Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection

• Published in: Scientific reports Vol. 12; no. 1; p. 5382
• Main Authors: Kim, So Young, Gupta, Purva, Johns, Scott C., Zuniga, Elina I., Teijaro, John R., Fuster, Mark M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-03-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/254; 631/80/221; 692/308/575; Adaptive immunity; Animals; Antigen-presenting cells; Bone marrow; CD11c antigen; CD4 antigen; CD8 antigen; Dendritic cells; Genotypes; Heparan sulfate; Heparitin Sulfate; Humanities and Social Sciences; Humans; Immune clearance; Immunomodulation; Infections; Inflammation; Inflammation - genetics; Influenza; Influenza A; Influenza A virus; Influenza A Virus, H1N1 Subtype; Influenza, Human; Inoculation; Ligands; Lungs; Lymphocytes T; Mice; multidisciplinary; Mutants; Mutation; NF-κB protein; Pathogens; Phosphorylation; Proteins; Science; Science (multidisciplinary); Sulfates; TLR7 protein; TLR9 protein; Toll-like receptors; Viral infections; Viruses; β-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-09197-7

Survival from influenza A virus (IAV) infection largely depends on an intricate balance between pathogen clearance and immunomodulation in the lung. We demonstrate that genetic alteration of the glycan heparan sulfate (HS) in CD11c + cells via
Ndst1f
/f
CD11cCre
 + mutation, which inhibits HS sulfation in a major antigen presenting cell population, reduces lung inflammation by A/Puerto Rico/8/1934(H1N1) influenza in mice. Mutation was also characterized by a reduction in lung infiltration by CD4
+
regulatory T (T
reg
) cells in the late infection/effector phase, 9 days post inoculation (p.i.), without significant differences in lung CD8 + T cells, or T
reg
cells at an earlier point (day 5) following infection. Induction of under-sulfated HS via Ndst1 silencing in a model dendritic cell line (DC2.4) resulted in up-regulated basal expression of the antiviral cytokine interferon β (IFN-β) relative to control. Stimulating cells with the TLR9 ligand CpG resulted in greater nuclear factor-κB (NFκB) phosphorylation in Ndst1 silenced DC2.4 cells. While stimulating cells with CpG also modestly increased IFN-β expression, this did not lead to significant increases in IFN-β protein production. In further IFN-β protein response studies using primary bone marrow DCs from
Ndst1f
/f
CD11cCre
 + mutant and
Cre
− control mice, while trace IFN-β protein was detected in response to CpG, stimulation with the TLR7 ligand R848 resulted in robust IFN-β production, with significantly higher levels associated with DC
Ndst1
mutation. In vivo, improved pathogen clearance in
Ndst1f
/f
CD11cCre
 + mutant mice was suggested by reduced IAV AA5H nucleoprotein in lung examined in the late/effector phase. Earlier in the course of infection (day 5 p.i.), mean viral load, as measured by viral RNA, was not significantly different among genotypes. These findings point to novel regulatory roles for DC HS in innate and adaptive immunity during viral infection. This may have therapeutic potential and guide DC targeted HS engineering platforms in the setting of IAV or other respiratory viruses.