Biology subjects

Griffiths, C. D.

Publications and source records attributed to Griffiths, C. D..

3 recordsLinked to original sources

bioRxiv2026

Lung Epithelial TLR7 is a Factor in Viral Replication and Pathogenesis

Respiratory virus infections are the leading causes of morbidity and mortality of infants and the elderly worldwide. Currently it is not known how Respiratory Syncytial Virus (RSV) vaccination of infants can cause enhancement of RSV disease, highlighting gaps in our understanding about how viruses like RSV interact with the immune system. Here we address this and show that ERK MAP kinase signaling from Toll-like Receptor-7 (TLR7) detection of RSV and influenza, but not human parainfluenza virus type 3 (HPIV3), infections in bronchial epithelial cells (BECs) drives replication of the viruses. Virus infection is detected by pattern recognition receptors like TLR7 that bind to single stranded RNA (ssRNA) viral replication intermediates in late endosomes. Here we report that TLR7 is expressed in BECs and detects RSV ssRNA, causing ERK MAP kinase signaling. RSV and influenza use this detection and signaling in BECs to drive its replication and infection, a mechanism that counters TLR7s role in antiviral defence. Experimental blockade of TLR7 binding or downstream signalling through ERK MAP kinase decreased RSV and influenza replication, but had no effect on HPIV3. RSV viral loads in mouse and human females were higher compared to males, consistent with higher sex-dependent expression of the TLR7 gene from two copies of the X chromosome in females. In a TLR7 gain of function mouse model there was a significant enhancement of RSV replication and RSV eosinophilic and Th2 disease markers like interleukin-5 (IL-5). In summary, TLR7 is expressed in human lung BECs in the lungs where it acts as a factor in RSV and influenza replication and disease pathogenesis. We propose that this is a major factor in determining the sex-disparity of viral disease.

microbiology↗

bioRxiv2024

Three Modes of Viral Adaption by the Heart

Viruses elicit long-term adaptive responses in the tissues they infect. Understanding viral adaptions in humans is difficult in organs such as the heart, where primary infected material is not routinely collected. In search of asymptomatic infections with accompanying host adaptions, we mined for cardio-pathogenic viruses in the unaligned reads of nearly one thousand human hearts profiled by RNA sequencing. Among virus-positive cases ([~]20%), we identified three robust adaptions in the host transcriptome related to inflammatory NF{kappa}B signaling and post-transcriptional regulation by the p38-MK2 pathway. The adaptions are not determined by the infecting virus, and they recur in infections of human or animal hearts and cultured cardiomyocytes. Adaptions switch states when NF{kappa}B or p38-MK2 are perturbed in cells engineered for chronic infection by the cardio-pathogenic virus, coxsackievirus B3. Stratifying viral responses into reversible adaptions adds a targetable systems-level simplification for infections of the heart and perhaps other organs.

systems biology↗

bioRxiv2023

Proteome-wide copy-number estimation from transcriptomics

Protein copy numbers constrain systems-level properties of regulatory networks, but absolute proteomic data remain scarce compared to transcriptomics obtained by RNA sequencing. We addressed this persistent gap by relating mRNA to protein statistically using best-available data from quantitative proteomics-transcriptomics for 4366 genes in 369 cell lines. The approach starts with a central estimate of protein copy number and hierarchically appends mRNA-protein and mRNA-mRNA dependencies to define an optimal gene-specific model that links mRNAs to protein. For dozens of independent cell lines and primary prostate samples, these protein inferences from mRNA outmatch stringent null models, a count-based protein-abundance repository, and empirical protein-to-mRNA ratios. The optimal mRNA-to-protein relationships capture biological processes along with hundreds of known protein-protein interaction complexes, suggesting mechanistic relationships are embedded. We use the method to estimate viral-receptor abundances of CD55-CXADR from human heart transcriptomes and build 1489 systems-biology models of coxsackievirus B3 infection susceptibility. When applied to 796 RNA sequencing profiles of breast cancer from The Cancer Genome Atlas, inferred copy-number estimates collectively reclassify 26% of Luminal A and 29% of Luminal B tumors. Protein-based reassignments strongly involve a pharmacologic target for luminal breast cancer (CDK4) and an -catenin that is often undetectable at the mRNA level (CTTNA2). Thus, by adopting a gene-centered perspective of mRNA-protein covariation across different biological contexts, we achieve accuracies comparable to the technical reproducibility limits of contemporary proteomics. The collection of gene-specific models is assembled as a web tool for users seeking mRNA-guided predictions of absolute protein abundance (http://janeslab.shinyapps.io/Pinferna). Significance statementIt is easier to quantify mRNA in cells than it is to quantify protein, but proteins are what execute most cellular functions. Even though protein is synthesized from mRNA in cells, relating a cellular quantity of mRNA to a quantity of protein is challenging. Here, we bring together quantitative measures of mRNA and protein for 4366 genes in 369 different cultured cell types to build equations that predict protein abundance from the abundance of mRNAs expressed. These equations capture facets of biological regulation and work better than existing alternatives that rely on consensus values or ratios. Since mRNA measurements are more widespread than protein, this study makes new analyses possible by protein estimation from mRNA.

systems biology↗