Biology subjects

Ferlic-Stark, L.

Publications and source records attributed to Ferlic-Stark, L..

3 recordsLinked to original sources

bioRxiv2026

RSV & rhinovirus coinfection order dictates outcome via type III interferon-mediated interference in infant respiratory epithelium

Coinfection with respiratory syncytial virus (RSV) and rhinovirus (RV) is the most frequently detected coinfection in infants, yet mechanisms governing viral interference and disease outcome remain poorly understood. Although infection order is a key determinant of coinfection outcome involving RSV, influenza, rhinovirus, and SARS-CoV-2, its role in RSV/RV coinfections has not been defined. Using infant-derived human nasal organoids at air-liquid interface, we demonstrate that coinfection order fundamentally determines the outcome of RSV/RV interactions. An initial RSV infection almost completely inhibits secondary RV coinfection, whereas primary RV infection only partially impairs a subsequent RSV coinfection. These distinct outcomes are accompanied by divergent temporal antiviral and pro-inflammatory responses. Mechanistically, we identify type III interferons as a sufficient mediator of RSV-induced restriction of RV, establishing a host-driven mechanism of viral interference. In contrast, partial impairment of RSV following RV infection occurs through an interferon-independent mechanism. Despite marked differences, RSV/RV coinfections do not exacerbate epithelial injury or innate immune responses beyond that induced by RSV alone, indicating RSV is the dominant driver of pathology in coinfections. Collectively, our data establishes coinfection order as a critical determinant of RSV/RV outcome and reveals novel and mechanistic insight into critical viral-host interactions in the infant nasal epithelium.

microbiology↗

bioRxiv2024

Pediatric human nose organoids demonstrate greater susceptibility, epithelial responses, and cytotoxicity than adults during RSV infection.

Respiratory syncytial virus (RSV) is a common cause of respiratory infections, causing significant morbidity and mortality, especially in young children. Why RSV infection in children is more severe as compared to healthy adults is not fully understood. In the present study, we infect both pediatric and adult human nose organoid-air liquid interface (HNO-ALIs) cell lines with two contemporary RSV isolates and demonstrate how they differ in virus replication, induction of the epithelial cytokine response, cell injury, and remodeling. Pediatric HNO-ALIs were more susceptible to early RSV replication, elicited a greater overall cytokine response, demonstrated enhanced mucous production, and manifested greater cellular damage compared to their adult counterparts. Adult HNO-ALIs displayed enhanced mucus production and robust cytokine response that was well controlled by superior regulatory cytokine response and possibly resulted in lower cellular damage than in pediatric lines. Taken together, our data suggest substantial differences in how pediatric and adult upper respiratory tract epithelium responds to RSV infection. These differences in epithelial cellular response can lead to poor mucociliary clearance and predispose infants to a worse respiratory outcome of RSV infection.

microbiology↗

bioRxiv2023

Longitudinal host transcriptional responses to SARS-CoV-2 infection in adults with extremely high viral load

Current understanding of viral dynamics of SARS-CoV-2 and host responses driving the pathogenic mechanisms in COVID-19 is rapidly evolving. Here, we conducted a longitudinal study to investigate gene expression patterns during acute SARS-CoV-2 illness. Cases included SARS-CoV-2 infected individuals with extremely high viral loads early in their illness, individuals having low SARS-CoV-2 viral loads early in their infection, and individuals testing negative for SARS-CoV-2. We could identify widespread transcriptional host responses to SARS-CoV-2 infection that were initially most strongly manifested in patients with extremely high initial viral loads, then attenuating within the patient over time as viral loads decreased. Genes correlated with SARS-CoV-2 viral load over time were similarly differentially expressed across independent datasets of SARS-CoV-2 infected lung and upper airway cells, from both in vitro systems and patient samples. We also generated expression data on the human nose organoid model during SARS-CoV-2 infection. The human nose organoid-generated host transcriptional response captured many aspects of responses observed in the above patient samples, while suggesting the existence of distinct host responses to SARS-CoV-2 depending on the cellular context, involving both epithelial and cellular immune responses. Our findings provide a catalog of SARS-CoV-2 host response genes changing over time.

microbiology↗