Awarded Pilot Projects
2024-2026
CHAT UP: Connecting Young Adults with a History of Cancer to HPV Vaccine Resources through A Technology Utilizing a Patient-Provider Matching
Clark, Viktor Ph.D. – Research Assistant Professor, Department of Surgery, Cancer Control (SMD)
Summary: our goal is to develop an HPV-specific patient and provider matching texts (HPV PPMT) to increase access of HPV vaccines for YACs. We will utilize text message prompts to provide information about HPV, HPV vaccines, as well as obtain data necessary for the HPV PPMT (zip code, insurance status, primary care engagement, and student enrollment status). From this information an algorithm will provide a tailored text message to participants with specific HPV vaccine providers they are eligible to receive services from or refer participants back to their primary care provider. We hypothesize that the HPV PPMT will be acceptable, feasible, useable, and accessible to YACs. In order to analyze the acceptability, feasibility, useability, and accessibility of the HPV PPMT we will utilize a mixed-method study among (N = 20) YACs recruited through URMS who have not received the HPV vaccine series. We will also examine barriers and modifications to the HPV PPMT to improve future patient engagement. We further address this hypothesis through the following aims: Aim 1: Develop the HPV PPMT and establish its acceptability, feasibility, useability, and accessibility among 20 YACs. Aim 2: Conduct exit interviews (k = 20) to gain insight from the YACs into any barriers and modifications to the HPV PPMT that they believe will improve future patient engagement. Clinical Significance: This pilot award will allow me to collect the necessary preliminary data for developing the HPV PPMT, a key component of a multi-level intervention to enhance access to HPV vaccines for YACs. Which will be further developed into a NIH award. Ultimately this application paves a way to creating an intervention that can be accessible, relevant, and useable by thousands of YACs to prevent HPV-related second cancers.
Profiling Antimalarial Resistance and Malaria Treatment Outcomes in Lira Region of Northern Uganda
Dobrzynski, David M.D. – Associate Professor, Department of Medicine, Infectious Diseases (SMD)
Summary: Malaria remains a significant public health concern with 95% of cases and deaths occurring in sub-Saharan Africa. In 2022, Uganda had the 3rd highest global burden of malaria cases (5%), with large increase from 2021-2022, and has 5.1% of all global malaria related deaths. Malaria control largely involves insecticide-treated bed nets, insecticide sprays and efficacious drugs for treatment and prevention. However, the emergence of significant resistance to older drugs e.g., chloroquine, caused a shift in treatment to artemisinin-based combination therapy (ACT) for uncomplicated Plasmodium falciparium malaria. ACT is a rapidly effective combination of short-acting artemisinin and another long-acting antimalarial drug e.g., piperaquine (PPQ) or lumefantrine (LF). Partial resistance to artemisinins (ART-R) was reported in Southeast Asia in 2009, and more recently in Uganda in 2016, which poses significant challenges to treatment strategies for malaria control per the Uganda Malaria Reduction and Elimination Strategic Plan 2021-2025. In Lira district in Northern Uganda, we are currently seeing a 30-40% treatment failure rate at the referral hospitals which may suggest growing resistance. Research shows that the primary mediator of the artemisinin resistance is mutations in the Plasmodium falciparum Kelch protein (PfK13) e.g., 675V, with several other secondary determinants. Increase expression and/or mutations to P. falciparum multidrug resistance protein 1 (PfMDR1) and P. falciparum chloroquine resistance transporter (PfCRT), P. falciparum plasmepsin II and plasmepsin III are pivotal for resistance to ACT partner drugs e.g., PPQ and LF (1, 2). In Uganda, the first reported artemisinin resistance mutation was 675V, and in northern Uganda, 469Y and 675V mutations were reported with increasing prevalence (3). Increased plasmepsin II copy number was reported in Uganda, however this was not significantly associated with changes piperaquine sensitivity. Despite on-going efforts to study antimalaria drug resistance to inform malaria control strategies in Uganda, there is still a dearth of data especially from Northern Uganda and Lira district in particular. We therefore seek to study the correlation between treatment outcomes and expression of antimalarial resistance genes and mutations among patients with P. falciparum malaria at Lira Regional Referral Hospital (LRRH) in Northern Uganda.
A Clinical Diagnostic to Predict Adverse Outcomes during Bone Infections
Muthukrishnan, Gowrishankar, Ph.D. - Assistant Professor, Department of Orthopaedics, Center for Musculoskeletal Research (SMD)
Summary: Bone implant-associated infections remain a major challenge in orthopaedic surgery1. Staphylococcus aureus, a significant human pathogen, continues to be the leading cause of persistent bone implant-associated infections. Reinfections rates during orthopaedic surgery have remained constant over the last half-century, which has led to the paradigm that S. aureus infection of bone is broadly incurable1,2. However, it is also known that some patients can resolve acute infections and live a full life with asymptomatic S. aureus bone infections2,3. Unfortunately, there are no diagnostics to guide conservative vs. aggressive surgical treatment of these patients, and such decisions are anecdotal, time-based, and not scientific evidence based. Moreover, prognostics to predict adverse treatment outcomes (arthrodesis, reinfection, amputation, and septic death) are non-existent. To the end of developing functional prognostic clinical biomarkers, we performed studies in a humanized mouse model of S. aureus implant-associated osteomyelitis and found that humanized mice have increased bacterial load, bone osteolysis, remarkable human T cell heterogeneity, and increased expression of immune checkpoint proteins (TIM-3 and LAG3) in Th1 and Th17 cells 2-weeks post-infection. Consistently, in a preliminary pilot study involving 37 patients with S. aureus osteomyelitis, these immune checkpoint proteins were also upregulated in serum. A preliminary multiparametric nomogram revealed that TIM-3, LAG3, and PD-1 levels were highly predictive of adverse outcomes following revision surgery in human disease (AUC=0.89). Thus, our results indicate that functional impairment of T cells can occur in chronic osteomyelitis. To unravel this and derive a prognostic to guide life-altering surgical decisions, we hypothesize that a blood-based multiparametric nomogram examining human checkpoint molecules and associated cytokines can predict treatment response during chronic osteomyelitis. The following objective embodies our approach to test the proposed hypothesis.
Determine the Role of HE4 in Pelvic Inflammatory Disease Pathogenesis, Utilizing a Novel Murine Knockout Model
Turner, Rachael M.D., Ph.D. – Assistant Professor, Department of Medicine, Hematology/Oncology (SMD)
Summary: Pelvic inflammation is a common cause of infertility in females. Infectious PID is characterized by upper reproductive tract inflammation secondary to bacterial infections, primarily Chlamydia trachomotis or Neisseria gonorrhea. While the bacteria can typically be treated with antibiotics, often diagnosis is delayed by the lack early of symptoms. The residual scarring and inflammation left after the infection clears, can lead to infertility, ectopic pregnancy, and pelvic pain, and for this there is no known treatment. To develop novel diagnostics and therapeutics to improve outcomes for people impacted by PID, a more detailed understanding of the gynecologic tract antimicrobial and immune response is needed. HE4 is a member of the WAP (whey acidic protein) family of immunomodulators, it is produced in normal respiratory tract and genital epithelium, and is highly overexpressed by ovarian cancer cells, where it is associated with poor patient outcomes. Our lab has shown that HE4 is a major mediator of immune suppression in ovarian cancer and thus enables cancer cells to escape an antitumor immune response. In normal physiology, HE4 seems to play a role in the maintenance of genital and respiratory tract health, as individuals with a deficiency in HE4 secretion are afflicted with bronchiectasis and female infertility. Additionally, HE4 is known to be upregulated in the setting of acute bacterial pelvic infection, where it may be playing a protective role to prevent excessive inflammation. Our prior attempts at murine germline HE4 knockout led to early embryonic lethality, so HE4 knockout was targeted to gynecologic organs (uterus, fallopian tube) by using PAX8 promoter driven Cre expression. These animals that lack HE4 in their reproductive organ epithelium do suffer from infertility at advanced ages, but not at onset of estrous. On microscopic examination, their uteri and fallopian tubes were impacted by inflammation and fibrosis --a phenomenon that increased with mouse age, thereby proving that HE4 is necessary for the maintenance of a healthy genital epithelium. These mice are kept in pathogen free (but not sterile) environments, and we hypothesize that it is the interplay of microbiota with the gynecologic tissue that ultimately instigates this cycle of inflammation and fibrosis. Therefore, we plan to test a well-established, and clinically relevant murine model of PID in our knockout animals, to define the role of HE4 in response to bacterial pathogens in both the uterus and fallopian tubes.
2023-2024
Novel Nasal Vaccine Strategy Using Galectin-1
Minsoo Kim, Ph.D. – Professor, Department of Microbiology and Immunology, Center for Vaccine Biology and Immunology (SMD)
Summary: Despite the availability of antiviral drugs and vaccines against seasonal strains, the influenza virus causes widespread infection, leading to more than 35,000 deaths in the United States annually. Emerging data suggest that mucosal vaccination against respiratory pathogens can elicit tissue resident immunity to prevent or eliminate infection at the site of entry. Intramuscular vaccines do not elicit tissue resident memory T (TRM) cells, while intranasal delivery of the live attenuated vaccine generate both neutralizing antibodies and lung TRM cells. Indeed, current intramuscular SARS-CoV-2 vaccines can prevent severe illness and mortality but lack substantial efficacy in preventing upper respiratory infection and viral transmission. A live-attenuated influenza vaccine (LAIV), in the form of a nasal spray, mimics a natural infection, which brings the advantage of triggering mucosal immunity to block primary infections within the airway epithelia. However, immunization of the respiratory tract with LAIV often results in inadequate protection. For example, the CDC recommended against using LAIV for the 2016 -18 seasons, and the 2021-2022 nasal vaccine was only <10% effective. Therefore, new nasal vaccine strategies are needed to establish robust mucosal immune responses. In preliminary studies for this project, we tracked the fate of diverse myeloid cells in the lung after influenza infection and discovered that a subset of newly recruited monocytes differentiates and persists in the mouse lung for more than 4 months after infection. Surprisingly, selective depletion of the novel monocyte subset significantly reduced TRM formation. This long-lasting monocyte subset produces a high level of galectin-1 (Gal-1), which directly activates CD2 expressed on CD8 T cells and enhances TRM-mediated sensing of TGF-b, a key cytokine that promotes virus-specific memory T cell differentiation and tissue persistence. Based on these findings, we hypothesize that a long-lasting monocyte subset with characteristics similar to innate immune memory is formed in the lung after influenza infection and supports the development of effective T cell memory response by producing a key immune mediator, Gal-1. In this proposal, (1) we will investigate how Gal-1 induces a robust CD8 TRM formation in the lung after LAIV immunization. (2) We will also test whether a novel recombinant mutant Gal-1 variant (“Tri-PEG-Tri Gal-1”) improves the LAIV vaccine efficacy. The results of these studies will provide a useful scientific basis with which to design vaccine strategies capable of establishing productive crosstalk between components of innate and adaptive immunity, leading to the induction/maintenance of durable immunity. Such results may have a tangible and significant impact on vaccine strategies against other respiratory viruses.
Immunological Response Following mRNA-Based Vaccination in Subjects with Chronic Obstructive Pulmonary Disease
Manoj J. Mammen, M.D. - Associate Professor, Department of Medicine, Pulmonary Diseases and Critical Care (SMD)
Summary: Chronic obstructive pulmonary disease (COPD) is a global public health concern, ranking as the third leading cause of death. COPD exacerbations contribute significantly to morbidity, mortality, and healthcare utilization, with respiratory viruses implicated in up to one-third of exacerbations.
mRNA vaccines, encoding viral glycoproteins, offer potential protection against viral infections associated with COPD exacerbations, including influenza, COVID-19, and respiratory syncytial virus. The rapid production capacity of mRNA vaccines allows for timely strain matching. However, understanding the post-vaccination host responses, specifically the innate immunity pathways remain a critical research gap. This knowledge can enhance future vaccine trial design for COPD populations.
This work is directed at identifying the mechanistic underpinnings of these innate immune responses in response to mRNA vaccination in COPD patients. The mRNA vaccines have been optimized to balance the innate immune response in healthy controls, it is uncertain if there is an optimal balanced for patients with COPD given their dysregulated innate immunity. Better understanding of the response of the mRNA vaccine in individuals with COPD may optimize design of mRNA vaccines for better protection for that subpopulation.
2022-2023
The Key Role of Monocyte Derived Delta Like 4 in COVID-19 Related Vascular Diseases
Pang, Jinjiang B.Med, Ph.D. – Associate Professor, Department of Medicine, Aab Cardiovascular Research Institute (SMD)
Summary: The Coronavirus disease 2019 (COVID-19) pandemic is currently the leading health crisis across the world. This disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has clinical features that range from asymptomatic disease to pneumonia, cognitive deficit, acute respiratory distress syndrome (ARDS), multi-organ failure, and even death1. In the past two years, enormous evidence suggests impaired vascular function including endothelial cell (EC) death or apoptosis, EC activation, damage of EC integrity and vascular remodeling contributes to the vascular complications in acute COVID-19 infection as well as long-/post-COVID-19 syndromes1-5. The underlying mechanisms are still unknown. The goal of the current proposal is to determine the role of monocyte derived extracellular Delta like-4 (Dll4) in the progression of vascular diseases related to COVID-19. Dll4 is a Notch ligand and is usually restricted in ECs of small vessels in adult human and mouse lungs and brain. The ectopic expression of Dll4 in monocyte provides the link between systemic inflammation and vascular diseases.
Age-driven Differences in anti-SARS-CoV-2 Immune Responses
Rowe, Regina, M.D., Ph.D. - Assistant Professor, Department of Pediatrics, Infectious Diseases (SMD)
Summary: SARS-CoV-2, the novel coronavirus that emerged in 2019, resulted in a global pandemic and millions of deaths worldwide. As a betacoronavirus, it is closely related to the endemic human seasonal coronaviruses (hCoVs), OC43 and HKU1. However, differing from endemic hCoVs, a broad spectrum of disease is observed from asymptomatic and mild infections to fatal viral sepsis/pneumonia with acute respiratory distress syndrome, and post-infectious sequelae (i.e. multisystem inflammatory syndrome, long COVID). A stark contrast in disease severity between children (less severe) and adults (higher morbidity/mortality) suggests agerelated differences in immunity may contribute to the diversity of disease manifestations. Age also likely impacts responses to the mRNA platforms on which SARS-CoV-2 vaccines are based. Despite numerous studies investigating SARSCoV- 2 immune responses, there still remains a large knowledge gap in the specific immune mechanisms governing age-related disease severity and long-term immune responses. The objective of this study is to identify age-specific differences in innate and memory T cell immune responses to SARS-CoV-2 as compared to related endemic human coronaviruses. It is known that immune responses in infants and children differ both quantitatively and qualitatively from those in adults, with Dr. Nayak’s group demonstrating important differences in influenza-specific CD4 T cell functionality between adults and children. Such early life differences in immune function (both innate and adaptive) to SARS-CoV-2 may be responsible for age-related variation in disease manifestations and vaccine responses. Finally, as children are frequently exposed to seasonal human coronaviruses (hCoVs), this prior exposure may alter SARS-CoV-2 immune responses to vaccination or natural infection.