Biology subjects

Boyd, D. F.

Publications and source records attributed to Boyd, D. F..

3 recordsLinked to original sources

bioRxiv2025

Immunomodulation of the Innate Host Response by Mesenchymal-Derived Versican during Influenza A Virus Infection

Viral and bacterial lung infections place a significant burden on public health. Versican, an extracellular matrix (ECM) chondroitin sulfate proteoglycan, coordinates the innate immune response in multiple experimental models. Versicans potential as an immunomodulatory molecule makes it a promising therapeutic target for controlling the hosts immune response to lung infection. However, versicans contribution to lung inflammation, injury, and immune cell activity during influenza A virus (IAV) infection represents a critical knowledge gap. To address our central hypothesis that mesenchymal-derived versican is pro-inflammatory and enhances the innate immune response to IAV infection, we generated a tamoxifen-inducible mouse deficient in mesenchymal-derived versican (B6. Col1a2-CreERT+/-/Vcantm1.1Cwf, Col1a2/Vcan-/-). We report that mesenchymal-derived versican plays a critical role in neutrophil, monocyte, and dendritic cell migration into the lungs and airways early in IAV infection. Intriguingly, mesenchymal-derived versican deficiency had the most substantial negative impact on neutrophil emigration into the lungs. We found that neutrophils were less adhesive to the ECM of Col1a2/Vcan-/- mouse lung fibroblasts (mLFs), which had a significant decrease in versican compared to wild-type mLFs. Additionally, Col1a2/Vcan-/- mLFs treated with poly(I:C) in vitro have reduced cell-associated hyaluronan. These findings suggest that fibroblast-derived versican is necessary for adhesion to lung fibroblasts by neutrophils as they transit into the lung interstitium and airways from the pulmonary vasculature. Our findings demonstrate that mesenchymal-derived versican is a key regulator of the early host immune responses to IAV. NEW & NOTEWORTHYWe report the novel finding that mesenchymal-derived versican is critical for neutrophil, monocyte, and dendritic cell migration into the lungs and airways early in influenza A virus infection. Additionally, a differentiated neutrophil-cell line is less adherent to versican-deficient fibroblasts, and versican-deficient fibroblasts have significantly reduced cell-associated hyaluronan (HA) content in vitro. These findings suggest that mesenchymal-derived versican and cell-associated HA are necessary for the adhesion of neutrophils and monocytes to lung fibroblasts.

molecular biology↗

bioRxiv2025

Perinatal Nicotine Exposure Disrupts Hematopoietic Stem Cell Development and Elevates Influenza Susceptibility in Adulthood

Tobacco use during pregnancy has many deleterious health consequences for not only the smoking mother, but also on the unborn fetus. Children of smoking mothers are reported to have higher frequency and severity of respiratory diseases later in life; however, the mechanisms driving this increased vulnerability are not clearly understood. One potential cause of increased disease susceptibility is an altered immune system, originating in epigenetically maladaptive hematopoietic stem cells (HSCs). Here, we show that perinatal nicotine exposure (PNE) alters the establishment of HSCs and fetal-derived non-traditional tissue immune cells, with no alterations in circulating immune cell numbers. Suppression of HSCs and lung immune cells persisted for weeks after PNE had ceased. Strikingly, PNE led to increased disease susceptibility and severity upon challenge with influenza A virus in adulthood. This was associated with significant and highly selective alterations in lung immune cells, emphasizing the importance of cellular mechanisms in resilience to infections. Together, these experiments demonstrate that perinatal exposures that have deleterious consequences on hematopoietic establishment can impair immune function for life and identify the cellular mechanisms by which perinatal nicotine exposure predisposes the offspring to a weakened defense against respiratory pathogens. HIGHLIGHTSO_LIPerinatal nicotine exposure (PNE) causes long-term alterations of hematopoiesis C_LIO_LIPNE perturbs hematopoietic stem cell (HSC) development and maintenance C_LIO_LIPNE diminishes the population of fetal-derived tissue-resident alveolar macrophages C_LIO_LIPNE alters cellular mechanisms, exacerbating disease severity later in life C_LIO_LINicotine suppression of central immunity is manifested mechanistically by altered immune cell output C_LI

developmental biology↗

bioRxiv2024

Phospholipid Scramblase 1 (PLSCR1) Regulates Interferon-Lambda Receptor 1 (IFN-lambdaR1) and IFN-lambda Signaling in Influenza A Virus (IAV) Infection

Phospholipid scramblase 1 (PLSCR1) is an antiviral interferon-stimulated gene (ISG) that has several known anti-influenza functions. However, the mechanisms in relation to its expression compartment and enzymatic activity have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. Our results showed that Plscr1 expression was highly induced by influenza A virus (IAV) infection in vivo and in airway epithelial cells treated with IFN-{lambda}. We found that infected Plscr1-/-mice exhibited exacerbated body weight loss, decreased survival rates, heightened viral replication, and increased lung damage. Interestingly, transcriptomic analyses demonstrated that Plscr1 was required for the expression of type 3 interferon receptor (Ifn-{lambda}r1) and a large subset of ISGs upon IAV infection. The impaired expression of Ifn-{lambda}r1 and downstream ISGs may be responsible for delayed viral clearance and worse lung inflammation in Plscr1-/- mice. PLSCR1 acts as a transcriptional activator of IFN-{lambda}R1 by directly binding to its promotor after IAV infection. In addition, PLSCR1 interacted with IFN-{lambda}R1 on the cell surface of pulmonary epithelial cells following IAV infection, suggesting it also modulated IFN-{lambda} signaling via protein-protein interactions. The lipid scramblase activity of PLSCR1 was found to be dispensable for its anti-flu activity. Finally, single-cell RNA sequencing data indicated that Plscr1 expression was significantly upregulated in ciliated airway epithelial cells in mice following IAV infection. Consistently, Plscr1floxStopFoxj1-Cre+ mice with ciliated epithelial cell-specific Plscr1 overexpression showed reduced susceptibility to IAV infection, less inflammation and enhanced Ifn-{lambda}r1 expression, suggesting that Plscr1 primarily regulates type 3 IFN signaling as a cell intrinsic defense factor against IAV in ciliated airway epithelial cells. Our research will elucidate virus-host interactions and pave the way for the development of novel anti-influenza drugs that target human elements like PLSCR1, thereby mitigating the emergence of drug-resistant IAV strains.

immunology↗