Grant Program: Collaborative Health Sciences Program

Human immunodeficiency virus (HIV) ─ a virus that attacks the cells that help the body fight infection ─ currently has treatment options available that suppress HIV infection and renders patients noncontagious. However, it remains incurable and a portion of people living with HIV have poor clinical outcomes, even when treatment is “working.” The researchers developed two tests that worked well with controls but were unable to reliably determine the amount of HIV reservoir. The first assay was an RNA purification version of a previous TILDA assay, and the second was a more complicated assay that required the development of a cell line. However, they were able to show a link between features on patients’ T cells and poor health outcomes. This knowledge will inform future work and the researchers continue to explore ways to stimulate patient samples that will be more reproducible.

In Wisconsin, people of Hmong ancestry are infected by a particular fungal lung disease at rates up to 100 times higher than people of European ancestry, a concerning public health disparity. The researchers identified the genetic basis for susceptibility to the fungal infection in people of Hmong ancestry, providing new opportunities for treatment and education.

In Wisconsin, Alzheimer’s disease (AD) is the fifth leading cause of death among those aged 65 and older. Despite decades of research, the etiology of dementia due to AD remains unknown, and there are currently no preventative or disease-modifying treatments available. The overarching goal of this project was to determine the role of the gut microbiome in AD and identify new treatment targets for the disease. This project was successful in identifying new relationships between gut and brain pathology in AD, defining how timing of microbial colonization influences the development of AD, and determining the role microbe-related metabolites may play in preclinical cognitive decline.

The overuse and misuse of antibiotics in Wisconsin nursing homes is a public health problem as unnecessary prescriptions can lead to antibiotic resistance. This project’s goal was to improve the quality and safety of antibiotic prescribing in Wisconsin nursing homes. By partnering with Wisconsin nursing homes, and the Wisconsin Department of Health Services, the grant team is supporting the implementation and dissemination of an intervention of a urinary tract infection (UTI) toolkit, to promote antibiotic stewardship in nursing homes.

The prevalence of allergic diseases is increasing worldwide, but little progress has been made in preventing them. Epidemiologic studies have identified strong associations between early life farming exposures and protection from developing allergic diseases. This project aimed to better define the important environmental exposures and immune signatures in providing protection from developing allergic disease. This project established a novel birth cohort including infants born into animal farming environments and traditional old world agrarian lifestyles. Researchers identified key differences between the immune cells and microbial communities of infants that were related to farming lifestyles. These findings are now being leveraged and integrated into a more expansive, NIH-funded project designed to build upon these research findings.

This project, Defining and Targeting Novel Anti-viral and Anti-cancer T cell Immunity, investigated the role of nuclear-to-cytoplasmic (N→C NF-κB) signaling in regulating CD8+ T cell responses to infections and cancer. The researchers aimed to understand how N→C NF-κB signaling affects CD8+ cell regulation during viral infections and tumor responses. They found that inhibiting the N→C NF-κB pathway led to improved anti-tumor responses in their mouse model, NEMODK. However, in chronic viral infections, the model had reduced virus control, suggesting its importance in CD8+ T cell differentiation. The research team explored a drug that targeted the NF-κB pathway and showed promising results in tumor regression. The study has received NIH funding to further investigate the mechanisms of a NF-κB inhibitory drug.

Emerging and recurring viral infections remain a threat to public health and personal well-being. This innovative project proposes to “rediscover” rheumatoid factor (RF), a naturally occurring autoimmune antibody generally considered a hallmark of rheumatoid arthritis, as a unique, universal antiviral agent. The primary goal of this proposal is to learn more about the role of RFs in COVID-19 in order to inform the development of a universal antiviral treatment for rapid deployment during seasonal, endemic and future viral pandemics. The findings have the potential to inform the development of novel therapeutics for treating wide range of viral infections.

This project, led by Jacques Galipeau, MD, aimed to to generate the data needed to secure Investigative New Drug licenses from the Food and Drug Administration (FDA) to use personalized GIFT4 B cells to treat cancer as part of first-in-human clinical trials at the UW Carbone Cancer Center. Previous work enabled researchers to convert normal mouse B cells to cancer-killing cells by treating them with a synthetic cell-signaling protein called GIFT4, and the resulting cells were able to initiate an anti-tumor immune response even in the absence of defined tumor markers. In this work, researchers tested these GIFT4 B cells in mice with prostate and neuroblastoma tumors to see if the cells could improve the immune system’s ability to fight cancer. The researchers made significant progress toward their goal. They found that B cells, when grown with dendritic cells and exposed to GIFT4 protein, could activate T cells which then target tumors. These findings demonstrated the importance of understanding B cell-dendritic cell interactions to advance cancer vaccine development. Additionally, combining GIFT4 B cells with radiation and immunotherapies improved survival, highlighting the efficacy of multifaceted therapies in targeting cancer. Overall, these results have the potential to enhance cell therapies leading to more effective treatment strategies for cancer in the future.

Gaps in lupus care contribute to higher kidney failure, more early death, and worse lupus damage in U.S. patients who are Black or poor. This project used new data analysis methods to study and identify steps in lupus care with the largest impact on patient health. Health care and patient partners then helped select, adapt, and pilot test strategies to reduce health disparities and improve outcomes.

Human papillomavirus (HPV) is the most common sexually transmitted disease in the United States and the number one risk factor for developing anogenital cancers, such as squamous cell carcinoma of the anus (SCCA). Once HPV-driven anal pre-cancers are diagnosed, there are few treatment options that are effective or well-tolerated. This project further explored recent findings that show select FDA-approved protease inhibitors, previously used orally to treat HIV infection, can also be used topically to prevent HPV-associated cancers, in particular SCCA. This team of interdisciplinary researchers worked to determine the molecular mechanisms supporting these effects and repurpose these drugs as an approach for anal cancer prevention in Wisconsin.