Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells. CXCL12 levels were negatively correlated with LDN numbers in longitudinal analyses of patient blood samples. CXCL12 blockade in SARS-CoV-2–infected mice increased blood/lung neutrophil numbers, thereby accelerating disease progression without changing lung virus titers. The exaggerated mortality caused by CXCL12 blockade could be reversed by neutrophil depletion. In addition, blocking interactions between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) reduced CXCL12 levels, suggesting a signal transduction from virus-mediated ACE2 ligation to increased CXCL12 secretion. Collectively, these results demonstrate a previously unappreciated role of CXCL12 in diminishing neutrophilia, including low-density neutrophilia, and its deleterious effects in SARS-CoV-2 infections. The results also support the involvement of SARS-CoV-2–endothelial cell interactions in viral pathogenesis.

Background/Objectives: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2), has resulted in 777 million cases worldwide. Various vaccines have been approved to control the spread of COVID-19, with mRNA vaccines (Pfizer and Moderna) being widely used in the USA. We conducted a prospective longitudinal study to analyze the immune response elicited by two/three and four doses of monovalent mRNA vaccines in both vaccinated individuals and those who experienced breakthrough infections. Participants were stratified into different age groups: 18–40, 41–60, and over 60 years. Methods: We assessed cross-variant neutralization responses in two cohorts—Cohort I: n = 167 (serum), Cohort II: n = 92 (serum and nasal swab) samples—using infectious virus microneutralization assay (MN) and antibody (IgG or IgA) binding ELISA titers to the spike protein receptor binding domain (RBD). Samples were collected from the Louisville Metro–Jefferson County Co-Immunity Project, a federally funded, population-based study for the surveillance of SARS-CoV-2 in Jefferson County, Kentucky during 2020–2022, involving both health care workers and a local community. Results: Individuals who received two doses of the mRNA vaccine exhibited reduced neutralization against Beta, Delta, and Omicron BA.1 variants compared to wildtype Wuhan, with further decline observed six months post-booster vaccination. However, individuals who experienced natural COVID-19 infection (breakthrough) after receiving two vaccine doses showed enhanced neutralization and antibody responses, particularly against Omicron BA.1. Following the 3rd dose, antibodies and neutralization responses were restored. Among triple-vaccinated individuals, reduced neutralization was observed against Omicron variants BA.1, BA.5, and BA.2 compared to Wuhan. Neutralization responses were better against BA.2 variant compared to BA.1 and BA.5. However, individuals who received three doses of vaccine and experienced a breakthrough infection (n = 45) elicited significantly higher neutralizing antibodies responses against all Omicron subvariants compared to vaccinated individuals. Interestingly, nasal swab samples collected from volunteers with breakthrough infection showed significantly elevated spike-reactive mucosal IgA antibodies and enhanced cross neutralization against BA.1, BA.2, and BA.5 compared to individuals who received only three vaccine doses. Conclusions: mRNA vaccination elicits a strong systemic immune response by boosting serum neutralizing antibodies (NAb), although this protection wanes over time, allowing new variants to escape neutralization. Breakthrough individuals have extra enrichment in nasal NAb offering protection against emerging variants. This longitudinal immune profiling underscores the strengthening of pandemic preparedness and supports the development of durable mucosal vaccines against respiratory infectious disease.

Among the seven coronaviruses that infect humans, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 usually cause mild and common cold symptoms; however, infection with three coronaviruses, namely severe acute respiratory syndrome coronavirus [SARS-CoV], Middle East respiratory syndrome coronavirus [MERS-CoV], and the newly identified severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], often results in respiratory distress, cytokine storm and multiorgan failure

Despite the critical role of lipid-mediated signaling in regulating host immunity, endorsed by growing evidence, the interaction between lipid metabolism and immune response remains largely unknown. This review aims to elucidate the immunomodulatory role of a lung-enriched lipid metabolic pathway mediated by the phospholipase A2 (PLA₂) family, which comprises a diverse range of lipid-hydrolyzing enzymes. Based on their location, structure, substrate specificity and physiological roles, PLA₂s can be classified into secreted PLA₂s (sPLA₂s), cytosolic PLA₂s (cPLA₂s), calcium-independent PLA₂s (iPLA₂s), and lysosomal-associated PLA₂s (lPLA₂s). These PLA₂ isoforms are similar in that they can all cleave cellular membrane-associated phospholipids, releasing free lysophospholipids and fatty acids such as arachidonic acid, which subsequently serve as precursors for a wide range of bioactive mediators responsible for physiological functions and pathological changes. Respiratory infections, especially those caused by bacteria and viruses, represent a substantial threat to the health of the population worldwide and cause billions of disease cases and millions of deaths annually. Respiratory infections provoke airway inflammation, characterized by increased vascular permeability and the influx of immune cells, resulting in tissue damage, impaired gas exchange, acute respiratory distress syndrome (ARDS) and even death. During infections and inflammatory milieu, airway-expressed PLA₂ can further increase and exhibit protection by restricting pathogens and inflammation or, in contrast, exacerbate the pathogenesis. In this manuscript, we will provide an overview of the current knowledge on the biological functions of PLA₂ isoforms, especially concerning membrane-associated isoforms in respiratory infections, and offer insight into the spatial and temporal regulation of immune responses mediated by PLA₂ and the subsequent modulation of host–pathogen interactions and the balance between protective effects and pathological outcomes.

The COVID-19 pandemic has triggered unparalleled global disruption