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Review
. 2015;6(4):316-26.
doi: 10.4161/21505594.2014.988096. Epub 2015 Mar 18.

Host response to Candida albicans bloodstream infection and sepsis

Affiliations
Review

Host response to Candida albicans bloodstream infection and sepsis

Seána Duggan et al. Virulence. 2015.

Abstract

Candida albicans is a major cause of bloodstream infection which may present as sepsis and septic shock - major causes of morbidity and mortality world-wide. After invasion of the pathogen, innate mechanisms govern the early response. Here, we outline the models used to study these mechanisms and summarize our current understanding of innate immune responses during Candida bloodstream infection. This includes protective immunity as well as harmful responses resulting in Candida induced sepsis. Neutrophilic granulocytes are considered principal effector cells conferring protection and recognize C. albicans mainly via complement receptor 3. They possess a range of effector mechanisms, contributing to elimination of the pathogen. Neutrophil activation is closely linked to complement and modulated by activated mononuclear cells. A thorough understanding of these mechanisms will help in creating an individualized approach to patients suffering from systemic candidiasis and aid in optimizing clinical management.

Keywords: Candida albicans; bloodsteam infection; innate immune response; sepsis.

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Figures

Figure 1.
Figure 1.
Advantages and disadvantages of C. albicans infection models. The most commonly employed C. albicans infection models are immortalized cell culture, primary immune cells, whole blood and mice. Each method bears both limitations and advantages, a thorough knowledge of which can be applied to determining the most suitable model.
Figure 2.
Figure 2.
Host innate immune responses to C. albicans blood stream infection. Upon transmigration of skin skin/mucosal barrier and entry to the bloodstream, C. albicans will activate the complement system and encounter circulating and resident leukocytes. Neutrophils are considered the forerunners of innate responses to C. albicans due to their efficient recognition and clearance of the fungus. Complement receptor 3 (CR3) and FCγR are the paramount human neutrophil receptors capable of recognizing C. albicans. Contact to the fungus initiates various signaling cascades, which in turn instigate effector mechanisms e.g. phagocytosis, oxidative burst and neutrophil extracellular trap (NET) formation. Mononuclear phagocytes include circulating monocytes as well as macrophages and dendritic cells residing in various tissues. These cells recognize C. albicans principally via dectin-1 which acts in concert with other pattern recognition receptors. They are a dominant source of IL-6 and TNF-α, both of which can exert direct effects on the fungus and also influence other immune cells. Although NK cells harbor many PRR capable of C. albicans recognition, NKp30 is the principal mediator of NK cell anti-Candida activity. NK cell-released perforin is directly candidacidal. Additionally, NK cells secrete GM-CSF and IFN-γ which both potently modulate other immune cells. Candida is a potent activator of human complement. Complement activation results in opsonization by deposition of C3b and release of anaphylatoxins C5a and C3a which influence immune cell recruitment and effector mechanisms. In addition to C3b, recognition of the fungal protein Pra1 and surface-recruited Factor H, a major regulator of complement activation, mediate recognition by immune cell CR3.

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