Prevention of Neonatal Sepsis by Therapeutic Targeting of MDSCs

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.