Browsing by Subject "Pathogenesis"

Now showing 1 - 10 of 21
  • Thumbnail Image
    Item
    Assessing the cancer hypothesis of pulmonary arterial hypertension: the devil is in the detail
    (American Physiological Society, 2020-06-01) Frump, Andrea L.; Lai, Yen-Chun; Lahm, Tim; Anatomy and Cell Biology, School of Medicine
  • Thumbnail Image
    Item
    Cilia-associated wound repair mediated by IFT88 in retinal pigment epithelium
    (Springer Nature, 2023-05-21) Ning, Ke; Bhuckory, Mohajeet B.; Lo, Chien‑Hui; Sendayen, Brent E.; Kowal, Tia J.; Chen, Ming; Bansal, Ruchi; Chang, Kun‑Che; Vollrath, Douglas; Berbari, Nicolas F.; Mahajan, Vinit B.; Hu, Yang; Sun, Yang; Biology, School of Science
    Primary cilia are conserved organelles that integrate extracellular cues into intracellular signals and are critical for diverse processes, including cellular development and repair responses. Deficits in ciliary function cause multisystemic human diseases known as ciliopathies. In the eye, atrophy of the retinal pigment epithelium (RPE) is a common feature of many ciliopathies. However, the roles of RPE cilia in vivo remain poorly understood. In this study, we first found that mouse RPE cells only transiently form primary cilia. We then examined the RPE in the mouse model of Bardet-Biedl Syndrome 4 (BBS4), a ciliopathy associated with retinal degeneration in humans, and found that ciliation in BBS4 mutant RPE cells is disrupted early during development. Next, using a laser-induced injury model in vivo, we found that primary cilia in RPE reassemble in response to laser injury during RPE wound healing and then rapidly disassemble after the repair is completed. Finally, we demonstrated that RPE-specific depletion of primary cilia in a conditional mouse model of cilia loss promoted wound healing and enhanced cell proliferation. In summary, our data suggest that RPE cilia contribute to both retinal development and repair and provide insights into potential therapeutic targets for more common RPE degenerative diseases.
  • Thumbnail Image
    Item
    Coxiella burnetii Virulent Phase I and Avirulent Phase II Variants Differentially Manipulate Autophagy Pathway in Neutrophils
    (American Society for Microbiology, 2022) Kumaresan, Venkatesh; Wang, Juexin; Zhang, Wendy; Zhang, Yan; Xu, Dong; Zhang, Guoquan; Medical and Molecular Genetics, School of Medicine
    Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes Q fever in humans. The virulent C. burnetii Nine Mile phase I (NMI) strain causes disease in animal models, while the avirulent NM phase II (NMII) strain does not. In this study, we found that NMI infection induces severe splenomegaly and bacterial burden in the spleen in BALB/c mice, while NMII infection does not. A significantly higher number of CD11b+ Ly6G+ neutrophils accumulated in the liver, lung, and spleen of NMI-infected mice than in NMII-infected mice. Thus, neutrophil accumulation correlates with NMI and NMII infection-induced inflammatory responses. In vitro studies also demonstrated that although NMII exhibited a higher infection rate than NMI in mouse bone marrow neutrophils (BMNs), NMI-infected BMNs survived longer than NMII-infected BMNs. These results suggest that the differential interactions of NMI and NMII with neutrophils may be related to their ability to cause disease in animals. To understand the molecular mechanism underlying the differential interactions of NMI and NMII with neutrophils, global transcriptomic gene expressions were compared between NMI- and NMII-infected BMNs by RNA sequencing (RNA-seq) analysis. Interestingly, several genes involved in autophagy-related pathways, particularly membrane trafficking and lipid metabolism, are upregulated in NMII-infected BMNs but downregulated in NMI-infected BMNs. Immunofluorescence and immunoblot analyses indicate that compared to NMI-infected BMNs, vacuoles in NMII-infected-BMNs exhibit increased autophagic flux along with phosphatidylserine translocation in the cell membrane. Similar to neutrophils, NMII activated LC3-mediated autophagy in human macrophages. These findings suggest that the differential manipulation of autophagy of NMI and NMII may relate to their pathogenesis.
  • Thumbnail Image
    Item
    Editorial: Models to study malaria parasite-host interactions and pathogenesis
    (Frontiers Media, 2022-09-22) Bernabeu, Maria; Conroy, Andrea L.; Craig, Alister G.; Renia, Laurent; Pediatrics, School of Medicine
  • Thumbnail Image
    Item
    Effects of donor-specific microvascular anatomy on hemodynamic perfusion in human choriocapillaris
    (Springer Nature, 2023-12-19) An, Senyou; Yu, Huidan; Islam, MD Mahfuzul; Zhang, Xiaoyu; Zhan, Yuting; Olivieri, Joseph J.; Ambati, Jayakrishna; Yao, Jun; Gelfand, Bradley D.; Mechanical and Energy Engineering, Purdue School of Engineering and Technology
    Evidence from histopathology and clinical imaging suggest that choroidal anatomy and hemodynamic perfusion are among the earliest changes in retinal diseases such as age-related macular degeneration (AMD). However, how inner choroidal anatomy affects hemodynamic perfusion is not well understood. Therefore, we sought to understand the influences of choroidal microvascular architecture on the spatial distribution of hemodynamic parameters in choriocapillaris from human donor eyes using image-based computational hemodynamic (ICH) simulations. We subjected image-based inner choroid reconstructions from eight human donor eyes to ICH simulation using a kinetic-based volumetric lattice Boltzmann method to compute hemodynamic distributions of velocity, pressure, and endothelial shear stress. Here, we demonstrate that anatomic parameters, including arteriolar and venular arrangements and intercapillary pillar density and distribution exert profound influences on inner choroidal hemodynamic characteristics. Reductions in capillary, arteriolar, and venular density not only reduce the overall blood velocity within choriocapillaris, but also substantially increase its spatial heterogeneity. These first-ever findings improve understanding of how choroidal anatomy affects hemodynamics and may contribute to pathogenesis of retinal diseases such as AMD.
  • Thumbnail Image
    Item
    Evaluation of Cerebrospinal Fluid Pressure by a Formula and Its Role in the Pathogenesis of Glaucoma
    (Hindawi, 2019-11) Landi, Laura; Casciaro, Federica; Telani, Serena; Traverso, Carlo E.; Harris, Alon; Verticchio Vercellin, Alice C.; Saint, Lauren; Iester, Michele; Ophthalmology, School of Medicine
  • Thumbnail Image
    Item
    Expression of Hemangioblast Proteins in von Hippel-Lindau Disease Related Tumors
    (MDPI, 2023-04-29) Vergauwen, Evelynn; Forsyth, Ramses; Vortmeyer, Alexander; Gläsker, Sven; Pathology and Laboratory Medicine, School of Medicine
    Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome that targets a highly selective subset of organs causing specific types of tumors. The biological basis for this principle of organ selectivity and tumor specificity is not well understood. VHL-associated hemangioblastomas share similar molecular and morphological features with embryonic blood and vascular precursor cells. Therefore, we suggest that VHL hemangioblastomas are derived from developmentally arrested hemangioblastic lineage keeping their potential of further differentiation. Due to these common features, it is of major interest to investigate whether VHL-associated tumors other than hemangioblastoma also share these pathways and molecular features. The expression of hemangioblast proteins has not yet been assessed in other VHL-related tumors. To gain a better understanding of VHL tumorigenesis, the expression of hemangioblastic proteins in different VHL-associated tumors was investigated. The expression of embryonic hemangioblast proteins Brachyury and TAL1 (T-cell acute lymphocytic leukemia protein 1) was assessed by immunohistochemistry staining on 75 VHL-related tumors of 51 patients: 47 hemangioblastomas, 13 clear cell renal cell carcinomas, 8 pheochromocytomas, 5 pancreatic neuroendocrine tumors, and 2 extra-adrenal paragangliomas. Brachyury and TAL1 expression was, respectively, observed in 26% and 93% of cerebellar hemangioblastomas, 55% and 95% of spinal hemangioblastomas, 23% and 92% of clear cell renal cell carcinomas, 38% and 88% of pheochromocytomas, 60% and 100% of pancreatic neuroendocrine tumors, and 50% and 100% of paragangliomas. We concluded that the expression of hemangioblast proteins in different VHL-associated tumors indicates a common embryological origin of these lesions. This may also explain the specific topographic distribution of VHL-associated tumors.
  • Thumbnail Image
    Item
    FeMV is a cathepsin-dependent unique morbillivirus infecting the kidneys of domestic cats
    (National Academy of Sciences, 2022) Nambulli, Sham; Rennick, Linda J.; Acciardo, Andrew S.; Tilston-Lunel, Natasha L.; Ho, Gregory; Crossland, Nicholas A.; Hardcastle, Kathy; Nieto, Betsy; Bainbridge, Graeme; Williams, Tracey; Sharp, Claire R.; Duprex, W. Paul; Microbiology and Immunology, School of Medicine
    Feline morbillivirus (FeMV) has been classified as a morbillivirus despite lacking several biological features shared by all other known viruses in the genus. We confirm that FeMV uses CD150 as a cellular receptor and employs a different protease to furin to process the fusion glycoprotein. As such, FeMV may represent an important evolutionary intermediate between morbilliviruses and the zoonotic henipaviruses. Feline chronic kidney disease is the leading cause of morbidity and mortality in cats and has no clear etiology. FeMV has been postulated to be a causative agent. We dissected FeMV pathogenesis using recombinant, fluorescent protein expressing viruses based on an unpassaged clinical isolate. This sheds light on the primary target cells infected and possible mechanisms of host-to-host transmission.
  • Thumbnail Image
    Item
    Group B Streptococcus cpsE is required for serotype V capsule production and aids in biofilm formation and ascending infection of the reproductive tract during pregnancy
    (American Chemical Society, 2021) Noble, Kristen; Lu, Jacky; Guevara, Miriam A.; Doster, Ryan S.; Chambers, Schuyler A.; Rogers, Lisa M.; Moore, Rebecca E.; Spicer, Sabrina K.; Eastman, Alison J.; Francis, Jamisha D.; Manning, Shannon D.; Rajagopal, Lakshmi; Aronoff, David M.; Townsend, Steven D.; Gaddy, Jennifer A.; Pediatrics, School of Medicine
    Group B Streptococcus (GBS) is an encapsulated Gram-positive pathogen that causes ascending infections of the reproductive tract during pregnancy. The capsule of this organism is a critical virulence factor that has been implicated in a variety of cellular processes to promote pathogenesis. Primarily comprised of carbohydrates, the GBS capsule and its synthesis is driven by the capsule polysaccharide synthesis (cps) operon. The cpsE gene within this operon encodes a putative glycosyltransferase that is responsible for the transfer of a Glc-1-P from UDP-Glc to an undecaprenyl lipid molecule. We hypothesized that the cpsE gene product is important for GBS virulence and ascending infection during pregnancy. Our work demonstrates that a GBS cpsE mutant secretes fewer carbohydrates, has a reduced capsule, and forms less biofilm than the wild-type parental strain. We show that, compared to the parental strain, the ΔcpsE deletion mutant is more readily taken up by human placental macrophages and has a significantly attenuated ability to invade and proliferate in the mouse reproductive tract. Taken together, these results demonstrate that the cpsE gene product is an important virulence factor that aids in GBS colonization and invasion of the gravid reproductive tract.
  • Thumbnail Image
    Item
    The growing repertoire of genetic tools for dissecting chlamydial pathogenesis
    (Oxford University Press, 2021) Banerjee, Arkaprabha; Nelson, David E.; Microbiology and Immunology, School of Medicine
    Multiple species of obligate intracellular bacteria in the genus Chlamydia are important veterinary and/or human pathogens. These pathogens all share similar biphasic developmental cycles and transition between intracellular vegetative reticulate bodies and infectious elementary forms, but vary substantially in their host preferences and pathogenic potential. A lack of tools for genetic engineering of these organisms has long been an impediment to the study of their biology and pathogenesis. However, the refinement of approaches developed in C. trachomatis over the last 10 years, and adaptation of some of these approaches to other Chlamydia spp. in just the last few years, has opened exciting new possibilities for studying this ubiquitous group of important pathogens.