Tammy Ozment

Invasive infections caused by opportunistic fungi are increasingly common in the ICU, and the mortality rate for fungal sepsis is 30-40%.  The septic aged patient is exquisitely susceptible to opportunistic fungal infection. Patients with critical illnesses such as sepsis have a decreased ability to clear primary infections and an increased susceptibility to secondary infections such as invasive fungal infection. Healthy aged adults show senescence of immune function that presents as a decreased response to immunization and increased susceptibility to infection.  In addition, the aged frequently have multiple co-morbidities and undergo more invasive procedures leading to a higher risk of sepsis.  In fact, 60% of septic patients are over 65 y.o. The underlying mechanisms that result in increased susceptibility to fungal infection in the aged and/or septic patient are not fully understood. Based on our preliminary data we propose that susceptibility to fungal sepsis in the aged septic patient is mediated via “three hit” mechanism.  First, our data demonstrate that aged patients have decreased Th17 mediated responses compared to young healthy controls.  Second, our data suggest that clinical sepsis decreases expression of Dectin-1, the primary pattern recognition receptor for fungal glucan.  Third, sepsis induces severe immune suppression that further exacerbates the age related decrement in Th17 mediated responses.  We hypothesize that the super imposition of all three of these immunologic derangements renders the aged critically ill patients highly susceptible to fungal infections.  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 normal healthy adults >60 y.o.  We will examine recognition and internalization of and Dectin-1/Th17 mediated signaling in response to Candida albicans or 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 recognition and internalization of and Th17 mediated signaling in response to Candida albicans or glucan in leukocytes from septic patients and compare them to 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, antibiotic use and survival outcome.