Biology subjects

Ficht, T. A.

Publications and source records attributed to Ficht, T. A..

4 recordsLinked to original sources

bioRxiv2026

A Synthetic Microbial Therapy Rewires Antitumor Immunity Across Multiple Cancer Types

Microbial immunotherapies show promise against cancer, yet broad efficacy and mechanistic insight remain elusive. Here, we introduce SPIKE 1.0 (S1.0), a metabolically engineered bacterium that converts tryptophan into immunomodulatory hydroxyindoles via tryptophan monooxygenase to remodel the tumor microenvironment (TME). A single systemic dose of S1.0 elicited potent, durable antitumor responses across multiple murine models, including humanized mice, with minimal toxicity. S1.0 enhanced inflammatory signaling, activated innate and adaptive immunity, and promoted T cell persistence, memory, and resistance to exhaustion. It outperformed checkpoint inhibitors and synergized with chemotherapy. Multi-omics profiling revealed that S1.0 rewired amino acid metabolism in tumor-infiltrating immune cells and disrupted immunosuppressive networks. These results establish S1.0 as a scalable, cost-effective microbial immunotherapy with broad translational potential for solid tumors.

immunology↗

bioRxiv2022

A metabolically engineered bacterium controls autoimmunity by remodeling the pro-inflammatory microenvironment

Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., Brucella melitensis 16M {Delta}vjbR, Bm{Delta}vjbR) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T cells (Tregs). We demonstrated that treatment with this strain polarized M2 macrophages (M{varphi}) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted Treg function; moreover, when combined with adoptive cell transfer (ACT) of Tregs, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity and reducing inflammation by remodeling the IME and augmenting Treg function.

immunology↗

bioRxiv2021

Diverse pathogens activate the host RIDD pathway to subvert BLOS1-directed immune defense

The phagocytosis and destruction of pathogens in lysosomes constitute central elements of innate immune defense. Here, we show that Brucella, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1-dependent decay (RIDD) of mRNAs encoding BLOS1, a protein that promotes endosome-lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1 were resistant to infection. Non-functional Blos1 struggled to assemble the BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Blos1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal-destruction, and resistance to infection. These findings demonstrate that host RIDD activity on BLOS1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus MHV also subverted the RIDD-BLOS1 axis to promote intracellular replication. Our work therefore establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.

microbiology↗

bioRxiv2020

Interactions between fungal hyaluronic acid and host CD44 promotes internalization by recruiting host autophagy proteins to forming phagosomes

Phagocytosis and autophagy play critical roles in immune defense. Cryptococcus neoformans (Cn), a fungal pathogen that causes fatal infection, subverts the host autophagy initiation complex (AIC) and its upstream regulatory proteins, to promote its phagocytosis and intracellular parasitism of host cells. The mechanisms by which the pathogen engages host AIC proteins remain obscure. Here, we show that the recruitment of host AIC proteins to forming phagosomes is dependent upon the activity of CD44, a host cell surface receptor that engages fungal hyaluronic acid (HA). This interaction elevates intracellular Ca2+ concentrations and activates CaMKK{beta} and its downstream target AMPK, which results in activation of ULK1 and the recruitment of AIC components. Moreover, we demonstrate that HA-coated beads efficiently recruit AIC components to phagosomes. Taken together, these findings show that fungal HA plays a critical role in directing the internalization and productive intracellular membrane trafficking of a fungal pathogen of global importance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/047621v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@72f2b9org.highwire.dtl.DTLVardef@9d5a2corg.highwire.dtl.DTLVardef@8b0218org.highwire.dtl.DTLVardef@3698d0_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefDing et al. reveal that interactions between fungal hyaluronic acid (HA) and host CD44 activate a Ca2+ - CaMKK{beta}-AMPK-ULK1 signaling pathway that recruits autophagy initiation complex components to forming phagosomes to drive fungal internalization. HighlightsO_LIFungal HA interactions with host cells drive a novel non-canonical, ligand-induced, autophagy pathway in phagocytic cells C_LIO_LICryptococcus neoformans recruits host CD44, together with AIC components and regulatory proteins, to forming phagocytic cups to initiate host cell internalization C_LIO_LIFungal HA interactions with CD44 on host cell surfaces elevate intracellular Ca2+ concentrations, leading to activation of CaMKK{beta} C_LIO_LIA Ca2+-CaMKK{beta}-AMPK-ULK1 signaling axis is involved in HA and CD44 induced autophagy protein recruitment during Cn internalization C_LI

microbiology↗