Vitamin D Promotes Pneumococcal Killing and Modulates Inflammatory Responses in Primary Human Neutrophils

J Innate Immun. 2017;9(4):375-386. doi: 10.1159/000455969. Epub 2017 Feb 28.


Streptococcus pneumoniae is a major human pathogen and a leading cause of pneumonia, septicemia, and meningitis worldwide. Despite clinical studies linking vitamin D deficiency and pneumonia, molecular mechanisms behind these observations remain unclear. In particular, the effects of vitamin D on neutrophil responses remain unknown. Using pneumococcal strains, primary neutrophils isolated from human blood, and sera from patients with frequent respiratory tract infections (RTIs), we investigated the effects of vitamin D on neutrophil bactericidal and inflammatory responses, including pattern recognition receptors, antimicrobial peptides, and cytokine regulation. We found that vitamin D upregulated pattern recognition receptors, TLR2, and NOD2, and induced the antimicrobial human neutrophil peptides (HNP1-3) and LL-37, resulting in increased killing of pneumococci in a vitamin D receptor-dependent manner. Antibodies targeting HNP1-3 inhibited bacterial killing. Vitamin D supplementation of serum from patients with bacterial RTIs enhanced neutrophil killing. Moreover, vitamin D lowered inflammatory cytokine production by infected neutrophils via IL-4 production and the induction of suppressor of cytokine signaling (SOCS) proteins SOCS-1 and SOCS-3, leading to the suppression of NF-κB signaling. Thus, vitamin D enhances neutrophil killing of S. pneumoniae while dampening excessive inflammatory responses and apoptosis, suggesting that vitamin D could be used alongside antibiotics when treating pneumococcal infections.

Keywords: Alpha-defensins; Human neutrophil peptides; Immunomodulation; Interleukin-4; Neutrophils; Pneumococci; SOCS-1; SOCS-3; Streptococcus pneumoniae; Suppressor of cytokine signaling; Vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteriolysis
  • Cells, Cultured
  • Humans
  • Immunomodulation
  • Inflammation / drug therapy*
  • Interleukin-4 / metabolism
  • NF-kappa B / metabolism
  • Neutrophils / immunology*
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / metabolism
  • Pneumococcal Infections / drug therapy*
  • Primary Cell Culture
  • Signal Transduction
  • Streptococcus pneumoniae / immunology*
  • Suppressor of Cytokine Signaling 1 Protein / genetics
  • Suppressor of Cytokine Signaling 1 Protein / metabolism
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism
  • Vitamin D / pharmacology*
  • alpha-Defensins / genetics
  • alpha-Defensins / metabolism


  • NF-kappa B
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • SOCS1 protein, human
  • SOCS2 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • alpha-Defensins
  • Vitamin D
  • Interleukin-4