The role of tissue-resident macrophages in invasive candidiasis

Principle Investigator

Scientific interest within the context of the graduate college:

We are interested in understanding the role of the macrophages that reside within the kidney, termed kidney-resident macrophages (krMΦs). Although krMΦs are fundamental for kidney homeostasis, it is unclear how they support normal renal function and renal homeostasis. We seek to unravel the underlying mechanisms of how krMΦs mediate kidney resilience at steady state and in inflammation.

Project description:

Introduction: Invasive candidiasis (i.e. candidemia and deep-seated tissue candidiasis) is the most common fungal infection among hospitalised patients in the developed world.¹ In Germany, the burden of invasive fungal infections is unknown, because invasive fungal infections do not belong to the list of reportable infectious diseases.² Yet, the limited available data highlight that yeasts of the Candida genus are the most common pathogens causing invasive fungal infections in Germany.^2,3 The incidence of invasive candidiasis has risen dramatically over the past decades.⁴  Invasive candidiasis is associated with a high mortality rate, exceeding 40%, even when patients receive antifungal therapy.¹ The current therapies for invasive candidiasis, based on the use of antifungal drugs, have low efficacy in immunocompromised and critically ill patients, and the emergence of resistance to antifungal agents is becoming a major concern.⁵ A better understanding of the mechanistic underpinnings of the disease is needed, in order to build new, more specific treatments. The innate immune response to candida (namely monocytes and neutrophils) has been extensively studied.⁶ Surprising, the role of tissue-resident macrophages has not been adequately addressed, although they are in an ideal position to detect, respond and orchestrate the immune response to invasive candidiasis. This proposal seeks to unravel the role of tissue-resident macrophages in invasive candidiasis in murine models.

Aim 1: To investigate the early events in experimental invasive candidiasis. Our results suggest that the immune response developed a few hours after infection is crucial for disease progression. In this aim, the student will use various genetically modified mouse models to characterize (by e.g. flow cytometry, qPCR) the inflammatory response to Candida early after infection, e.g. macrophage activation, neutrophil recruitment. Herein, the student will acquire expertise in flow cytometry, qPCR, and mouse genetics (e.g. fate-mapping).

Aim 2: To investigate the early events of in vivo cell-cell interactions of Candida. In this part the student will utilize confocal microscopy and intravital (live) imaging to study the in vivo cell-cell interactions of Candida within the kidney (e.g. endothelial transmigration, phagocytosis by macrophages), in order to understand better the pathogenesis of the infection. The student will acquire training in surgical skills, live imaging and confocal microscopy.

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