Oxysterols drive inflammation via GPR183 during influenza virus and SARS-CoV-2 infection (preprint)

Rationale: Severe 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. Objectives: To 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. Methods: Preclinical murine models of influenza virus and SARS-CoV-2 infection. Results: Oxidized 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. Conclusion: This 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.

Meeting Needs of Diverse Older Adults and Caregivers During Public Health Emergencies: What Can We Learn From COVID-19?

With support from the CDC Foundation and technical assistance from the Centers for Disease Control and Prevention, NORC at the University of Chicago conducted studies to examine the needs and concerns of older adults and unpaid caregivers during COVID-19, including their trusted sources of COVID-19 information and available public health interventions. Methods included a nationally representative survey of 1,030 adults aged 50+ years using computer-assisted telephone and web interviewing;online focus groups with older adults and caregivers in Spanish and English;a survey and interviews with stakeholder organizations;secondary analysis of U.S. caregiver surveys;analysis of public social media posts;and searches of peer-reviewed and grey literature in Spanish and English to identify interventions. Results suggest that needs and concerns differed among older adult subpopulations, including racial and ethnic minority populations, people with lower incomes, rural and tribal populations, people with limited English proficiency, and people with disabilities as well as caregivers. Older adults perceived news media, the internet, and healthcare providers as important resources for COVID-19 information, although trusted sources varied by race and ethnicity, urbanicity, and income. Findings suggested the need to increase awareness of existing public health interventions and resources to support older adults and caregivers during public health emergencies like COVID-19. Strategies for tailoring communication for diverse older adults and caregivers include partnering with national organizations, leveraging community-level infrastructure, and disseminating information through trusted sources. Studying the needs of older adults and caregivers during COVID-19 can inform future public health emergency response priorities.