The global burden of neonatal and infant mortality due to infection is
staggering, particularly in resource-poor settings. Early childhood vaccination
is one of the major interventions that can reduce this burden, but there are
specific limitations to inducing effective immunity in early life, including
impaired neonatal leukocyte production of Th1-polarizing cytokines to many
stimuli. Characterizing the ontogeny of Toll-like receptor (TLR)-mediated innate
immune responses in infants may shed light on susceptibility to infection in
this vulnerable age group, and provide insights into TLR agonists as candidate
adjuvants for improved neonatal vaccines. As little is known about the leukocyte
responses of infants in resource-poor settings, we characterized production of
Th1-, Th2-, and anti-inflammatory- cytokines in response to agonists of TLRs 1-9
in whole blood from 120 Gambian infants ranging from newborns (cord blood) to 12
months of age. Most of the TLR agonists induced TNFα, IL-1β, IL-6, and
IL-10 in cord blood. The greatest TNFα responses were observed for TLR4, -5,
and -8 agonists, the highest being the thiazoloquinoline CLO75 (TLR7/8) that
also uniquely induced cord blood IFNγ production. For most agonists,
TLR-mediated TNFα and IFNγ responses increased from birth to 1 month of
age. TLR8 agonists also induced the greatest production of the Th1-polarizing
cytokines TNFα and IFNγ throughout the first year of life, although the
relative responses to the single TLR8 agonist and the combined TLR7/8 agonist
changed with age. In contrast, IL-1β, IL-6, and IL-10 responses to most
agonists were robust at birth and remained stable through 12 months of age.
These observations provide fresh insights into the ontogeny of innate immunity
in African children, and may inform development of age-specific adjuvanted
vaccine formulations important for global health.
Detection and clearance of bacterial infection require balanced effector and resolution signals to avoid chronic inflammation. Detection of GNB LPS by TLR4 on m induces inflammatory responses, contributing to chronic inflammation and tissue injury. LXs and Rvs are endogenous lipid mediators that enhance resolution of inflammation, and their actions on primary human m responses toward GNB are largely uncharacterized. Here, we report that LXA(4), LXB(4), and RvD1, tested at 0.1-1 μM, inhibited LPS-induced TNF production from primary human m, with ATL and 17(R)-RvD1, demonstrating potent inhibition at 0.1 μM. In addition, 17(R)-RvD1 inhibited LPS-induced primary human m production of IL-7, IL-12p70, GM-CSF, IL-8, CCL2, and MIP-1α without reducing that of IL-6 or IL-10. Remarkably, when stimulated with live Escherichia coli, m treated with 17(R)-RvD1 demonstrated increased TNF production and enhanced internalization and killing of the bacteria. 17(R)-RvD1-enhanced TNF, internalization, and killing were not evident for an lpxM mutant of E. coli expressing hypoacylated LPS with reduced inflammatory activity. Furthermore, 17(R)-RvD1-enhanced, E. coli-induced TNF production was evident in WT but not TLR4-deficient murine m. Thus, Rvs differentially modulate primary human m responses to E. coli in an LPS- and TLR4-dependent manner, such that this Rv could promote resolution of GNB/LPS-driven inflammation by reducing m proinflammatory responses to isolated LPS and increasing m responses important for clearance of infection.
Identification of safe, effective treatment strategies to mitigate toxicity after extensive radiation exposure has proven challenging. Only a limited number of candidate approaches have emerged, and the Federal Drug Administration has yet to approve any agent for a mass-casualty radiation disaster indication. As preparative treatments for hematopoietic stem cell transplantation (HSCT) produce toxicities similar to such radiation exposures, we studied patients early after myeloablative HSCT to identify new approaches to this problem. Patients rapidly developed endotoxemia and reduced plasma bactericidal/permeability-increasing protein (BPI), a potent endotoxin-neutralizing protein, in association with neutropenia. We hypothesized that a treatment supplying similar endotoxin-neutralizing activity might replace the BPI deficit and mitigate radiation toxicity. We tested this idea in mice. A single 7 Gy radiation dose, which was 95% lethal by 30 days, was followed 24 hours later by twice daily subcutaneous injections of the recombinant BPI fragment rBPI21 or vehicle alone for 14 or 30 days, with or without an oral fluoroquinolone antibiotic with broad-spectrum anti-bacterial activity including that against endotoxin-bearing Gram-negative bacteria. Compared to either fluoroquinolone alone or vehicle/fluoroquinolone, combined rBPI21/fluoroquinolone treatment improved survival, accelerated hematopoietic recovery and promoted expansion of stem and progenitor cells. The observed efficacy of rBPI21 and fluoroquinolones initiated 24 hours after lethal irradiation, combined with their favorable bioactivity and safety profiles in critically-ill humans, suggest the potential clinical utility of this radiation mitigation strategy and support its further evaluation.
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