Mycobacterium tuberculosis is a worldwide public health problem, and the need to develop new vaccines to prevent further deaths is critical. However, vaccine development is hindered by the difficulty of translating pre- clinical animal model data to human trials. There may be multiple factors associated with the difference in outcomes between pre-clinical and clinical settings. Of significant interest is the role that co-infections play in mediating immunity to M. tuberculosis infection and how these co-infections increase the risk of developing tuberculosis disease. Co-infections, such as with human Cytomegalovirus virus (HCMV), are important drivers of immune activation in HIV, particularly in sub-Saharan Africa. HCMV associated immune activation in the HIV exposed is known to drive CD4+ T cell decline, hasten immuno-senescence and lead to eventual immune exhaustion. There also emerging evidence to support the fact that HCMV plays a significant role in exacerbating tuberculosis disease in immunocompetent individuals, thus it is important to investigate the interaction between these pathogens and how they mediate the immunity. The current proposal is designed to develop an in vivo experimental co-infection in mice with M. tuberculosis and Cytomegalovirus and with M. tuberculosis. Thus the primary focus of this application is to develop a mouse model to investigate the role of co-infection in the immune mechanisms required to kill M. tuberculosis, and once these have been identified can we start to understand better how to make effective TB vaccines. We will focus on cytomegalovirus co-infection during M. tuberculosis infection to determine how it contributes to exacerbation of TB disease using a mouse model. We will develop the model to understand innate and adaptive immune responses during co-infection (Aim 1), test the hypothesis that excessive reactive species contribute to TB disease using a Type I interferon independent mechanism (Aim 2) and determine how infection with each pathogen interacts with neighboring cells and determine if CMV infection of macrophages and dendritic cells skews development of macrophages towards an M2 or suppressive phenotype resulting in poor adaptive immunity to M. tuberculosis in-vitro.
(Aim 3). These studies will provide the basis for future model development to identify mechanisms that may interfere with the efficacy of new and existing anti-tuberculosis vaccines.
A significant problem associated with developing better vaccines against tuberculosis (TB), is our limited understanding of the critical immune mechanism required to kill Mycobacterium tuberculosis. To-date a large number of animal models have been used to identify mechanisms that have been translated to the human experience, but despite these discoveries, we still do not have a vaccine that can induce protective immunity. Our understanding of immune mechanisms induced by vaccines is also quite limited and evolving and may provide answers about why it fails to protect adequately. Animal models have suggest that BCG vaccination induces strong immunity and provides the host with the ability to kill M. tuberculosis, but this effect is rarely observed in human clinical trials. So it needs to be asked: why is there such discordance between animal models and human trials? One difference that may play a significant role is the presence of co-infection in humans to whom the vaccines are targeted. The importance of developing co-infections models in our existing TB animal models is highlighted by the failure of novel TB vaccines in clinical trials (e.g. MVA85A Phase II trial), after being efficacious in the TB animal models. Co-infections in animal models of TB have been poorly investigated. Thus the primary focus of this application is to develop a mouse model to investigate the role of co-infection in the immune mechanisms required to kill M. tuberculosis, and once these have been identified can we start to understand better how to make effective TB vaccines. We will focus on cytomegalovirus co-infection during M. tuberculosis infection to determine how it contributes to exacerbation of TB disease using a mouse model. We will develop the model to understand innate and adaptive immune responses during co-infection (Aim 1), test the hypothesis that excessive reactive species contribute to TB disease using a Type I interferon independent mechanism (Aim 2) and determine how infection with each pathogen interacts with neighboring cells and determine if CMV infection of macrophages and dendritic cells skews development of macrophages towards an M2 or suppressive phenotype resulting in poor adaptive immunity to M. tuberculosis in-vitro. (Aim 3). These studies will provide the basis for future model development to identify mechanisms that may interfere with the efficacy of new and existing anti-tuberculosis vaccines.. These studies will provide the basis for future model development to identify mechanisms that may interfere with the efficacy of new and existing anti-tuberculosis vaccines.
