine models of influenza virus and SARS-CoV-2 infection. ResultsOxidized cholesterols and the oxysterol-sensing receptor GPR183 were identified as drivers of monocyte-macrophage infiltration to the lung during influenza virus (IAV) and SARS-CoV-2 infections. Both IAV and SARS-CoV-2 infections upregulated the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) in the lung, resulting in local production of the oxidized cholesterols 25-hydroxycholesterol and 7,25-dihydroxycholesterol (7,25-OHC). Loss-of-function mutation of GPR183, or treatment with a GPR183 antagonist, reduced macrophage infiltration and inflammatory cytokine production in the lungs of IAV- or SARS-CoV-2-infected mice. The GPR183 antagonist also significantly attenuated the severity of SARS-CoV-2 infection by reducing weight loss and viral loads. ConclusionThis study demonstrates that oxysterols drive inflammation in the lung and provides the first preclinical evidence for therapeutic benefit of targeting GPR183 during severe viral respiratory infections. Author SummaryViral infections trigger oxysterol production in the lung, attracting macrophages via GPR183. Blocking GPR183 reduced inflammation and disease severity in SARS-CoV-2 infection, making GPR183 a putative target for therapeutic intervention.
ABSTRACT
This article, a qualitative exploration of the experiences of subsequent children, endeavors to clarify common issues and experiences of this population. Subsequent children, also known as subsequent siblings, are children born after the death of a brother or sister. For this study, 25 adult subsequent siblings participated in semi-structured interviews. Few researchers have written about this population, and much of what has been documented was researched from single case studies, or from very small samples. This study aims to explore the commonalities of the unique experience of being a subsequent child. Themes which emerged include various replacement child dynamics, impaired bonding with parents or altered parenting as a result of the loss, family grief and its repercussions, meaning making and spiritual questioning, fantasies about the lost sibling, disenfranchised and unresolved grief, taking on a caregiver role, and survivor guilt. The implications for clinical practice are presented.
