Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome

点击翻译按钮获取中文摘要

Despite major advances in global health care, there were an estimated 1.5 millions deaths and 10 million new cases of tuberculosis (TB) in 2018. Nearly 1 million people living with HIV developed tuberculosis (TB). Co- infection with HIV and TB is associated with high morbidity and mortality and treatment with TB drugs and anti- retroviral (ART) therapy is now universally available. TB drug treatment followed by ART improves long term survival, particularly among those whose immune systems are severely suppressed from HIV infection. Signs and symptoms of disease improve soon after treatment is started but, in many cases, disease can recur and appear clinically worse as the immune system is being re-established from ART. This is known as TB- associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and is more common among patients with severely suppressed immune systems before treatment and those who have a short time interval between starting TB treatment and ART. Very little is known about how or why TB-IRIS occurs and how to best to treat or even prevent it. We hypothesize that symptoms of TB-IRIS are driven by the dynamic interaction between the immune system, Mycobacterium tuberculosis (Mtb, the bacteria that causes TB) and HIV deep within infected tissues in the body such as the lung granuloma. Virtually nothing is known about what happens in the tissues where both Mtb and HIV interact during TB-IRIS. This proposal will develop an animal model of TB- IRIS by taking advantage of our pre-existing model of HIV-TB co-infection in which animals with SIV-Mtb co- infection undergo TB drug treatment and ART just like humans. We will use sophisticated imaging, immunology and microbiologic tools to better understand how and why TB-IRIS develops and what factors can predict its emergence. Aim 1 will determine how often TB-IRIS occurs in this model and to what extent Mtb and SIV remain in the tissues during treatment. We will also perform a detailed examination of the changes that occur in the tissues but especially the lungs (granulomas) and lymph nodes through serial in vivo images to better understand the events that lead to TB-IRIS and its predictors. In Aim 2, we will perform a detailed examination of the immunologic events in the tissues and blood during TB-IRIS. Tissue specific (lung granulomas and lymph nodes) immune responses will be correlated with the amount of Mtb bacteria and virus with the imaging findings so that we can better understand the causes of TB-IRIS. Our short term goal is to better understand the pathogenesis of TB-IRIS in this proposal and these findings will ultimately lead to better treatment and prevention of TB-IRIS which is our long term goal.