IMPACT OF RNA VIRUSES ON THE REGULATION OF IL-23 IN MOUSE AND HUMAN MODELS OF INFECTION.

Interluekin-23 (IL-23) is a pro-inflammatory cytokine critical to the regulation of innate and adaptive immune responses. The main role for this cytokine is in the proliferation and differentiation of the IL-17 producing CD4 T helper cell, Th17. Virus infection deregulates IL-23 expression and function, but little is known about the mechanism behind this phenomena. Here, I demonstrate a reduction of Toll like receptor (TLR) ligand-induced IL-23 expression in lymphocytic choriomeningitis virus (LCMV)-infected bone marrow-derived dendritic cells (BMDCs), indicating that a function of these cells is disrupted during virus infection. I propose a mechanism of TLR ligand-induced IL-23 expression inhibition upon LCMV infection via the deactivation of p38, AP-1, and NF-κB. Further analysis revealed a direct relationship between LCMV infection with the IL-10 and SOCS3 expression. To understand IL-23 function, I characterized IL-23-induced JAK/STAT signalling pathway and IL-23 receptor expression on human CD4 T cells. My results demonstrate that IL-23 induces activation of p-JAK2, p-Tyk2, p-STAT1, p-STAT3, and p-STAT4 in CD4 T cells. For the first time I show that IL-23 alone induces the expression of its own receptor components, IL-12Rβ1 and IL-23Rα, in CD4 T cells. Blocking JAK2, STAT1, and STAT3 activation with specific inhibitors detrimentally effected expression of IL-23 receptor demonstrating that activation of JAK/STAT signalling is important for IL-23 receptor expression. I also addressed the effect of viral infection on IL-23 function and receptor expression in CD4 T cells using cells isolated from HIV positive individuals. These studies were based on earlier reports that the expression of IL-23 and the IL-23 receptor are impaired during HIV infection. I demonstrate that the phosphorylation of JAK2, STAT1, and STAT3 induced by IL-23, as well as IL-23 receptor expression are deregulated in CD4 T cells isolated from HIV positive individuals. This study has furthered the understanding of how the expression and function of IL-23 is regulated during viral infections.

Essays on Economics of Entrepreneurship

This dissertation examines three important issues. The first issue is about the human capital investment and entrepreneurship as a career choice. The standard human capital theory shows that firms (employees) never invest in general (firm-specific) human capital of the employee as they do not extract any return from it. However, when entrepreneurship is introduced as a career option for an innovative employee, both firm’s and employee’s human capital investments change. Employee starts investing in his firm-specific human capital to increase the probability to innovate (and to become an entrepreneur). However, the firm uses general human capital investment to reduce the risk of employee’s departure. The second issue is regarding the factors motivating entry regulations reforms and the possible nonlinear effects of entry regulation reforms. The current literature and the policy recommendations assume that these reforms have linear effects on entrepreneurship. Nevertheless, the anecdotal evidence shows that the outcomes of such reforms vary greatly from country to country. To investigate this issue, I collect a sample data on entry regulations and firm creation from World Bank. The empirical analysis indicates that the effect of entry regulation reforms depends on the pre-reform level of bureaucracy in the country. More specifically, while low-bureaucracy countries benefit from entry regulation reforms, high-bureaucracy countries do not benefit. Moreover, the probability of making a reform increases if the country has reformist neighbors, cumbersome entry regulations, high unemployment rate, or low corruption level. The last issue is related to the individual and joint effects of bureaucracy and corruption on different types of entrepreneurs. The current literature investigates these effects only on unified measures of entrepreneurship. However, entrepreneurs are very different in many senses. To address this issue, I collect the necessity-based and opportunity-based entrepreneurship data from Global Entrepreneurship Monitor. The empirical analysis yield two important results: First, bureaucracy has a direct negative (positive) effect on necessity-based (opportunity-based) entrepreneurs. Second, corruption mitigates the effect of bureaucracy for both groups of entrepreneurs. All three chapters offer useful insights and important implications to academics and policymakers.