UC San Diego

Streptococcus agalactiae (Group B Streptococcus, GBS) is the most common neonatal

pathogen capable of causing devastating disease in newborns, yet healthy adults are largely

unaffected. The cellular and molecular mechanisms for neonatal susceptibility to GBS

pneumonia and sepsis are incompletely understood. Here we optimized a mouse model of

GBS pneumonia to test the role of alveolar macrophage (AM) maturation in host

vulnerability to severe disease. Compared with juvenile and adult mice, neonatal mice

infected with GBS had increased mortality and persistence of lung injury. In addition,

neonatal mice were defective in GBS phagocytosis and killing. AM depletion and disruption

of AM differentiation in Csf2-/- mice both impaired GBS clearance. AM engage the heavily

sialylated GBS capsule via the cell surface Siglec receptors Sialoadhesin (Sn) and Siglec-E.

Newborn AM expressed significantly lower levels of Sn, although both newborn and adult

AM expressed Siglec-E. Sn is exclusively expressed by CD11b lo and CD11b hi AM, while

Siglec-E is more commonly expressed by lung myeloid cells. AM Sn expression decreased

after GBS infection in both adults and neonates, this decrease seemed to be mediated by the

GBS Sia-Siglec-E ligation. The GBS Sia mutant, neuA, failed to decrease Sn expression in

either adults or neonates. Cell surface protein expression of Sn also decreased at 24 h after

GBS infection in the WT neonates, however, Sig-E-/- neonates maintained surface expression

of Sn at 24 h of infection. We propose that a developmental delay in Sn expression on AM

may prevent effective killing and clearing of GBS from the newborn lung. Next we

investigated the impact host Sia could have on AM development and responsiveness to

infection. While the fetal lung lacks expression of 2-3 Sia in the lung, the major sialylated

glycoprotein in the urine, Tamm-Horsfall Protein (THP), was found in the fetal lung. THP-/-

neonates, at PND1, 2, and 8 all showed decreased expression of Siglec-E, and higher

expression of Siglec-F at PND2. We hypothesize that the developing fetus aspirates amniotic

fluid, of which a major component is fetal urine containing THP, into the lung during

gestation bringing a source of Sia into the lungs and regulates fetal AM development and

suppresses inflammatory activity.