Biology subjects

Byrne, C. M.

Publications and source records attributed to Byrne, C. M..

3 recordsLinked to original sources

bioRxiv2025

Human cell-derived extracellular vesicles exhibit anti-biofilm effects against Pseudomonas aeruginosa

The need for new antimicrobial approaches is one of the most pressing issues in modern medicine. A particular pathogen of concern is multidrug resistant Pseudomonas aeruginosa, which is implicated in over 1 million deaths worldwide yearly. One potential class of novel antimicrobials is extracellular vesicles (EVs), which have been found to have intrinsic antimicrobial and anti-virulence properties. Here, the antimicrobial activity of EVs on P. aeruginosa was explored in the context of biofilms of hyper-virulent strain PA14. We identified the human monocyte cell line THP-1 as a promising source of EVs for this application, inducing reduced PA14 biofilm formation in a dose-dependent manner. THP-1 EVs were not found to affect P. aeruginosa growth planktonically within the biofilm assay or in shaken culture. Additionally, we demonstrate that anti-biofilm effects were conserved with similar efficacy across THP-1 monocyte and differentiated THP-1 macrophage-derived EVs. Further, EVs from induced pluripotent stem cell-derived mesenchymal stem/stromal cells (iMSCs) also reduced PA14 biofilm formation to a similar extent as THP-1 EVs, while EVs from human embryonic kidney cells (HEK293T) had a similar effect to its media control. This work indicates that human cell-derived EVs from several sources possess biological and/or physical properties that reduce PA14 biofilm formation.

microbiology↗

bioRxiv2024

Spatial kinetics and immune control of murine cytomegalovirus infection in the salivary glands

Human cytomegalovirus (HCMV) is the most common congenital infection. Several HCMV vaccines are in development, but none have yet been approved. An understanding of the kinetics of CMV replication and transmission may inform the rational design of vaccines to prevent this infection. The salivary glands (SG) are an important site of sustained CMV replication following primary infection and during viral reactivation from latency. As such, the strength of the immune response in the SG likely influences viral dissemination within and between hosts. To study the relationship between the immune response and viral replication in the SG, and viral dissemination from the SG to other tissues, mice were infected with low doses of murine CMV (MCMV). Following intra-SG inoculation, we characterized the viral and immunological dynamics in the SG, blood, and spleen, and identified organ-specific immune correlates of protection. Using these data, we constructed compartmental mathematical models of MCMV infection. Model fitting to data and analysis indicate the importance of cellular immune responses in different organs and point to a threshold of infection within the SG necessary for the establishment and spread of infection. Author SummaryCytomegalovirus (CMV) is the most common congenital infection and causes an enormous burden of childhood disease. To gain insight into the immune requirements for controlling infection, we used a mouse model to reproduce characteristics of natural CMV infection, employing a low viral inoculum, and delivering the virus to the salivary glands (SG), a key site of CMV replication. Our results provide detailed data on the spatial and temporal spread of infection throughout the body and identify key immune correlates of the control of viral replication. By translating these findings into mechanistic mathematical models, we revealed the importance of organ-specific immune responses, particularly the requirement of TNF- and IFN-{gamma} to control infection within the salivary glands. Furthermore, our mathematical modeling allowed us to compare known characteristics of human CMV infection related to infection establishment and spread to those predicted in mice, underscoring the suitability of the MCMV model to study its human homologue. These insights provide guidance for developing targeted vaccines to prevent CMV infection and disease.

microbiology↗

bioRxiv2019

Increased oral Epstein-Barr virus shedding with HIV-1 co-infection is due to a combination of B cell activation and impaired cellular immune control

Epstein-Barr virus (EBV) infection is transmitted by saliva and is a major cause of cancer in people living with HIV/AIDS as well as in the general population. To better understand the determinants of oral EBV shedding we evaluated the frequency and quantity of detectable EBV in the saliva in a prospective cohort study of 85 adults in Uganda, half of whom were co-infected with HIV-1. Participants were not receiving antiviral medications, and those with HIV-1 co-infection had a CD4+ T cell count >200 cells/mm3. Daily, self-collected oral swabs were collected over a 4-week period. Compared with HIV-1 uninfected participants, co-infected participants had an increased frequency of oral EBV shedding (IRR=1.27, 95% CI=1.10-1.47). To explain why EBV oral shedding is greater in HIV-1 co-infected participants, we developed a stochastic, mechanistic mathematical model that describes the dynamics of EBV, infected cells, and antiviral cellular immune responses within the tonsillar epithelium, and examined parameter-specific differences between individuals of different HIV-1 infection statuses. We fit the model to our observational data using Approximate Bayesian Computation. After fitting, model simulations showed high fidelity to daily oral shedding time-courses and matched key summary statistics. Examination of the model revealed that higher EBV loads in saliva are driven by B cell activation causing EBV lytic replication in the tonsils, in combination with a less effective EBV-specific cellular immune response. Thus, both these factors contribute to higher and more frequent EBV shedding in HIV-1 co-infected individuals compared to HIV-1 uninfected individuals. These conclusions were further validated by modelling daily oral EBV shedding in a 26-participant North American cohort. Our results provide insights into the determinants of EBV shedding and implicate B cell activation to be a potential therapeutic target to reduce EBV replication in HIV-1 co-infected individuals at high risk for EBV-related malignancies.\n\nAuthor summaryEpstein-Barr virus (EBV) is a ubiquitous infection worldwide. Infection with EBV is associated with the development of several kinds of cancer, including B cell lymphoma and nasopharyngeal carcinoma. Rates of EBV replication and disease are higher in individuals who are also infected with HIV-1. HIV-1 infection is associated with increased B cell activation, which is known to induce EBV reactivation, as well as immunodeficiency resulting from loss of T cells. However, whether these factors contribute to higher rates of EBV replication during co-infection, and by how much, was unknown. We analysed oral EBV shedding data in a cohort of adults from Uganda that were chronically infected with EBV. We found that participants that were HIV-1 infected were much more likely to have detectable quantities of EBV in their saliva. Also, when detected, the quantity of EBV present in the saliva was usually higher in HIV-1 infected participants. To better understand these findings, we developed a mathematical model to describe the dynamics of EBV, EBV-infected cells, and the cellular immune response within the tonsils. By rigorously matching our model to our participant data, we determined that high EBV loads in saliva are caused by high rates of infected B cell activation, as well as worse cellular immune control of EBV infection. These results provide an explanation of the impact of HIV-1 on EBV infection. Further, they suggest that strategies that suppress B cell activation may prevent EBV-related malignancy in people who are also infected with HIV-1.

pathology↗