Browsing by Subject "Monocytes"
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Item Regulation of Human Monocyte Function by Cross-Linking of Immunoglobulin E(2013-05-17) Pyle, David Michael, 1984-; Farrar, J. David; Gill, Michelle A.; Gruchalla, Rebecca S.; Yarovinsky, Felix; Kahn, JeffreyCross-linking of IgE by allergen triggers many cellular processes that drive allergic disease. While the role of IgE in mediating allergic responses is best described on basophils and mast cells, expression of the high-affinity IgE receptor on other innate immune cells, including monocytes, suggests that it may impact the function of these cells in allergic environments. Exacerbations of allergic disease have been associated with allergen exposure as well as viral and bacterial infection, but the mechanisms of these phenomena are not well understood. Monocytes are recruited to sites of inflammation in both allergic disease and infection, serving a number of important functions, including cytokine secretion, phagocytosis, and stimulation of adaptive immune responses. However, the impact of IgE cross-linking on monocyte functions is poorly understood. To determine how IgE cross-linking affects monocyte phenotype and function I isolated primary human monocytes from blood samples and stimulated them in the presence or absence of a cross-linking anti-IgE antibody. My studies reveal that IgE cross-linking induces up regulation of CD14, an important component of inflammatory responses. IgE cross-linking on monocytes also induces secretion of inflammatory cytokines - including tumor necrosis factor α, and interleukin-1, -6, and -23 - as well as autoregulatory interleukin-10. These inflammatory responses to IgE cross-linking are enhanced in monocytes from individuals with elevated serum IgE concentration, compared to monocytes from individuals with normal IgE concentration. In contrast, IgE cross-linking suppresses expression of an important mediator of phagocytosis, CD64. Indeed, IgE cross-linking specifically impairs monocyte phagocytic function without disrupting the capacity of monocytes to kill intracellular bacteria. IgE cross-linking also reduces expression of several surface molecules associated with antigen presentation and inhibits virus-induced up regulation of these molecules. Furthermore, IgE cross-linking during virus exposure suppresses monocyte-driven differentiation of type 1 helper T cells. My findings suggest that IgE cross-linking on monocytes may contribute to allergic disease as well as pathogen-associated exacerbations of disease by three mechanisms: 1) enhancing detrimental inflammatory responses in a serum IgE-dependent manner, 2) concomitantly crippling phagocytosis, a primary mechanism utilized by these cells to resolve inflammation, and 3) suppressing stimulation of appropriate T cell responses in response to infection.Item [Southwestern News](1998-11-24) McNeill, Bridgette RoseItem [Southwestern News](1999-04-09) McNeill, Bridgette RoseItem Toward the Rational Design of Better Antivirals: The Development of cGAMP as an HIV-1 Anti-Retroviral and the Genetic Surveillance of WNV Evolution(2017-04-17) Aroh, Chukwuemika Nnabuike; Pasare, Chandrashekar; Wakeland, Edward K.; Yan, Nan; Schoggins, John W.; Pfeiffer, Julie K.The innate immune response is the first line of defense against pathogens and thus represents the first hurdle viruses must overcome to cause severe disease in humans. Understanding the consequences of viral evolution can give insights to mechanisms of viral pathogenesis as well as the development of novel therapeutics. Here I studied two clinically important viruses: Human Immunodeficiency Virus (HIV) and West Nile Virus (WNV). HIV-1 has evolved several mechanisms to evade immune detection by the cGAS-STING cytosolic DNA sensing pathway. A small cyclic di-nucleotide, cGAMP, activates the same pathway by directly binding STING. Treatment with cGAMP, delivered by ultra-pH sensitive nanoparticles or by liposomes, in human peripheral blood mononuclear cells (PBMCs) induced potent and long-acting protection against replication of several laboratory-adapted and clinical HIV-1 isolates in contrast to the short-lasting effect of current anti-retroviral therapy (ARTs). These results present the first evidence for potentially developing cGAMP or other STING agonists as a long-acting antiretroviral immunotherapy. West Nile Virus (WNV) is a mosquito-borne Flavivirus which was introduced to North America in 1999 and is currently the leading cause of viral encephalitis. The lack of specific therapeutics or human vaccines makes WNV an ongoing public health threat. Now endemic, WNV is steadily evolving, but the contribution of positively-selected mutations to human disease remains unclear. In 2012 the second largest outbreak of human West Nile disease occurred in the U.S., with one-third of the cases happening in Texas. The outbreak was associated with groups of WNV carrying positively-selected mutations. By sequencing WNV in Texas from 2012-2015, we show that positively-selected mutations in WNV mediate increased circulation and over-wintering in the environment, which may promote increases of human disease. Additionally, we show evidence that the WNV population is still evolving new alleles. These results advance our understanding of the impact of WNV evolution to human disease, and may afford insights to the evolution of other invading flaviviruses, such as Dengue and Zika virus. Altogether, these results show that understanding the consequences of viral evolution can be harnessed towards overcoming challenges to the development of more effective therapeutics.