Biology subjects

Razi, N.

Publications and source records attributed to Razi, N..

3 recordsLinked to original sources

bioRxiv2026

Multiomic and Spatial Profiling of Colorectal Tissue Reveals Viral Persistence and Immune Dysregulation in Long COVID

Long COVID (LC) - a chronic condition characterized by persistent, debilitating symptoms following SARS-CoV-2 infection - has emerged as a major public health challenge. Although many interrelated mechanisms have been proposed as drivers of LC, the root causes have yet to be identified, posing significant challenges for therapeutic development. While many blood-based studies have been conducted, they have not yielded conclusive mechanistic insights into LC pathogenesis. Attention has therefore turned toward direct tissue investigation, with the gastrointestinal (GI) tract becoming a major focus due to evidence that virus or viral components can persist at this site for months to years following an episode of COVID-19. Here, we performed a high-dimensional characterization of colorectal tissue and peripheral blood in a highly characterized cohort of 44 people with LC and 13 recovered controls. We profiled SARS-CoV-2 persistence, host immune responses, and tissue inflammation using bulk and single-cell RNA sequencing, nCounter RNA probe hybridization, quantitative PCR, metagenomic next-generation sequencing, plasma proteomics, high-dimensional spectral flow cytometry, in situ-hybridization/immunohistochemistry, and single-cell digital spatial omics. Our results support a model in which LC is driven by long-term immune dysregulation and perturbations of the regulatory gut immune environment which imply ongoing viral persistence, although direct viral detection was only observed in a subset of participants. Specifically, we identify a tissue-based transcriptional environment in which SARS-CoV-2 activates innate myeloid immune signaling, driving chronic inflammation while simultaneously downregulating pathways responsible for immune-mediated clearance of infected cells, including antigen presentation, phagocytosis, cytotoxic immune cell trafficking, and granzyme production. Importantly, signatures in peripheral blood are considerably weaker than those observed in tissue. Together, these findings provide a direct biological rationale for therapeutic strategies in LC aimed at enhancing or redirecting cytotoxic immune function to overcome immune dysregulation and clear persistent viral reservoirs.

immunology↗

bioRxiv2025

Bicistronic CAR T-cells Against CD70 & Active Integrin β2 Overcome Antigen Heterogeneity and Preserve Safety in Acute Myeloid Leukemia

The surface antigen landscape of acute myeloid leukemia (AML) displays significant heterogeneity and overlap with healthy hematopoietic cells. This imparts a substantial hurdle to the development of AML-targeting chimeric antigen receptor (CAR) T-cells that can avoid on- target, off-tumor toxicity. Here, we develop a dual-antigen targeting CAR-T against CD70 and the active conformation of integrin {beta}2 (aITGB2), each previously reported as promising AML targets due to minimal off-tumor expression. We show an OR-gated approach for these antigens significantly increases the proportion of AML blasts that can be targeted, in part using a novel ex vivo co-culture method to restore surface protein homeostasis following a freeze-thaw cycle. We test dual-targeting CAR-T constructs with different combinations of costimulatory domains, identifying constructs with superior anti-tumor cytotoxicity in vitro against AML cell line and patient-derived xenograft models. We further show significantly improved in vivo tumor clearance and survival for a dual-targeting CAR in murine models of AML tumor heterogeneity. Finally, we show that this dual-targeting CAR does not increase off-tumor toxicity, especially against hematopoietic stem and progenitor cells. Together, these findings demonstrate a promising clinically-translatable approach for the treatment of AML without the notable toxicity liabilities associated with other leading CAR-T targets for this disease.

immunology↗

bioRxiv2023

Inhibition of SARS-CoV-2 Infection in Human Airway Epithelium with a Xeno-Nucleic Acid Aptamer

BackgroundSARS-CoV-2, the agent responsible for the COVID-19 pandemic, enters cells through viral spike glycoprotein binding to the cellular receptor, angiotensin-converting enzyme 2 (ACE2). Given the lack of effective antivirals targeting SARS-CoV-2, we previously utilized systematic evolution of ligands by exponential enrichment (SELEX) and selected fluoro-arabino nucleic acid (FANA) aptamer R8-9 that was able to block the interaction between the viral receptor-binding domain and ACE2. MethodsHere, we further assessed FANA-R8-9 as an entry inhibitor in contexts that recapitulate infection in vivo. ResultsWe demonstrate that FANA-R8-9 inhibits spike-bearing pseudovirus particle uptake in cell lines. Then, using an in-vitro model of human airway epithelium (HAE) and SARS-CoV-2 virus, we show that FANA-R8-9 significantly reduces viral infection when added either at the time of inoculation, or several hours later. These results were specific to the R8-9 sequence, not the xeno-nucleic acid utilized to make the aptamer. Importantly, we also show that FANA-R8-9 is stable in HAE culture secretions and has no overt cytotoxic effects. ConclusionsTogether, these results suggest that FANA-R8-9 effectively prevents infection by specific SARS-CoV-2 variants and indicate that aptamer technology could be utilized to target other clinically-relevant viruses in the respiratory mucosa.

microbiology↗