Biology subjects

Terekhova, M.

Publications and source records attributed to Terekhova, M..

4 recordsLinked to original sources

bioRxiv2025

The Nox2 NADPH oxidase regulates neutrophilic inflammation in the oral cavity

The leukocyte NADPH oxidase 2 (NOX2) is an important regulator of inflammatory responses, independent of its antimicrobial activity. Inactivating mutations in NOX2 cause chronic granulomatous disease (CGD), a severe immunodeficiency associated with recurrent infections and dysregulated neutrophilic inflammation. Recurrent oral ulcers, stomatitis, gingivitis, and other inflammatory issues affecting the oral mucosa have been observed in patients with CGD; however, the underlying mechanisms are not known. Here, we present evidence that the extensive inflammatory destruction of oral mucosal tissues observed in Nox2-deficient or CybbKOmice was not caused by impaired antimicrobial surveillance against oral pathobionts but instead resulted from a cell-intrinsic dysregulation of neutrophil inflammatory responses. Transcriptional and cellular profiling of oral tissues isolated from wild-type and CybbKO mice showed a dominant neutrophil signature, which was accompanied by a significant upregulation of several bone-resorbing, tissue-degrading inflammatory cytokines and a reduced expression of nuclear factor erythroid 2-related factor 2 (Nrf2) regulated genes. Mechanistically, hyperinflammatory responses were mitigated by restoring Nrf2 transcriptional activity using a synthetic agonist. Thus, our studies show that Nox2 oxidase and its derived reactive oxygen species are crucial for balanced recruitment and cell-intrinsic regulation of neutrophil inflammatory responses within oral tissues in an Nrf2-dependent manner.

immunology↗

bioRxiv2025

Virion stripping: A new role for bacterial proteases

We demonstrate that proteases produced by the oro-pharyngeal bacterial colonizer Porphyromonas gingivalis (Pg) reduce viral burden and modulate host interferon responses during respiratory syncytial virus (RSV) infection. Several oral bacteria, including Pg, have been shown to translocate to the upper airways through sub-clinical micro-aspiration. Our findings reveal that Pg, upon translocating to this new niche, significantly attenuated lung damage by reducing viral loads during respiratory viral infections in the lungs of wild-type mice. This protective effect was attributed to the activity of gingipains, cysteine endopeptidases produced by Pg, which cleaved envelope glycoproteins on RSV as well as on related murine-specific Sendai virus (SeV), thereby impairing their infectious capacity. Notably, the reduction in viral loads was independent of interferon lambda (IFN-{lambda}) signaling, which is actively suppressed by Pg in airway epithelial cells. However, the complete absence of IFN-{lambda} signaling resulted in a stronger inflammatory response despite a low viral load. Thus, we show a previously undescribed role for the oro-respiratory bacterial colonizer Pg in creating bottlenecks to viral infection by the activity of its proteases. SIGNIFICANCE STATEMENTReciprocal interactions between microbial colonizers and host epithelial cells are critical for providing initial defense against viral infections. However, our understanding of this phenomenon has been limited to microbiota-derived ligands that activate host pattern recognition receptors (PRRs), inducing basal interferon expression and downstream antiviral genes. Here, we present a novel mechanism that relies on microbial proteases to directly reduce viral load. Specifically, we discovered that the infectious capacity of the Respiratory Syncytial Virus (RSV) was significantly inhibited upon contact with the proteases (gingipains) produced by the oropharyngeal colonizer Porphyromonas gingivalis. Gingipains caused proteolytic degradation of the RSV envelope and attachment proteins, rendering them inactive. This preemptive reduction in viral infectious capacity consequently diminished the severity of respiratory viral infections in an IFN-independent manner.

microbiology↗

bioRxiv2024

CD226+ adipose tissue macrophages arise from MDP-derived monocytes and regulate lipid metabolism.

Macrophages are innate immune cells present in all tissues, in which they participate in immune responses and maintenance of tissue homeostasis. They develop either from embryonic precursors or from circulating monocytes, and their origin impacts their functions. We previously observed robust recruitment of monocytes to brown adipose tissue in which they could differentiation into two distinct macrophage subsets identifiable by CD206 or CD226 expression. In the present study, we investigated monocyte differentiation pathways in brown adipose tissue and the function of monocyte-derived macrophages. Fate mapping analysis revealed a low contribution of GMP- and a high contribution of MDP-derived monocytes to the CD226high macrophage subset. Importantly, adoptive transfer experiments demonstrate that MDP- but not GMP-derived monocytes are pre-conditioned to give rise to CD226high macrophages. We found that MDP-derived CD226high macrophages were also present in other tissues including peritoneal cavity, adrenal glands and all adipose depots. CD226high macrophages were regulated by both GM-CSF and CSF1R. Genetic depletion of CD226high macrophages caused increased BAT and plasma triglyceride content. We thus identify CD226high MDP-derived macrophages as a new myeloid cell type conserved across tissues and tied to lipid metabolism homeostasis.

immunology↗

bioRxiv2023

Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction

Chimeric antigen receptor (CAR) engineered T cells often fail to enact effector functions after infusion into patients. Understanding the biological pathways that lead CAR T cells to failure is of critical importance in the design of more effective therapies. We developed and validated an in vitro model that drives T cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains contribute to T cell failure. We found that dysfunctional CD28-based CARs targeting CD19 bear hallmarks of classical T cell exhaustion while dysfunctional 41BB-based CARs are phenotypically, transcriptionally and epigenetically distinct. We confirmed activation of this unique transcriptional program in CAR T cells that failed to control clinical disease. Further, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is a significant contributor to this dysfunction and disruption of FOXO3 improves CAR T cell function. These findings identify that chronic activation of 41BB leads to novel state of T cell dysfunction that can be alleviated by genetic modification of FOXO3. SummaryChronic stimulation of CARs containing the 41BB costimulatory domain leads to a novel state of T cell dysfunction that is distinct from T cell exhaustion.

immunology↗