ABSTRACT
Neonatal sepsis results in more than 3 million deaths per annum worldwide and the highest risk of mortality
occurs in preterm infants (=37 weeks). This increased vulnerability is due to altered myelopoiesis and an intrinsic
hypo-responsiveness to pathogens, concomitant with activation of immunosuppressive mechanisms that sustain
maternal-fetal tolerance. Following birth, the neonatal immune system undergoes transition from a semi-
allogeneic sterile condition to a microbial-rich postnatal environment, which is modulated in part by neonatal
myeloid-derived suppressor cell (MDSC) and innate immune effector cell responses. In newborns, the role of
MDSCs is highly controversial, as they may not only control inflammation during early microbial colonization, but
also contribute to neonatal susceptibility to infection by inducing immunosuppression. Innate immune effector
cell function is also aberrant in prematurity. Our overarching hypothesis is that the increased susceptibility to and
mortality from sepsis in preterm neonates can be explained in part by the presence of immature,
immunosuppressive myeloid cell populations (MDSCs) and deviant terminal differentiation of innate immune
effector cells (e.g. monocytes, PMNs). Furthermore, we propose that the prophylactic administration of
immunomodulatory agents early in life can stimulate host protective immunity by altering MDSC numbers and
function, leading to augmentation of innate immune effector cell numbers and function (especially PMNs). This
strategy will reduce the incidence and severity of microbial infections in this fragile ‘born-too-soon’ population.
The two specific aims are as follows: (1) to test the hypothesis that neonatal prematurity and sepsis in early life
induce MDSC expansion, which is inversely correlated with innate immune cell function. Circulating MDSCs
(CD33+CD11b+HLADRlow/-) will be quantified in 120 preterm and 40 full-term infants at birth and during
hospitalization and in those who develop sepsis. We will determine how human MDSC and PMN phenotypes
are influenced by gestational age and sepsis, as well as whether expansion of MDSCs and PMN dysfunction at
birth is beneficial or increases susceptibility to infections. (2) In complimentary studies that cannot be performed
in humans, we hypothesize that myelopoiesis and myeloid function (especially MDSCs) can be influenced to
differentiate into functional terminal innate immune effector cells by the administration of immunomodulatory
agents. Using a model of neonatal sepsis, we will test the role of MDSCs in immune cell effector functions and
outcomes to sepsis through the induction of non-specific effects (NSEs) or ‘trained immunity’. In summary, the
proposed studies will focus on mechanisms critical to regulate neonatal immune responses in neonates. With
the use of -omics technology, we expect to provide: 1) a global view of changes that myeloid populations undergo
in preterm neonates during hospitalization and sepsis, and 2) insights into underlying mechanisms of how
immunomodulation through the use of adjuvants (BCG and TLR4 agonists) influences myeloid cells and prevents
sepsis in this highly vulnerable population.