Biology subjects

Sims, A. C.

Publications and source records attributed to Sims, A. C..

5 recordsLinked to original sources

bioRxiv2025

ProteoMeter: A pipeline for integrating multi-PTM and limited proteolysis data to reveal modification-structure coupling at the residue level

Systemic perturbations trigger extensive changes across the proteome-altering protein abundance, post-translational modifications (PTMs), conformational states, and complex assembly. Interpreting these effects demands computational pipelines capable of integrating diverse proteomics modalities, such as multi-PTM profiling, limited proteolysis mass spectrometry (LiP-MS), and cross-linking mass spectrometry (XL-MS), within a unified and interoperable framework. Because instrument data are quantified at the peptide level, mapping these measurements to individual residue or modification site is essential for biologically meaningful interpretation. We introduce ProteoMeter, an open-source Python library designed to integrate multi-modal proteomics datasets and map them to single-residue resolution using a standardized coordinate framework. We showcase its capabilities in a combined multi-PTM and LiP-MS analysis profiling the proteomic response to human coronavirus 229e (HCoV-229E) infection.ProteoMeteris actively maintained and is freely available-including all source code and figure-generation scripts-at the following repository: https://github.com/PNNL-Predictive-Phenomics/ProteoMeter.

systems biology↗

bioRxiv2024

Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East Respiratory Syndrome coronavirus disease severity

Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoV from past 20 years (SARS-CoV, SARS-CoV-2, MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers and acute lung injury among lethal and sub-lethal virus doses. Virus induced apoptosis of type I and II alveolar epithelial cells suggest that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B-cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness. ImportanceEmerging coronaviruses like SARS-CoV, SARS-CoV-2 and MERS-CoV cause a range of disease outcomes in humans from asymptomatic, moderate and severe respiratory disease which can progress to death but the factors causing these disparate outcomes remain unclear. Understanding host responses to mild and life-threatening infection provides insight into virus-host networks within and across organ systems that contribute to disease outcomes. We used multi-omics approaches to comprehensively define the host response to moderate and severe MERS-CoV infection. Severe respiratory disease was associated with dysregulation of the immune response. Key lung epithelial cell populations that are essential for lung function get infected and die. Mice lacking key immune cell populations experienced greater virus replication but decreased disease severity implicating the immune system in both protective and pathogenic roles in the response to MERS-CoV. These data could be utilized to design new therapeutic strategies targeting specific pathways that contribute to severe disease.

microbiology↗

bioRxiv2022

Host network-based discovery of critical regulators of innate immunity, virus growth, and pathogenesis in influenza virus infection

Innate immunity is protective against viruses, but also can facilitate pathological infection responses. Despite intensive research, our understanding of the mechanisms that regulate innate immunity in virus infection remains incomplete. Systems biology-based data-driven modeling approaches hold substantial promise toward discovery of crucial innate immune signaling regulators, yet model-derived predictions are almost completely unexplored. Here, we carried out systematic experimental validation of candidate regulators predicted by a transcriptional association network model of influenza virus-infected cells. We identified dozens of novel innate immune signaling regulators with potent effects on the replication of influenza and other viruses, and importantly, we established the biological relevance of a validated regulator in vivo. Collectively, these findings aid in clarifying mechanisms of influenza virus pathogenicity and might lead to innovative approaches for treating influenza virus disease. Similar data-driven modeling strategies may be applicable for the study of other pathogen systems or immunological disorders.

microbiology↗

bioRxiv2020

An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus

Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we show that the ribonucleoside analog {beta}-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV 2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to another nucleoside analog inhibitor. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (b-D-N4-hydroxycytidine-5-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis. The potency of NHC/EIDD-2801 against multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo, all highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.

microbiology↗

bioRxiv2017

MERS-CoV NSP16 necessary for IFN resistance and viral pathogenesis

Coronaviruses encode a mix of highly conserved and novel genes as well as genetic elements necessary for infection and pathogenesis, raising the possibility for common targets for attenuation and therapeutic design. In this study, we focus on the highly conserved nonstructural protein (NSP) 16, a viral 2O methyl-transferase (MTase) that encodes critical functions in immune modulation and infection. Using reverse genetics, we disrupted a key motif in the conserved KDKE motif of MERS NSP16 (D130A) and evaluated the effect on viral infection and pathogenesis. While the absence of 2O MTase activity had only marginal impact on propagation and replication in Vero cells, the MERS dNSP16 mutant demonstrated significant attenuation relative to control both in primary human airway cultures and in vivo. Further examination indicated the MERS dNSP16 mutant had a type I IFN based attenuation and was partially restored in the absence of IFIT molecules. Importantly, the robust attenuation permitted use of MERS dNSP16 as a live attenuated vaccine platform protecting from challenge with a mouse adapted MERS-CoV strain. These studies demonstrate the importance of the conserved 2O MTase activity for CoV pathogenesis and highlight NSP16 as a conserved universal target for rapid live attenuated vaccine design in an expanding CoV outbreak setting.\n\nSignificanceCoronavirus emergence in both human and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of SARS-CoV, MERS-CoV, PEDV and swine delta coronavirus in the 21st century. These studies describe an approach that effectively targets the highly conserved 2O methyl-transferase activity of coronaviruses for attenuation. With clear understanding of the IFN/IFIT based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-coronavirus functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2O MTase function across coronaviruses.

microbiology↗