Biology subjects

McCowan, J.

Publications and source records attributed to McCowan, J..

3 recordsLinked to original sources

bioRxiv2024

POLYGENIC DETERMINANTS OF H5N1 ADAPTATION TO BOVINE CELLS

Avian influenza H5N1 clade 2.3.4.4b viruses caused a global panzootic and, unexpectedly, widespread outbreaks in dairy cattle, therefore representing a pandemic threat. To inform effective control strategies, it is critical to determine whether the potential to adapt to bovine cells is a generalised feature of H5N1 viruses, or is specific to clade 2.3.4.4b, or even more restricted to specific genotypes within this clade (e.g., B3.13 and D1.1). Using a large panel of H5N1 viruses representing >60 years of their natural history and other IAV for comparative purposes, we demonstrate that virus adaptation to bovine cells is: (i) highly variable across 2.3.4.4b genotypes, (ii) limited in viruses predating the global expansion of this clade, (iii) determined by the viral internal gene cassette, and (iv) not restricted to udder epithelial cells. Mutations in the PB2 polymerase subunit, particularly M631L, emerge as key determinants of adaptation, although their phenotypic effects are context dependent and have limited enhanced viral polymerase activity in human cells. Bovine B3.13 and some avian genotypes also exhibit enhanced modulation of bovine interferon-induced antiviral responses, determined by at least the viral PB2, nucleoprotein, and the non-structural protein NS1. Our results highlight the polygenic nature of IAV host range and reveal that the potential to cross the species barrier varies during the evolutionary trajectory of H5N1, with some avian viruses more predisposed to spillover than others.

microbiology↗

bioRxiv2024

Influenza A viruses induce tunnelling nanotube-like structures through the onset of apoptosis

As well as spreading through virions, influenza A viruses (IAVs) can evade antiviral drugs and neutralising antibodies by spreading directly from cell to cell. In cell culture this can occur by the induction of intercellular membrane connections known as tunnelling nanotube-like structures (TLSs), which are capable of trafficking the viral genome between cells. Here, we showed that TLSs are present at the site of IAV infections in vivo, and then used in vitro models to ask how IAVs induce their formation. We found that TLS induction cannot be induced by cytokine signalling from infected to uninfected cells, but requires IAV replication within cells. IAV replication can form filamentous virions with structural similarities to TLSs, but we found that TLS induction is independent of virion morphology. We therefore looked at the intracellular responses to infection. Using a pan-caspase inhibitor, we found that TLS induction by IAVs requires the onset of apoptosis. Our results, which suggest that IAVs control their ability to spread directly from cell to cell by driving infected cells into apoptosis, identifies a new way in which a virus can manipulate its host to evade antiviral immune responses. Author SummaryInfluenza A viruses (IAVs) spread efficiently through the respiratory tract in the form of extracellular virus particles, but can be restricted by neutralising antibodies and antiviral drugs. IAVs can avoid this restriction by transporting viral genomes directly from one cell to the next. They can do this by inducing the formation of long, thin intercellular connections known as tunnelling nanotube-like structures, which are capable of trafficking viral genomes. In this study, we demonstrate for the first time that tunnelling-nanotube like structures form within IAV infected lungs. We then asked how IAVs induce these structures. We found that cell death pathways triggered by IAV replication induce the formation of tunnelling nanotube-like structures, thereby establishing routes of infection spread to other cells. In this way, the virus exploits the cell death response of its host to ensure that its infection can continue to spread even within the restrictive environment of the respiratory tract.

microbiology↗

bioRxiv2021

The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair

Alveolar macrophages are the most abundant macrophages in the healthy lung where they play key roles in homeostasis and immune surveillance against air-borne pathogens. Tissue-specific differentiation and survival of alveolar macrophages relies on niche-derived factors, such as colony stimulating factor 2 (CSF-2) and transforming growth factor beta (TGF-{beta}). However, the nature of the downstream molecular pathways that regulate the identity and function of alveolar macrophages and their response to injury remains poorly understood. Here, we identify that the transcriptional factor EGR2 is an evolutionarily conserved feature of lung alveolar macrophages and show that cell-intrinsic EGR2 is indispensable for the tissue-specific identity of alveolar macrophages. Mechanistically, we show that EGR2 is driven by TGF-{beta} and CSF-2 in a PPAR-{gamma}-dependent manner to control alveolar macrophage differentiation. Functionally, EGR2 was dispensable for lipid handling, but crucial for the effective elimination of the respiratory pathogen Streptococcus pneumoniae. Finally, we show that EGR2 is required for repopulation of the alveolar niche following sterile, bleomycin-induced lung injury and demonstrate that EGR2-dependent, monocyte-derived alveolar macrophages are vital for effective tissue repair following injury. Collectively, we demonstrate that EGR2 is an indispensable component of the transcriptional network controlling the identity and function of alveolar macrophages in health and disease. One Sentence SummaryEGR2 controls alveolar macrophage function in health and disease

immunology↗