Biology subjects

Houston, S.

Publications and source records attributed to Houston, S..

6 recordsLinked to original sources

bioRxiv2026

Deep Learning-Based Structure Modeling of the Treponema pallidum Proteome: Insights into Pathogenesis and Syphilis Vaccine Development

Treponema pallidum ssp. pallidum, the causative agent of syphilis, has a small proteome and encompasses numerous strains. Knowledge gaps remain in understanding the molecular mechanisms of pathogenesis of this bacterium, as well as the structure and function of the full complement of proteins encoded by T. pallidum. Here, an AI-based structure-to-function modeling workflow was used to investigate the complement of proteins encoded by T. pallidum. High-confidence structure models were generated for 976 T. pallidum proteins, covering 99% of the proteome. Analysis of the generated models using the protein structure comparison server DALI enabled high-confidence, structure-based functional annotation of 877 T. pallidum proteins, including 240 of the 323 proteins of unknown function encoded by this pathogen. Additionally, 63 putative pathogenesis related proteins (PPRPs) and seven treponemal proteins with previously uncharacterized similarity to outer membrane proteins (OMPs) from Gram-negative bacteria were identified. A workflow for B cell epitope (BCE) prediction identified 1133 surface-exposed, host-facing potential epitopes in known and predicted T. pallidum OMPs, of which 92 were prioritized based on bioinformatic analyses, biophysical properties, amino acid sequence conservation, and previous protein expression data. This work provides insight into T. pallidum pathogenesis through structure modeling-based functional annotation, including characterization of proteins of unknown function. This study also informs syphilis vaccine design by identifying new potential T. pallidum OMPs, as well as host-facing regions of T. pallidum OMPs that have conserved amino acid sequences in globally circulating strains. Statement of importance/impactThis study presents the first AI-based global structure modeling-to-function analysis of the proteome of Treponema pallidum, the bacterium that causes syphilis. Structure-based functional predictions of previously uncharacterized proteins, including proteins potentially involved in virulence, provide novel insight into mechanisms of pathogenesis. The work also informs syphilis vaccine development by the identification and structural characterization of new candidate vaccine proteins in globally circulating strains of T. pallidum.

microbiology↗

bioRxiv2025

Understanding wood decay diseases in western redcedar through development of ITS-sequencing and qPCR assays

Root and butt rot diseases cause high rates of wood decay in living stands of western redcedar (WRC; Thuja plicata Donn), one of the most valuable forest species in western North America. However, WRC susceptibility and the virulence of wood-decay-causing fungal pathogens are understudied, presenting a high risk for the WRC forest industry. To evaluate susceptibility of WRC to root and butt rot diseases and decay incidence, four pathogenic fungi, including Armillaria ostoyae, Coniferiporia weirii, Heterobasidion occidentale, and Perenniporia subacida, were used to inoculate WRC seedlings using two artificial methods. Next-generation sequencing (NGS) of internal transcribed spacer (ITS) region of the nuclear ribosomal DNA (rDNA) and quantitative polymerase chain reaction (qPCR) assays were developed to evaluate successful infection through detection of targeted pathogens inside the WRC tissues while development of disease was assessed by visual observation of wood decay. Disease incidence rates ranged from 20% to 60% while infection rates ranged from 80% to 100%, validating the effectiveness of the inoculation protocols. The qPCR assays designed with species-specific primers were validated for quantification of absolute abundance of C. weirii inside WRC host tissues with high sensitivity and specificity. These newly developed qPCR assays provide rapid, cost-effective, and accurate tools to detect early infection and latent infection in asymptomatic trees, with wide potential applications for surveillance of C. weirii-caused wood decay disease in greenhouse and field studies, as well as for screening of disease resistance in WRC breeding.

pathology↗

bioRxiv2023

Structure of the human Duffy antigen receptor

The Duffy antigen receptor, also known as FY glycoprotein or CD234, is a seven transmembrane protein expressed primarily at the surface of red blood cells, which displays promiscuous binding to multiple chemokines. Not only does it serve as the basis of the Duffy blood group system but it also acts as the primary attachment site for malarial parasite Plasmodium vivax on erythrocytes and as one of the nucleating receptors for the pore forming toxins secreted by Staphylococcus aureus. Despite a predicted 7TM architecture and efficient binding to a spectrum of chemokines, it fails to exhibit canonical second messenger response such as calcium release, likely due to a lack of G protein coupling. Unlike prototypical GPCRs and {beta}-arrestin-biased atypical chemokine receptors, the Duffy antigen receptor also appears to lack {beta}-arrestin binding, making it an enigmatic 7TM chemokine receptor. In order to decipher the molecular mechanism of this intriguing functional divergence exhibited by the Duffy antigen receptor, we have determined its cryo-EM structure in complex with a C-C type chemokine, CCL7. The structure reveals a relatively superficial binding mode of CCL7, with the N-terminus of the receptor serving as the key interaction interface, and a partially formed orthosteric binding pocket lacking the second site for chemokine recognition compared to prototypical chemokine receptors. The structural framework allows us to employ HDX-MS approach to uncover ligand-induced structural changes in the receptor and draw important insights into the promiscuous nature of chemokine binding. Interestingly, we also observe a dramatic shortening of TM5 and 6 on the intracellular side, compared to prototypical GPCRs, which precludes the coupling of canonical signal-transducers namely G proteins, GRKs and {beta}-arrestins, as demonstrated through extensive cellular assays. Taken together, our study uncovers a previously unknown structural mechanism that imparts unique functional divergence on the 7TM fold encoded in the Duffy antigen receptor while maintaining its scavenging function and should facilitate the designing of novel therapeutics targeting this receptor.

biochemistry↗

bioRxiv2023

A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross-reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+ effector memory T (TEM) cells activate the important immunoregulatory cytokine TGF{beta}, via expression of an integrin, v{beta}8. Integrin v{beta}8 expression marks a transcriptionally distinct sub-population of CD4+ TEM, enriched for anti-inflammatory pathways. Loss of integrin v{beta}8 on murine CD4+ TEM, but not Foxp3+ regulatory T cells (TREG), led to exacerbated virus-specific CD8+ T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin v{beta}8 expression on CD4+ TEM resulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of v{beta}8+ CD4+ TEM cells. These data highlight a new pathway by which a distinct CD4+ memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.

immunology↗

bioRxiv2020

AMPlify: attentive deep learning model for discovery of novel antimicrobial peptides effective against WHO priority pathogens

Antibiotic resistance is a growing global health concern prompting researchers to seek alternatives to conventional antibiotics. Antimicrobial peptides (AMPs) are emerging therapeutic agents with promising utility in this domain and using in silico methods to discover novel AMPs is a strategy that is gaining interest. Such methods can filter through large volumes of candidate sequences and reduce lab screening costs. Here we introduce AMPlify, an attentive deep learning model for AMP prediction, and demonstrate its utility in prioritizing peptide sequences derived from the Rana [Lithobates] catesbeiana (bullfrog) genome. We tested the bioactivity of our predicted peptides against a panel of bacterial species, including representatives from the World Health Organizations "priority pathogens" list. Four of our novel AMPs were active against multiple species of bacteria, including a multi-drug resistant isolate of carbapenemase-producing Escherichia coli, demonstrating the utility of tools like AMPlify in our fight against antibiotic resistance.

bioinformatics↗

bioRxiv2019

CD71+ erythroid cells exacerbate HIV-1 infection by reactive oxygen species and trans-infect HIV to CD4+ T cells

CD71+ erythroid cells (CECs) have a wide range of immunomodulatory properties but their potential role in HIV has never been investigated before. Here, we demonstrate that CECs are abundant in the human cord blood, placental tissue and peripheral blood of pregnant mothers. We found that CECs exacerbate HIV-1 infection/replication when co-cultured with CD4+ T cells; and that pre-exposure of CD4+ T cells to CECs make them more permissible to HIV-infection. Our observations indicate how interactions of CECs with CD4+ T cells via reactive oxygen species (ROS)-dependent mechanism results in the upregulation of NF-kB, which affects the cell cycle machinery to facilitate HIV-1 replication. We found the complement receptor-1 (CD35) and the Duffy antigen receptor for chemokines (DARC) as potential HIV-target molecules are expressed significantly higher on CECs compared to mature red blood cells. However, blocking CD35 or DARC did not inhibit HIV-1 trans-infection to uninfected CD4+ T cells. We demonstrate that CECs bind to HIV-1 via CD235a and subsequently trans-infect the virus to uninfected CD4+ T cells. In addition, we found significant abundance of CECs in the blood of HIV-1 infected and anemic subjects, which enhanced HIV infection/replication in autologous CD4+ T cells similar to what we observed for the cord blood and placenta-derived CECs. In agreement, a positive correlation between the frequency of CECs with the plasma viral load in HIV-1 infected antiretroviral therapy naive individuals was observed. In addition, we found that CECs even in the presence of Tenofovir, can trans-infect HIV-1 to CD4+ T cells. Our studies provide a novel insight into the role of CECs in HIV pathogenesis as potential contributing cells for viral persistence in the presence of antiretroviral therapy.\n\nAuthor summaryDespite current antiretroviral therapy, HIV-1 persists in a small pool of infected cells. A better understanding of HIV-reservoirs and influence of other non-immune cells on HIV-1 replication and transmission is a pre-requisite to the development of HIV-eradication strategies. Immature red blood cells (CD71+ erythroid cells) are physiologically abundant in newborns, cord blood, placenta and blood of pregnant women, with a wide range of immunological properties. This study demonstrates that these cells not only enhance HIV-1 infection/replication by reactive oxygen species in HIV-target cells (CD4+ T cells) but also bind to HIV and trans-infect the virus to the target cells in the presence of Tenofovir, an HIV drug.\n\nWe found that these immature red blood cells are abundant in the blood of HIV-patients and anemic individuals. In addition, we observed a positive correlation between the levels of plasma viral load with the frequency of immature red blood cells in HIV-infected individuals. Therefore, our studies discover a novel role for these immature red blood in HIV pathogenesis, which encourages efforts to target these cells as adjuncts of current treatment strategies.

immunology↗