Murine Model of Cryptococcus-associated Immune Reconstitution Inflammatory Syndrome (IRIS)

Cryptococcus neoformans is an opportunistic fungal pathogen that is able to cause pneumonia and life-threatening infections of the central nervous system. This pathogen is particularly problematic for immunocompromised individuals, such as those with AIDS or undergoing immunosuppressive therapies. Since the initial outbreak of HIV/AIDS, controlling the infection is now possible through combination antiretroviral therapy (ART) which helps to restore immune function in this population. However, approximately 30% of patients who have recieved ART treatment can develop an uncontrolled inflammatory response following reconstitution of the immune system while they still have a latent HIV infection. This poorly understood inflammatory response is known as Immune Reconstitution Inflammatory Syndrome (IRIS) and can be caused by C. neoformans. Our aim is to develop a clinically relevant small animal model of Cryptococcus-related IRIS using wild type mice, as opposed to current murine models of IRIS using genetically immune deficient mice. We established a Cyrptococcus-related IRIS model using immune competent BALB/c mice that were depleted of T cells via complement-fixing antibodies and challenged with a small infectious dose of C. neoformans yeast. The T cell depletions were continued for several weeks post infection, before allowing for the immune system to reconstitute, mimicking what occurs in the IRIS patient population. The mice were monitored for mortality, fungal burden and cytokine production in the CNS. Establishment of this model will allow for the characterization of therapies designed to reduce the mortality associated with Cryptococcus-related IRIS in humans.