Biology subjects

Motozono, C.

Publications and source records attributed to Motozono, C..

4 recordsLinked to original sources

bioRxiv2025

A probiotic bacterium modulates antitumor γδ T-cell responses in lung cancer

The link between the intestinal microflora and cancer outcomes has been recognized for over a decade. Several recent studies have demonstrated that the gut microbiome is associated with the efficiency of T-cell checkpoint blockade therapy for cancer raising interest in strategies to harness this effect via consumption of live microorganisms (probiotics). The probiotic Clostridium butyricum strain MIYAIRI 588 (CBM588) enhances both response rates and overall survival in patients receiving immune checkpoint blockade therapy for non-small cell lung cancer and metastatic renal cell carcinoma but the mechanism underpinning this benefit remains unclear. Here, we show that CBM588 spores induce a population of V{gamma}9V{delta}2 T-cells from the peripheral blood of healthy donors and lung cancer patients. A subset of these T-cells responded to, and directly lysed, cancer cell lines via a butyrophilin 3A-dependant mechanism. In patients taking CBM588 alongside checkpoint blockade, peripheral V{delta}2 T-cells expressed the activation marker CD69 more frequently than those receiving checkpoint blockade alone and the frequency of V{delta}2CD69 cells increased following initiation of CBM588 treatment (p = 0.0041). Our findings provide a potential mechanism by which the manipulation of the intestinal microflora might directly contribute to cancer prognosis by activating immune effector cells with intrinsic anticancer properties.

immunology↗

bioRxiv2023

HIV-Tocky system to visualize proviral expression dynamics

The stably integrated pool of HIV-1 proviruses in the host genome stands against curative strategies. This reservoir is extremely heterogeneous with respect to host cell type, anatomical location, integration site, and replication fitness. During the initial phase of infection, only a few infected cells can resist host immune clearance or cytopathic effect and establish this resistant pool. The mechanisms underlying HIV latency initiation are not fully resolved yet. In the current study, we propose and validate a new reporter model for monitoring HIV-1 provirus silencing and reactivation using Timer of cell kinetics and activity (Tocky). HIV-Tocky system uses a fluorescent Timer protein whose emission spectrum spontaneously shifts from blue to red to reveal HIV-1 provirus dynamics. We dissected provirus transcriptional phases into early, persistent, recently silenced, and latent. To our knowledge, this is the first report to distinguish two latent subsets: a directly non-expressing population and a recently silenced after brief expression. In-depth integration site analysis suggested that the distribution of proviruses in directly latent cells was similar to that in actively transcribing cell population, whereas recently silenced cells tended to harbor proviruses integrated into heterochromatin. Furthermore, we established a library of various single integration clones at which we utilized to demonstrate the efficiency of the block-and-lock strategy by capturing the fast dynamics of silencing that were overlooked in previous models. In summary, we propose HIV-Tocky system to serve as a time-sensitive model that can capture the dynamics of provirus expression, making it a useful tool for HIV latency research. Significance StatementDeterminants of HIV-1 latency establishment are yet to be elucidated. This reservoir comprises a rare fraction of infected cells that can survive host and virus-mediated killing. In vitro reporter models so far offered a feasible means to inspect this population, but with limited capabilities to dissect provirus silencing dynamics. Here, we describe a new HIV reporter model (HIV-Tocky) with dual fluorescence spontaneous shifting to reveal provirus silencing and reactivation dynamics. This unique feature allowed; for the first time, identifying two latent populations: a directly latent, and a recently silenced subset, with the latter having integration features suggestive of stable latency. Our proposed model can help address the heterogeneous nature of HIV reservoirs and offers new possibilities for evaluating eradication strategies. ClassificationBiological Sciences, Microbiology.

microbiology↗

bioRxiv2022

The SARS-CoV-2 Omicron BA.1 spike G446S potentiates HLA-A*24:02-restricted T cell immunity

Although the Omicron variant of the SARS-CoV-2 virus is resistant to neutralizing antibodies, it retains susceptibility to cellular immunity. Here, we characterized vaccine-induced T cells specific for various SARS-CoV-2 variants and identified HLA-A*24:02-restricted CD8+ T cells that strongly suppressed Omicron BA.1 replication. Mutagenesis analyses revealed that a G446S mutation, located just outside the N-terminus of the cognate epitope, augmented TCR recognition of this variant. In contrast, no enhanced suppression of replication was observed against cells infected with the prototype, Omicron BA.2, and Delta variants that express G446. The enhancing effect of the G446S mutation was lost when target cells were treated with inhibitors of tripeptidyl peptidase II, a protein that mediates antigen processing. These results demonstrate that the G446S mutation in the Omicron BA.1 variant affects antigen processing/presentation and potentiates antiviral activity by vaccine-induced T cells, leading to enhanced T cell immunity towards emerging variants.

immunology↗

bioRxiv2021

An emerging SARS-CoV-2 mutant evading cellular immunity and increasing viral infectivity

During the current SARS-CoV-2 pandemic that is devastating the modern societies worldwide, many variants that naturally acquire multiple mutations have emerged. Emerging mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has recently been investigated, that to human leukocyte antigen (HLA)-restricted cellular immunity remains unaddressed. Here we demonstrate that two recently emerging mutants in the receptor binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429) and Y453F (in B.1.298), can escape from the HLA-24-restricted cellular immunity. These mutations reinforce the affinity to viral receptor ACE2, and notably, the L452R mutation increases protein stability, viral infectivity, and potentially promotes viral replication. Our data suggest that the HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes, and the escape from cellular immunity can be a further threat of the SARS-CoV-2 pandemic. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/438288v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@153428forg.highwire.dtl.DTLVardef@136ca5aorg.highwire.dtl.DTLVardef@1ee490org.highwire.dtl.DTLVardef@2fe478_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗