Texas Center for Infectious Disease

Coccidioidomycosis (CM) is a fungal infection caused by the inhalation of airborne arthroconidia released by Coccidioides spp. Endemic areas include the southwestern United States, Mexico, and parts of South America. The estimated CM cases exceed 300,000 per year. Current treatment for CM is limited and primarily relies on antifungals such as azoles and Amphotericin B. Moreover, concerns about drug cytotoxicity and rising of azole-resistance underscore the need for alternative or adjunctive immune-based prevention and therapies. This review presents recent advances in immune CM intervention and discusses the potential application of emerging antifungal immunotherapy to treat invasive CM. For preventive vaccination, we reviewed the recent development of subunit protein vaccines and mRNA-based vaccines. Prospects for formulating vaccines with potent adjuvants and delivery systems to enhance protective immunity against CM are also provided. For immunotherapy, we reviewed recent reports of antifungal treatment with immunomodulators, CAR-cells and checkpoint inhibitors. Finally, we discuss the application of experimental animal and in vitro models for advancing vaccine and immunotherapeutic development for CM.

Patients with brain cancers are diagnosed based on MRI in the clinical setting while molecular signatures offer potential therapeutic targets. The necessity to re-form molecular and imaging information motivated our meta-analysis to decipher the correlation between the MRI-classified tumor locations, gene expression, and protein signatures in GBM. We analyzed spatial and omics data alongside the assessment of post-translational modifications. We first utilized MRI data to classify GBM into 4 groups. We then integrated imaging groups with RNA-Seq and proteomic data to determine the association between tumor locations, gene signatures, and protein abundance. Furthermore, we scrutinized independent measurements of post-translational modifications in each group of MRI-classified GBM. The coherent layer of imaging and molecular data collectively showed the dysregulation of cell cycle, ECM organization, immune infiltration or surveillance in all GBM cases regardless of tumor locations. Several neuronal and synaptic-specific genes were differentially altered, indicative of aberrant neuroactivity in GBM. These dysregulated genes and networks provided druggable targets that led to small compounds identification, possessing cytotoxicity against primary GBM and spanning histological boundaries. Our analysis also revealed lesion-specific molecular signatures in each group of GBM, suggesting pathological features uniquely in subgroups of GBM with prognostic or therapeutic potential. Moreover, alterations in post-translational modifications would be noteworthy to explore clinical applications. Deliverables from our meta-analysis hold the potential to inform therapeutic intervention. Despite heterogeneity in GBM, our findings implicate new directions of emerging treatments that may be used as concomitants to chemo-, radio- or immunological therapies.

This study evaluated the effectiveness of large language models (LLMs) and vision-language models (VLMs) in gastroenterology. We used board-style multiple-choice questions to assess the performance of both proprietary and open-source LLMs and VLMs—including GPT, Claude, Gemini, Mistral, Llama, Mixtral, Phi, and Qwen, across different interfaces, computing environments, and levels of compression (quantization). Among the proprietary models, o1-preview (82.0%) and Claude3.5-Sonnet (74.0%) had the highest accuracy, outperforming the top open-source models: Llama3.3-70b (65.7%) and Qwen-2.5-72b (61.0%). Among the small quantized open-source models, the 8-bit Llama 3.2-11b (51.7%) and 6-bit Phi3-14b (48.7%) performed the best, with scores comparable to their full-precision counterparts. Notably, VLM accuracy on image-containing questions improved (~10%) when given human-generated captions, remained unchanged with original images, and declined with LLM-generated captions. Further research is warranted to evaluate model capabilities in real-world clinical decision-making scenarios.

We developed an optimization-based engine that generates around-the-clock music playlists for radio stations, balancing strategic goals and business rules. By leveraging song metadata, machine learning–based song research, and listenership data, the system optimizes both playlist strength and diversity.

Lyme disease (LD), caused by Borrelia burgdorferi (Bb), is the most common vector-borne disease in the United States. Methods to control the transmission of Bb to humans via ticks are critical for prevention and elimination of LD. Previously, we showed that deletion of Borrelia hostadaptation Regulator (badR mutant) and replacement of 8 conserved residues in Carbon Storage Regulator A of Borreliaburgdorferi (CsrABb, 8S mutant) resulted in upregulation of several lipoproteins due to increased levels of RpoS. Both strains were incapable of colonization in C3H/HeN mice. Clonal isolates lacking linear plasmid 25 derived from strain Bb-B31 or Bb B31-A3 incapable of infection served as control strains. Infection derived mouse serum and serum from Lyme disease patients exhibited reactivity to lysates and purified borrelial lipoproteins (PBLs) from these mutants. Proteomic analysis of PBLs from the mutants revealed similar and unique antigenic components. Two intradermal vaccinations with the live mutant strains induced anti-borrelial antibody responses and reduced Bb load in different tissues compared to unvaccinated C3H/HeN mice following needle challenge with infectious Bb strain B31-A3 strain. The badR mutant exhibited greater protective efficacy following needle challenge with Bb or infected Ixodes scapularis (Is) nymphs. Transmission of Bb to naïve ls larvae was reduced from vaccinated mice compared to unvaccinated mice challenged with Bb strain B31-A3. PBLs from mutant strains induced protective immunity in C3H/HeN mice against challenge with infected nymphs. Overall, non-infectious mutant strains can serve as a source of antigens for biologics to interfere with the natural life cycle of Bb.

Mycobacterium tuberculosis can infect the native vertebral body and nearby structures to cause tuberculous spondylodiscitis, also known as Pott disease. We present a case of extensive, multifocal Pott disease in a United States-born veteran without human immunodeficiency virus. We briefly comment on when to consider Pott disease in cases of vertebral osteomyelitis. We also discuss treatment considerations for Pott disease with and without tuberculous involvement of the central nervous system, the recognition of tuberculosis-associated immune reconstitution inflammatory syndrome, and certain indications for surgery in Pott disease.

We report here transport of full-length epidermal growth factor receptor (EGFR), Insulin Receptor, 7-pass transmembrane receptor Smoothened, and 13-pass Sodium-iodide symporter to extracellular vesicles (EVs) for structural and functional studies. Mass spectrometry confirmed the transported proteins are the most abundant in EV membranes, and the presence of many receptor-interacting proteins in EVs demonstrates their utility for characterizing membrane protein interactomes. Cryo-electron tomography of EGFR-containing EVs reveals that EGFR forms clusters in both the presence and absence of EGF with a ~3 nm gap between the inner membrane and cytoplasmic density. EGFR extracellular region (ECR) dimers do not form regular arrays in these clusters. Subtomogram averaging of the 150 kDa EGF-bound EGFR ECR dimer yielded a 15 Å map into which the crystal structure of the ligand-bound EGFR ECR dimer fits well. These findings refine our understanding of EGFR activation, clustering, and signaling and establish EVs as a versatile platform for structural and functional characterization of human membrane proteins in cell-derived membranes.

Increased use of implanted medical devices, use of immunosuppressants and an ageing population have driven the rising frequency of fungal biofilm-related diseases. Fungi are now recognized by the World Health Organization (WHO) as an emergent threat to human health, with most medically important species defined as critical or high-priority organisms capable of forming biofilms. Although we strive for a better understanding of diagnostic and therapeutic approaches to detect and treat these fungal diseases more generally, the issue of hard-to-treat biofilms is an ever-increasing problem. These are communities of interspersed cells that are attached to one another on a surface, such as a catheter, or trapped into a cavity such as a paranasal sinus. Biofilms are difficult to detect, difficult to remove and intrinsically tolerant to most antifungal agents. These factors can lead to devastating consequences for the patient, including unnecessary morbidity and mortality, need for reoperations and prolonged hospital stay. This Review describes the breadth and growing impact fungal biofilms have on patient management and explains the mechanisms promoting biofilm formation, focusing on how targeting these can improve therapeutic options.

Diabetic retinopathy (DR) causes vision loss due to sustained inflammation and vascular damage. The vascular damage is evident by fibrinogen leakage, angiogenesis, and hypoxia. Neuronal regulation of microglia via the CX3CL1 (Fractalkine or FKN)-CX3CR1 pathway plays a significant role in retinal pathology. Defects in FKN or CX3CR1 exacerbate inflammation, vascular damage, and vision impairment. However, the contribution of hypoxic astrocytes to the pathological process of DR is unclear. A hypoxic model (7 days of systemic 7.5% O2) was utilized to induce retinal damage in adult mice in the absence of systemic inflammatory signals. This model induced vascular and microglial responses similar to 10 weeks of STZ-induced hyperglycemia. The goal of this study is to characterize retinal damage in WT and mice with defects in the FKN-CX3CR1 signaling axis and hence assess the impact of the microglial inflammatory responses to hypoxic retinopathy. Tissues were analyzed by immunostaining, RNA sequencing, and cytokine quantification. We found that CX3CR1 deficiency in hypoxic animals induced reactive astrogliosis and that Müller glial responses to hypoxia and systemic inflammation were dependent on FKN signaling. Exacerbated microglial reactivity to hypoxic conditions significantly altered the expression of HIF transcripts. Microglial dysregulation was found to reduce the anti-inflammatory response to hypoxic conditions, downregulate hypoxia-responsive gene expression, and restrained LPS-induced inflammatory responses. We found that microglia dysregulation alters the hypoxic response by inhibiting the upregulation of HIF2α/3α, increasing CD31 immunoreactivity, and altering the expression of ECM-associated transcripts such as type I, III, and XVIII collagens to hypoxic conditions.