Candida albicansescapes from mouse neutrophils

Abstract

Candida albicans, the most commonly isolated human fungal pathogen, is able to grow as budding yeasts or filamentous forms, such as hyphae. The ability to switch morphology has been attributed a crucial role for the pathogenesis of C. albicans. To mimic disseminated candidiasis in humans, the mouse is the most widely used model organism. Neutrophils are essential immune cells to prevent opportunistic mycoses. To explore potential differences between the rodent infection model and the human host, we compared the interactions of C. albicans with neutrophil granulocytes from mice and humans. We revealed that murine neutrophils exhibited a significantly lower ability to kill C. albicans than their human counterparts. Strikingly, C. albicans yeast cells formed germ tubes upon internalization by murine neutrophils, eventually rupturing the neutrophil membrane and thereby, killing the phagocyte. On the contrary, growth and subsequent escape of C. albicans are blocked inside human neutrophils. According to our findings, this blockage in human neutrophils might be a result of higher levels of MPO activity and the presence of α-defensins. We therefore outline differences in antifungal immune defense between humans and mouse strains, which facilitates a more accurate interpretation of in vivo results.

Candida albicans Quorum Sensing Molecules Stimulate Mouse Macrophage Migration

“…Our observation that farnesol stimulates macrophages to migrate is consistent with work showing that farnesol affects aspects of host immune responses differently (21,22). Recently, Leonhardt et al (22) showed that neutrophils, which are more capable of killing C. albicans (19,20), are only weakly stimulated by farnesol at physiologically relevant concentrations (50 to 100 M). Similarly, monocytes are stimulated by farnesol to produce proinflammatory cytokines (21,22).…”

“…This difference is intriguing because engulfed white cells are able to survive within and then escape from macrophages in vitro (16)(17)(18). This in vitro result is compatible with the importance of macrophages in vivo for the early elimination of C. albicans (19,20) because macrophages which have engulfed C. albicans secrete immunoregulatory cytokines including interleukin-6 (IL-6), IL-1␤, IL-10, and tumor necrosis factor alpha (TNF-␣) (21) prior to the escape of C. albicans. These cytokines presumably promote the development and chemotactic migration of other innate immune cells, including neutrophils, which are more capable of killing C. albicans (22).…”

“…This idea suggests that the first step in the "Trojan horse strategy" for dissemination of some bacterial and viral pathogens (40,41) is also used by C. albicans (19,42). In terms of the overall balance between host and pathogen, it is highly relevant that prior to their death, macrophages that ingest C. albicans secrete immunoregulatory cytokines, including IL-6, IL-1␤, IL-10, and TNF-␣ (21), presumably in order to promote the development and chemotactic migration of other, more capable members of the innate immune system, such as neutrophils (19,20). This idea is consistent with the importance of macrophages in early elimination of C. albicans (43,44), as well as the predisposition to invasive candidiasis of patients with neutropenia (1).…”

Host response toCandida albicansbloodstream infection and sepsis

“…Initial experiments already revealed the gallbladder as an unexpected site of C. albicans persistence during anti-microbial therapy. 36 As for all murine infection models, it has to be kept in mind that peripheral blood components in mice differ, both in numbers and function, from their human counterparts 37,38 and conclusions from defined animal models are not necessarily transferable to human patients. To overcome some of these limitations, human whole blood infection models can be used to analyze host-pathogen interactions in a situation which closely mirrors that in vivo.…”

Prostaglandins from Cytosolic Phospholipase A2α/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages

“…C. albicans viability was measured using the XTT cell viability kit as described (29). The procedure measures the ability of viable cells to convert XTT to formazan by enzymes that are inactivated in dead cells.…”