Liliane Mukaremera, PhD, MSc
Nominated From: University of Minnesota
Research Site: Uganda
Research Area: HIV/AIDS; Cryptococcal Meningitis
Primary Mentor: Dr. Kirsten Nielsen, PhD
Alteration of the innate immune response by different cryptococcal morphologies in HIV-infected individuals
Innate immune cells play important roles in the initial defense against pathogens. Upon contact with pathogens, innate immune cells produce cytokines that initiate and direct the host adaptive immune response. Thus, cytokines are good indicators of pathogen recognition and the resulting immune response.
Different cryptococcal morphologies have been observed both in mouse models and in human specimens. In this project, we will purify C. neoformans cells from infected mice and cerebrospinal fluid from HIV+ patients with cryptococcosis. Typical, micro and titan cells will be separated by cell size and used to induce cytokine production in a whole blood assay, similar to the QUANTIferon assay used for TB. Samples will be collected from HIV+ patients with and without cryptococcosis and equivalent immune deficiency (CD4+ T-cell counts of less than 100). Our analysis will identify (a) differences in immune response to various morphological forms of C. neoformans and, (b) similarities/differences in immune response to C. neoformans in AIDS patients with or without cryptococcosis.
The types of cytokines produced depend on the recognition of the microbial pathogen by receptors expressed on host immune cells. To identify receptors and immune pathways involved in the recognition of C. neoformans, we will block individual receptors with their known ligands and then analyze the resulting differences in cytokine responses. Ligands for receptors known to be important in other fungal infections will be targeted first to identify receptors involved in the recognition of C. neoformans cells, or individual C. neoformans cell surface components by human immune cells. The expected outcome will be the determination of receptors recognizing the entire cryptococcal cell and individual surface components.
The overall rationale for this project is to understand the activation and/or regulation of the human immune response by different C. neoformans morphologies. By determining how this recognition differs in HIV+ patients with/without cryptococcosis, we can predict high risk of cryptococcal infection and/or mortality in immunocompromised individuals with AIDS. Identification of this high risk population, many of whom may also fail current therapy, is important because this population could be targeted in the future for clinical trials of immunomodulatory therapies in addition to conventional therapy.
C. neoformans causes serious infections in immunocompromised individuals, and cryptococcal meningitis has extremely high mortality rates of ~30% in HIV/AIDS patients, even with optimal therapy. It is estimated that there are ~3 million new AIDS patients annually in Africa, and ~1 million patients will get cryptococcosis. To improve clinical outcome and survival rates, effort should be focused on developing effective and customized treatments based both on C. neoformans virulence and human immune response to cryptococcosis. This project will identify important components of the human innate immune response to C. neoformans in AIDS patients without cryptococcosis that are absent in AIDS patients with cryptococcosis. The proposed project is significant because it will result in an important advance in our knowledge of key factors (specific host immune deficiencies and pathogen attributes) that promote C. neoformans infections in immunocompromised AIDS patients. It will define specific immune responses associated with, (a) the acquisition of cryptococcosis within the AIDS-infected population and, (b) survival versus death within the human population infected with both HIV and C. neoformans. This critical information will help to identify individuals, at time of HIV status determination, at risk of developing cryptococcosis and provide supplemental treatment to enhance specific immune functions until restoration of immune system by anti-retroviral treatment.