Differential Regulation of Kidney and Spleen Cytokine Responses in Mice Challenged with Pathology-Standardized Doses of Candida albicans Mannosylation Mutants

Abstract

Cell surface polysaccharides are key determinants of host responses to fungal infection. We determined the effects of alterations in Candida albicans cell surface polysaccharide composition and gross changes in the host immune response in groups of mice challenged intravenously with five C. albicans strains at doses adjusted to give equal disease progression 3 days later. The five strains used were the parental strain NGY152, two mutants with defective cell wall mannosylation, pmr1⌬ mutant and mnt1/2⌬ mutant, and the same two strains with a copy of PMR1 and MNT1 reintegrated, respectively. Renal and spleen levels of chemokines and cytokines previously shown to be key components of early host response to C. albicans were determined at intervals up to 3 days after challenge. By 12 h after C. albicans challenge, the levels of granulocyte colony-stimulating factor (G-CSF), keratinocyte-derived chemokine (KC), interleukin 6 (IL-6), monocyte chemotactic peptide 1 (MCP-1), macrophage inflammatory protein 1␣ (MIP-1␣), MIP-1␤, and MIP-2 were higher in the kidneys of mice challenged with the pmr1⌬ mutant than in animals challenged with the other strains and were lower by day 3, suggesting an earlier host response to the pmr1⌬ mutant. The production of these chemokines also diminished earlier than controls in mice infected with the mnt1/2⌬ strain. Although these differences were statistically significant, their magnitude was seldom great, and no unambiguous evidence was obtained for individual responses specific to any cell surface glycosylation change. We conclude that complex, multifactorial local responses offset and obscure any differences resulting from differences in surface mannosylation of C. albicans strains when infection results from pathology-standardized challenges.

Specific Human and Candida Cellular Interactions Lead to Controlled or Persistent Infection Outcomes during Granuloma-Like Formation

“…In light of our observations, it is not clear, however, how these structures could be the consequence of late immune infiltrates. Furthermore, the translational relevance of this granulomatous reaction is in agreement with murine models of hematogenously disseminated candidiasis in which infection occurs in hosts with weak or normal immune responses (29, 30). …”

“…In these models, C. albicans dissemination causes extensive disease, mostly in the kidneys, that are also characterized by multiple compact immune infiltrates (28–30). In vitro studies describing the infection of peripheral blood mononuclear cells (PBMC) are complementary to animal models giving information about Candida pathogenesis in the context of human-like environments.…”

The contribution of mouse models to our understanding of systemic candidiasis

“…Modelling disseminated C. albicans infection by intravenous injection in normal mice demonstrated that fungal growth was controlled in the liver and spleen, while fungal burdens increased in the kidneys (MacCallum & Odds, 2005; Lionakis et al , 2010). In the kidneys, fungal burden increases were accompanied by increasing immune infiltrates (MacCallum et al , 2009a; Castillo et al , 2011). This did not occur in other organs.…”

Candida albicans Pathogenesis: Fitting within the Host-Microbe Damage Response Framework

“…via lateral tail vein injection, which results in rapid dissemination of C. albicans in a reproducible fashion (67,68). Although fungal growth is controlled in the spleen and to a lesser extent in the liver, due to the presence of resident phagocytes, C. albicans causes extensive disease in the kidneys that is accompanied by increased immune infiltrates (68,69). Whereas with lower inocula tissue burdens and host responses within the kidney are controlled, with higher inocula sepsis might occur, leading to high fatality rates (67,70).…”