This disease is caused by small RNA viruses that attack specific cells of the human immune system. The infection is essentially lifelong, because the virus inserts a DNA copy of its genome into a chromosome of the infected immune cells where it remains quiescent. When the viruses reproduce, this results in its genetic diversification. Drug cocktails have been developed, which prevent disease; they do so by reducing proliferation of the virus, but the drugs do not result in elimination of the virus. CIDR is focused on the development of vaccines that can prevent infection and treat disease. We aim to also understand the disease caused by the viruses in order to prevent infection. HIV/AIDS is a worldwide disease. It is estimated that as of 2013, there are 35 million people living with HIV/AIDS globally, with 1,300,000 in the U.S. There have been 1.5 million deaths, with 18,000 deaths occurring in the U.S. Annually, there are 2.1 million new infections worldwide and 50,000 in the U.S.
TB is caused by a bacterium that infects the lung via airborne droplets. These droplets reside within macrophages, which are key white blood cells. The infections are persistent and dynamic, albeit typically slow to progress. The infected cells often become surrounded by immune cells, resulting in granulomas that contain numerous live and dead white blood cells and TB bacteria. The granulomas are sites of intense immune activity, as well as disease pathology. Infected lungs can contain multiple granulomatous sites, which can progress to the tuberculosis disease state. The TB bacteria are slow-growing and are able to enter quiescent states. This renders them relatively insensitive to drug treatment – treatment that lasts about six months at the least. TB has become resistant to multiple drugs over time as a consequence of patients not completing the full course of treatment. It is estimated that 2 billion people worldwide are infected with TB (11 million in the U.S. alone). Most infections are held in check, but not eliminated, by the immune response. Many of those infected with TB will progress to disease each year for reasons that are not completely understood. However, immunosuppression due to chemotherapy or HIV/AIDs results in rapid disease progression, which can be fatal. TB is a worldwide disease. There are about 10,000 cases of active TB disease per year in the U.S. CIDR is studying the immune control of TB, how it progresses to the disease stage, and the characteristics of the bacterial pathogen. Through this research, we seek to develop effective drug strategies to treat TB.
Malaria is caused by a protozoan parasite that is introduced by a mosquito bite. The parasite travels to the liver, where it proliferates extensively inside liver cells. Here, it does not cause disease. The liver cells eventually burst and release numerous parasites that infect red blood cells where they undergo 48-hour cycles of proliferation, red blood cell disruption, and reinfection. The infected red blood cells adhere to the inside of the vascular system via proteins that are inserted onto the red blood cell surface. This adherence prevents the elimination of infected red cells by the spleen. It is a key factor in the disease pathogenesis. The immune system generates antibodies against these adhesive proteins, resulting in the elimination of those parasites. Malaria changes the proteins by a process called antigenic variation and, thus, escapes immune elimination. When mosquitoes bite an infected person, the parasites are picked up and undergo complex changes. These changes result in the generation of infected parasites in the mosquito’s salivary gland, which are then transferred upon the next bite. In 2016, there were approximately 212 million people infected with malaria and almost 445,000 deaths. Malaria is currently restricted to tropical and subtropical areas. There are drugs to treat and prevent infections, but malaria has developed resistance to the drugs. CIDR is focused on developing antimalarial vaccines that can prevent infection and on developing new antimalarial drugs.
Trypanosomiasis and Leishmaniasis
African and American trypanosomiasis and Leishmaniasis are caused by three related single-celled parasites that cause different diseases and are transmitted by three different biting insects. The African and American disease are restricted to Sub-Saharan Africa and the Southern Americas (including the southern US), respectively. Leishmaniasis is widespread in tropical and subtropical regions of the Americas, Europe, the Middle East, Asia, and Africa. The distribution of the diseases is governed by the insects that transmit them. Residents and travelers to these endemic areas are at risk of infection by these parasites. African trypanosomiasis is transmitted by Tsetse flies, proliferates rapidly in the blood, and infects the central nervous system. It is fatal if left untreated. American tryopanosomiasis is transmitted by Reduviid bugs and infects many cell types, resulting in chronic infections that last decades. It also results in debilitating and untimely lethal heart disease, and less frequently, it causes life-threatening intestinal disease. Leishmaniasis is transmitted by tiny sandflies and infects key white blood cells (macrophages), resulting in chronic, lifelong infections. There are many different Leishmania species, ranging from asymptomatic to horribly disfiguring or lethal disease. All of these parasites evade immune elimination by different processes. It is estimated that in 2012, these three diseases resulted in about 85,000 deaths. There are a small number of drugs for these diseases, but none are ideal because of toxicity (which can be life-threatening), limited efficacy, or unaffordability. Resistance to these drugs is also increasing. CIDR is focused on the development of drugs for these parasites. CIDR also has projects that are studying viruses, such as Dengue and parasites, such as Toxoplasma. All of the above studies are generating new biological knowledge that offers great value.