Cellular and Molecular Mechanisms of Fungal Sepsis in the Critically Ill Patient

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Abstract Invasive infections caused by opportunistic fungi are increasingly common in the surgical ICU. The mortality rate for fungal sepsis in the ICU patient is 30-40%. It is well accepted that aging plays a critical role in the incidence of sepsis and age is a known independent predictor of mortality in sepsis. Fungal infections have become an increasing problem in older ICU patients. This is due, in part, to the fact that sepsis results in immune suppression. However, it is also known that healthy aged adults show senescence of immune function. In addition, aging patients frequently have multiple co-morbidities and undergo more invasive procedures leading to a higher risk of sepsis. The underlying cellular and molecular mechanisms that result in increased susceptibility to fungal infection in the aged and/or septic patient are not fully understood. The research outlined in this application is focused on addressing that deficit in our knowledge. We have acquired preliminary data which demonstrate that healthy aged individuals (>60 y.o.) show decreased anti-fungal Th17 mediated responses when compared to young healthy controls. We also have preliminary data which indicate that clinical sepsis decreases leukocyte expression of Dectin-1, the primary pattern recognition receptor for induction of anti-fungal innate immunity. Based on these data and the published literature we hypothesize that “susceptibility to fungal sepsis in the aged critically ill patient is mediated by specific cellular and molecular defects in anti-fungal innate immunity”. To test our hypothesis we propose the three following specific aims. In aim 1 we will identify the age related defects in Dectin-1/Th17 dependent signaling in human leukocytes from healthy adults >60 y.o. We will examine Dectin-1/Th17 mediated intracellular signaling in response to Candida albicans or C. albicans cell wall glucan in leukocytes from adults >60 y.o. and compare them to those from adults <30 y.o. In aim 2 we will identify defects in Dectin-1/Th17 dependent signaling in leukocytes from patients with sepsis. In this aim we will critically evaluate Dectin-1/Th17 mediated signaling in response to Candida albicans or glucan in leukocytes from septic patients and compare them to age matched healthy adults. In aim 3 we will investigate the impact of clinical sepsis on human leukocyte Dectin-1 expression. We will correlate Dectin-1 expression with the type of infection, acute physiology scores and injury indices, length of hospital stay, days in ICU and survival outcome. These experiments will provide new knowledge of the mechanisms that render the aged critically ill patient susceptible to life threatening fungal infections. In addition, we will acquire new clinical data that may identify novel predictors of susceptibility to fungal infection. Finally, we will investigate strategies to increase resistance to opportunistic fungal infections in the critically ill patient.