Biology subjects

Gartner, M. J.

Publications and source records attributed to Gartner, M. J..

3 recordsLinked to original sources

bioRxiv2026

Viral replication and host response in airway epithelial cells predicts coronavirus pathogenicity and identifies HCoV-229E as an atypical seasonal coronavirus

Human coronaviruses (HCoVs) range from mild seasonal strains to pathogenic viruses that cause severe pneumonia. The virological and host determinants that distinguish pathogenic coronaviruses (MERS-CoV, SARS-CoV-2) from seasonal strains (HCoV-229E, HCoV-NL63 and HCoV-OC43) remain poorly defined. To identify determinants of pathogenicity, we systematically compared replication, cellular tropism, innate responses and cytopathogenicity of pathogenic compared with seasonal HCoVs across nasal, bronchial, small airway and embryonic stem cell derived alveolar type II (AT2) epithelial cell cultures. All HCoVs preferentially infected ciliated cells in the upper airway, but only pathogenic viruses replicated to high titres in AT2 cells. Pathogenic HCoVs reprogrammed AT2 function and suppressed key innate immune signatures, consistent with distal lung epithelial dysfunction. In contrast, seasonal HCoVs were associated with limited alveolar replication and milder disruption of AT2 homeostasis. Strikingly, despite modest replication in all cell types, HCoV-229E induced pronounced epithelial injury, cilia loss and strong interferon stimulated gene expression, as well as induction of cellular stress/death programmes resembling those induced by MERS-CoV. These findings highlight the striking differences in cellular responses throughout the airways and between distinct HCoV strains and emphasizes the importance of assessing distal lung tropism and epithelial host responses to evaluate emergent coronaviruses to inform pandemic preparedness strategies.

microbiology↗

bioRxiv2025

Contemporary seasonal human coronaviruses display differences in cellular tropism compared to laboratory-adapted reference strains

Seasonal human coronaviruses (sHCoVs) cause 15-30% of common colds. The reference strains used for research were isolated decades ago and have been passaged extensively but contemporary sHCoVs have been challenging to study as they are notoriously difficult to grow in standard immortalized cell lines. Here we addressed these issues by utilizing primary human nasal epithelial cells (HNECs) and immortalized human bronchial epithelial cells (BCi) differentiated at an air-liquid interface, as well as human embryonic stem cell-derived alveolar type II (AT2) cells to recover contemporary sHCoVs from human nasopharyngeal specimens. From 21 specimens we recovered four 229E, three NL63 and eight OC43 viruses. All contemporary sHCoVs showed sequence differences from lab-adapted CoVs, particularly within the spike gene. Evidence of nucleotide changes in the receptor binding domains within 229E and detection of recombination for both 229E and OC43 isolates was also observed. Importantly, we developed methods for the amplification of high titre stocks of NL63 and 229E, that maintained sequence identity, and we established methods for the titration of contemporary sHCoV isolates. Comparison of lab-adapted and contemporary strains in immortalised cell lines and airway epithelial cells revealed differences in cell tropism, growth kinetics and cytokine production between lab-adapted and contemporary sHCoV strains. These data confirm that contemporary sHCoVs differ from lab-adapted reference strains and, using the methods established here, should be used for study of CoV biology and evaluation of medical countermeasures. ImportanceZoonotic coronaviruses have caused significant public health emergencies. The occurrence of a similar spillover event in the future is likely and efforts to further understand coronavirus biology should be a high priority. Several seasonal coronaviruses circulate within the human population. Efforts to study these viruses have been limited to reference strains isolated decades ago due to the difficulty in isolating clinical isolates. Here, we use human airway and alveolar epithelial cultures to recover contemporary isolates of NL63, 229E and OC43. We establish methods to make high titre stocks and titrate 229E and NL63 isolates. We show that contemporary isolates of NL63 and OC43 have a different tropism within the respiratory epithelium compared to lab-adapted strains. Although 229E clinical and lab-adapted strains similarly infect the respiratory epithelium, differences in host response and replication kinetics are observed. Using the methods developed here, future research should include contemporary isolates when studying coronavirus biology.

microbiology↗

bioRxiv2022

Parallel use of pluripotent human stem cell lung and heart models provide new insights for treatment of SARS-CoV-2

SARS-CoV-2 primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe COVID-19. To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR- Cas9 mediated knock-out of ACE2, we demonstrated that angiotensin converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but further processing in lung cells required TMPRSS2 while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems. One-sentence summaryRational treatment strategies for SARS-CoV-2 derived from human PSC models

microbiology↗