Altered Immune Response Differentially Enhances Susceptibility to Cryptococcus neoformans and Cryptococcus gattii Infection in Mice Expressing the HIV-1 Transgene

Abstract

e Cryptococcus neoformans var. grubii is the most frequent cause of AIDS-associated cryptococcosis worldwide, while Cryptococcus gattii usually infects immunocompetent people. To understand the mechanisms which cause differential susceptibility to these cryptococcal species in HIV infection, we established and characterized a model of cryptococcosis in CD4C/HIV MutA transgenic (Tg) mice expressing gene products of HIV-1 and developing an AIDS-like disease. Tg mice infected intranasally with C. neoformans var. grubii strain H99 or C23 consistently displayed reduced survival compared to non-Tg mice at three graded inocula, while shortened survival of Tg mice infected with C. gattii strain R265 or R272 was restricted to a single high inoculum. HIV-1 transgene expression selectively augmented systemic dissemination to the liver and spleen for strains H99 and C23 but not strains R265 and R272. Histopathologic examination of lungs of Tg mice revealed large numbers of widely scattered H99 cells, with a minimal inflammatory cell response, while in the non-Tg mice H99 was almost completely embedded within extensive mixed inflammatory cell infiltrates. In contrast to H99, R265 was dispersed throughout the lung parenchyma and failed to induce a strong inflammatory response in both Tg and non-Tg mice. HIV-1 transgene expression reduced pulmonary production of CCL2 and CCL5 after infection with H99 or R265, and production of these two chemokines was lower after infection with R265. These results indicate that an altered immune response in these Tg mice markedly enhances C. neoformans but not C. gattii infection. This model therefore provides a powerful new tool to further investigate the immunopathogenesis of cryptococcosis.

Immunity to Cryptococcus neoformans and C. gattii during cryptococcosis

“…Furthermore, CD4+ T cell granulysin mediated killing of cryptococci is not activated in cells from HIV patients ( Zheng et al, 2007 ). A murine model of HIV infected with Cryptococcus produced reduced levels of chemokines CCL2 and CCL5, which are immune cell attractants, in comparison to non-infected mice ( Leongson and Cousineau-Côté, 2013 ). Thus, HIV infection may lead to specific innate immune cell recruitment defects as well as general immune imbalance and this will further reduced host capability to combat Cryptococcus .…”

Antifungal activity of topical microemulsion containing a thiophene derivative

“…Inhalation of its basidiospores or cells present in the environment can result in lung infection and its subsequent spread to the central nervous system, causing meningoencephalitis, recognized as one of the most important opportunistic infections in patients with HIV with a worldwide incidence of approximately 957,000 cases per year (Leongson et al , 2013). …”

Conservation of Intracellular Pathogenic Strategy among Distantly Related Cryptococcal Species

“…Alveolar macrophages (Mac), dendritic cells (DC), and neutrophils are the early responders to Cryptococcus infection, while CD4 ϩ T helper cells are the main effector cell of the adaptive cellular immune response to Cryptococcus (12). There have been inconsistent reports about which cryptococcal species complex is more virulent, but C. gattii Vancouver Island outbreak strains (mainly VGIIa strains) elicit weaker immune responses with lower levels of interleukin 6 (IL-6), tumor necrosis factor alpha, monocyte chemotactic protein 1, Th1, and Th17 cytokines than strains not associated with the outbreak (13)(14)(15). The VGII strains further inhibit neutrophil and CD4 ϩ T helper cell migration to the lung (13,16,17).…”