Biology subjects

Hobman, T. C.

Publications and source records attributed to Hobman, T. C..

5 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↗

bioRxiv2026

Progressive Post-Acute Gut Microbiome Disruption Following SARS-CoV-2 Infection in Mice

SARS-CoV-2 infection is increasingly recognized to produce long-lasting physiological disturbances that extend beyond the acute phase. The gut microbiome has emerged as a potential contributor to post-infection outcomes, yet the longitudinal progression of microbial disruption following infection remains poorly defined. Here, we used a mouse model of SARS-CoV-2 infection to characterize gut microbiome dynamics at 7 (late acute phase), 14 (early recovery), and 21 (post-COVID condition, PCC) days post-infection (dpi). Viral RNA was detected in the lungs through 21 dpi. Longitudinal microbiome profiling revealed a two-phase restructuring marked by early shifts in Bacillota and Bacteroidota abundance, followed by pronounced post-acute dysbiosis characterized by reduced diversity, expansion of Bacillota, and near-complete loss of Bacteroidota. Functional pathway predictions showed progressive metabolic remodeling, including disruptions in nucleotide turnover, fermentation, and vitamin-related pathways. Together, these findings demonstrate that SARS-CoV-2 infection drives progressive and sustained alterations in gut microbial composition and function after the transition from acute infection through recovery into PCC.

microbiology↗

bioRxiv2025

Potent broad-spectrum anti-coronaviral frameshift inhibitors from virtual screen of RNA binding

Coronavirus genomes contain an RNA pseudoknot that directs -1 programmed ribosomal frame-shifting (-1 PRF) to control expression of viral proteins crucial for replication. Ligands that inhibit -1 PRF can thus attenuate viral propagation and have potential as drugs for limiting corona-virus infections. To search for novel small-molecule frameshift inhibitors with anticoronaviral activity, we computationally screened over 14 million compounds for binding to the SARS-CoV-2 pseudoknot, followed by experimental validation of the top hits for inhibition of -1 PRF and viral replication. We identified multiple potent -1 PRF inhibitors, effective at nM concentrations, some of which significantly suppressed SARS-CoV-2 replication in cell culture. Several compounds also inhibited -1 PRF in multiple representative bat coronaviruses, indicating broad-spectrum activity. These results showcase the promise of viral RNA structures like frameshift-stimulatory pseudoknots as targets for broad-spectrum antiviral drugs.

biophysics↗

bioRxiv2020

Nodosome inhibition as a novel broad-spectrum antiviral strategy against arboviruses and SARS-CoV-2

In the present report, we describe two small molecules with broad-spectrum antiviral activity. These drugs block formation of the nodosome. The studies were prompted by the observation that infection of human fetal brain cells with Zika virus (ZIKV) induces expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a host factor that was found to promote ZIKV replication and spread. A drug that targets NOD2 was shown to have potent broad-spectrum antiviral activity against other flaviviruses, alphaviruses and SARS-CoV-2, the causative agent of COVID-19. Another drug that inhibits the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) which functions downstream of NOD2, also decreased replication of these pathogenic RNA viruses. The broad-spectrum action of nodosome targeting drugs is mediated, at least in part, by enhancement of the interferon response. Together, these results suggest that further preclinical investigation of nodosome inhibitors as potential broad-spectrum antivirals is warranted.

microbiology↗

bioRxiv2020

Engineered ACE2 receptor traps potently neutralize SARS-CoV-2

An essential mechanism for SARS-CoV-1 and -2 infection begins with the viral spike protein binding to the human receptor protein angiotensin-converting enzyme II (ACE2). Here we describe a stepwise engineering approach to generate a set of affinity optimized, enzymatically inactivated ACE2 variants that potently block SARS-CoV-2 infection of cells. These optimized receptor traps tightly bind the receptor binding domain (RBD) of the viral spike protein and prevent entry into host cells. We first computationally designed the ACE2-RBD interface using a two-stage flexible protein backbone design process that improved affinity for the RBD by up to 12-fold. These designed receptor variants were affinity matured an additional 14-fold by random mutagenesis and selection using yeast surface display. The highest affinity variant contained seven amino acid changes and bound to the RBD 170-fold more tightly than wild-type ACE2. With the addition of the natural ACE2 collectrin domain and fusion to a human Fc domain for increased stabilization and avidity, the most optimal ACE2 receptor traps neutralized SARS-CoV-2 pseudotyped lentivirus and authentic SARS-CoV-2 virus with half-maximal inhibitory concentrations (IC50) in the 10-100 ng/ml range. Engineered ACE2 receptor traps offer a promising route to fighting infections by SARS-CoV-2 and other ACE2-utilizing coronaviruses, with the key advantage that viral resistance would also likely impair viral entry. Moreover, such traps can be pre-designed for viruses with known entry receptors for faster therapeutic response without the need for neutralizing antibodies isolated or generated from convalescent patients.

bioengineering↗