Biology subjects

Avci, F.

Publications and source records attributed to Avci, F..

4 recordsLinked to original sources

bioRxiv2026

Mechanistic basis of teichoic acid transport by a gatekeeper flippase

The cell wall is a complex structure that protects bacteria from environmental threats. Phosphocholine-containing teichoic acids are key cell wall biopolymers critical for host colonization, immune evasion, competence, and persistence in Streptococcus pneumoniae. The flippase TacF, a member of the multidrug/oligosaccharide-lipid/polysaccharide (MOP) superfamily, monitors the phosphocholine content of teichoic acids during transport, yet the underlying mechanism of this process remains unknown. We present a cryo-EM structure of S. pneumoniae TacF in lipid nanodiscs. In vivo complementation assays and molecular dynamics simulations reveal key residues involved in teichoic acid recognition and transport, while coevolutionary and conservation analyses delineate common mechanistic elements among MOP flippases, indicating a shared mechanism for polyprenyl-diphosphate-linked oligosaccharide lipid transport. Our findings provide mechanistic insights into an essential flippase involved in S. pneumoniae pathogenesis and a potential drug target.

biochemistry↗

bioRxiv2025

Molecular mechanisms of immune evasion by host protein glycosylation of a bacterial immunogen used in nucleic acid vaccines

Nucleic acid vaccines (DNA and mRNA) induce immunity by driving in situ antigen expression in host cells. For non-viral pathogens, however, host expression can impose post-translational modifications absent from the native microbial antigen. Tuberculosis (TB) remains a leading cause of infectious mortality, and nucleic acid vaccines targeting the Mycobacterium tuberculosis antigen 85 (Ag85) complex did not confer protective efficacy in clinical trials. We hypothesized that host-derived N-glycosylation of Ag85 immunogens expressed in mammalian cells compromises immune recognition. Here, we define structural, biochemical and immunological mechanisms by which host-imposed N-glycosylation remodels a bacterial antigen expressed in mammalian cells. We show that Ag85B expressed in human Expi293 cells is microheterogeneously N-glycosylated at four canonical sequons (N52, N224, N234, N280) with predominantly complex, highly fucosylated, and frequently sialylated glycans. Molecular dynamics simulations indicate that these glycans occupy substantial conformational space and reduce solvent and antibody-accessible surface area, occluding multiple established B-cell and T-cell epitope regions. Consistent with glycan-mediated shielding, mammalian-expressed Ag85B shows markedly reduced binding to an Ag85-complex monoclonal antibody by competitive ELISA and biolayer interferometry, and sialylated glycans enable Siglec-9 binding that is abrogated by sialidase treatment. Together, these findings define the structural and biochemical mechanisms by which host glycosylation can remodel bacterial vaccine antigens, supporting glycosylation-aware immunogen engineering as a design principle for nucleic acid vaccines targeting non-viral pathogens.

biochemistry↗

bioRxiv2024

A regulatory B cell subpopulation expressing CD301b lectin promotes breast cancer growth

Aberrant tumor glycosylation can alter immune recognition; however, the specific influence of glycan-lectin interactions on tumor progression remains poorly understood. Here, we identify the C-type lectin receptor CD301b (encoded by Mgl2) as a regulator of immune activity within the breast tumor microenvironment (TME). Using a murine triple-negative breast cancer model, we demonstrate that tumors expressing the Tn glycoantigen grow more rapidly, and this growth is facilitated by CD301b immune cells. Depletion or genetic loss of CD301b markedly suppressed tumor growth, indicating that CD301b promotes tumor progression through myeloid-tumor interactions. Phenotypic analyses revealed that CD301b cells within tumors are type 2 conventional dendritic cells (cDC2s), a subset known to influence immune polarization. Single-cell RNA sequencing of human breast cancers showed that the human ortholog CLEC10A is expressed in cDC2-like dendritic cells and select macrophage subsets, suggesting a conserved role for CD301 myeloid populations. Transcriptomic profiling of tumors developed in Mgl2-deficient mice revealed a shift toward an inflammatory, immune-activated state consistent with enhanced antitumor immunity. Together, these findings establish a link between tumor glycosylation and lectin signaling of myeloid cells, highlighting CD301b as a potential target for reprogramming the tumor immune microenvironment in breast cancer.

immunology↗

bioRxiv2021

Modulation of immunosuppressant drug treatment to improve SARS-CoV-2 vaccine efficacy in mice

The COVID-19 pandemic dramatically demonstrated the need for improved vaccination strategies and therapeutic responses to combat infectious diseases. However, the efficacy of vaccines has not yet been demonstrated in combination with commonly used immunosuppressive drug regimens. We sought to determine how common pharmaceutical drugs used in autoimmune disorders can alter immune responses to the SARS-CoV-2 spike protein vaccination. We treated mice with five immunosuppressant drugs (cyclophosphamide, leflunomide, methotrexate, methylprednisolone, and mycophenolate mofetil), each with various mechanisms of action prior to and following immunization with SARS-CoV-2 spike protein. We assessed the functionality of antibody responses to spike protein and compared immune cell populations in mice that received no treatment with those that received continuous or temporarily suspended immune suppressive therapy. All tested immunosuppressants significantly reduced the antibody titers in serum and functional antibody response against SARS-CoV-2 spike protein in immunized mice. Temporarily halting selected immunosuppressants (methylprednisolone and methotrexate, but not cyclophosphamide) improved antibody responses significantly. Through proof-of-principle experiments utilizing a mouse model, we demonstrated that immune suppression in autoimmune disorders through pharmaceutical treatments may impair vaccine response to SARS-CoV-2, and temporary suspension of immunosuppressant treatment may be necessary to mount an effective antibody vaccine response. This work provides feasibility for future clinical assessment of the impact of immunosuppressants on vaccine efficacy in humans. Significance StatementImmunosuppressant regimens are widely used as therapies for a variety of diseases, including autoimmune, inflammatory, and cancer. However, immunosuppressants can impair critical immune responses to vaccination. The impact of standard immunosuppressant use on the critical, developing SARS-CoV-2 vaccination strategies has not been well-described. In this study, we use a mouse model to determine how different immunosuppressant drugs that act through different mechanisms can impair the antibody response to SARS-CoV-2 spike protein, and how modulating these drug regimens may restore antibody levels and function.

immunology↗