Biology subjects

Quenum, A. J. I.

Publications and source records attributed to Quenum, A. J. I..

3 recordsLinked to original sources

bioRxiv2025

NLRC5 expression in tumor cells is critical to activate adaptive and innate antitumor immune responses

Tumors evade cytotoxic T lymphocyte (CTL)-mediated killing by downregulating MHC class-I, mainly resulting from the loss of its transcriptional activator NLRC5. Expressing full-length NLRC5 (NLRC5-FL) or a shorter NLRC5-CIITA fusion protein termed NLRC5 super-activator (NLRC5-SA) in cancer cells upregulates MHC-I expression and promotes antitumor immunity. To distinguish the role of NLRC5 expressed within tumor cells and antigen presenting cells, we studied B16-F10 melanoma expressing NLRC5-FL (B16-N-FL) or NLRC5-SA (B16-N-SA) in Nlrc5+/+ and Nlrc5-/- mice. Both tumors were efficiently controlled in both Nlrc5+/+ and Nlrc5-/- hosts with abundant immune cell infiltration, enriched for activated and differentiated CD8+ and CD4+ T cells, NK, NKT and iNKT cells. B16-N-FL and B16-N-SA tumors showed increased collagen deposition and vascularization, with upregulation of CCL4 and CXCL9 chemokine genes in B16-N-SA tumors. Depletion of either CD8+ T cells or NK1.1+ cells increased the growth of B16-N-FL and B16-N-SA tumors in Nlrc5+/+ mice, and that of B16-N-SA tumors in Nlrc5-/- hosts. Proteomes of B16-N-FL and B16-N-SA cells showed downmodulation of dominant tumor antigens and upregulation of ubiquitination and protein processing pathway proteins. Differentially expressed proteins shared between B16-N-FL and B16-N-SA cells showed enrichment in phagosome and autophagy pathways. We conclude that tumor cell-intrinsic NLRC5 expression is critical for the activation of adaptive and innate immune cells, and establishment of an immune-supportive tumor microenvironment to permit immune cell infiltration and their effector functions and achieve tumor control. NLRC5 expression in APCs is dispensable to mediate these effects. Delivering NLRC5-SA is a promising approach to restore antitumor immune responses in MHC-I-low immune evasive tumors. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/695247v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1bc4f51org.highwire.dtl.DTLVardef@1fb5b03org.highwire.dtl.DTLVardef@11448edorg.highwire.dtl.DTLVardef@bff26c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Molecular Insights into Long COVID: Plasma Proteomics Reveals Oxidative Stress, Coagulation Cascade Activation, and Glycolytic Imbalance

Persistent symptoms following SARS-CoV-2 infection are the hallmark of post-COVID condition (PCC), also referred to as long COVID. However, our knowledge is limited on the underlying molecular mechanisms. In this study, we performed data-independent acquisition mass spectrometry plasma proteomics (DIA-MS) to identify molecular alterations associated with PCC. DIA-MS proteomic analysis revealed a few proteins linked to oxidative stress that had altered expression. Notably, PCC samples exhibited downregulation of the antioxidant protein peroxiredoxin 6 (PRDX6) and upregulation of oxidative stress-associated proteins particularly vanin-1 (VNN1) and paraoxonase-3 (PON3). Additionally, the PCC group showed significantly higher levels of six proteins (PCSK9, CST3, C1Q, CPB2, KNG1 GAPDH), which were linked to pathways involving glycolysis, complement and coagulation cascades, and inflammation. Oxidative stress analysis confirmed that PCC samples had significantly higher levels of DNA damage (8-OHdG) than the convalescent group, whereas antioxidant markers, such as reduced and oxidized glutathione (GSH and GSSG), were significantly lower in PCC samples than in uninfected controls. Our observations point towards ongoing oxidative and inflammatory processes in PCC and suggest potential targets for biomarker development and therapeutic intervention.

immunology↗

bioRxiv2023

SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition

BackgroundFollowing SARS-CoV-2 infection a significant proportion of convalescent individuals develop the post-COVID condition (PCC) that is characterized by wide spectrum of symptoms encompassing various organs. Even though the underlying pathophysiology of PCC is not known, detection of viral transcripts and antigens in tissues other than lungs raise the possibility that PCC may be a consequence of aberrant immune response to the viral antigens. To test this hypothesis, we evaluated B cell and antibody responses to the SARS-CoV-2 antigens in PCC patients who experienced mild COVID-19 disease during the pre-vaccination period of COVID-19 pandemic. MethodsThe study subjects included unvaccinated male and female subjects who developed PCC or not (No-PCC) after clearing RT-PCR confirmed mild COVID-19 infection. SARS-CoV-2 D614G and omicron RBD specific B cell subsets in peripheral circulation were assessed by flow cytometry. IgG, IgG3 and IgA antibody titers toward RBD, spike and nucleocapsid antigens in the plasma were evaluated by ELISA. ResultsThe frequency of the B cells specific to D614G-RBD were comparable in convalescent groups with and without PCC in both males and females. Notably, in females with PCC, the anti-D614G RBD specific double negative (IgD-CD27-) B cells showed significant correlation with the number of symptoms at acute of infection. Anti-spike antibody responses were also higher at 3 months post-infection in females who developed PCC, but not in the male PCC group. On the other hand, the male PCC group also showed consistently high anti-RBD IgG responses compared to all other groups. ConclusionsThe antibody responses to the spike protein, but not the RBD-specific B cell responses diverge between convalescent males and females, and those who develop PCC or not. Our findings suggest that sex-related factors may also be involved in the development of PCC via modulating antibody responses to the SARS-CoV-2 antigens. Short SummaryPost-COVID Condition (PCC) is lingering illness that afflicts a significant proportion of COVID-19 patients from three months after clearing SARS-CoV-2 infection. Therapy for PCC is only palliative and the underlying disease mechanisms are unclear. The wide spectrum of PCC symptoms that can affect different organs and the detection of viral components in tissues distant from lungs raise the possibility that PCC may be associated with aberrant immune response due to presence of viral antigens. Therefore, we studied B cell and antibody responses to the spike and nucleoprotein antigens in PCC patients who cleared mild SARS-CoV-2 infection during the pre-vaccination COVID-19 pandemic period. We observed divergent patterns of immune reactivity to the spike protein in PCC males and females at different times post-infection, suggesting that the immune responses in PCC may also be influenced by sex-related factors.

immunology↗