Human Rhinovirus Infection of the Respiratory Tract Affects Sphingolipid Synthesis

Area of Science:

• Immunology
• Genetics
• Biochemistry

Background:

• The 17q21 locus is linked to asthma risk alleles associated with reduced sphingolipid synthesis, potentially due to ORMDL3 upregulation inhibiting serine-palmitoyl transferase (SPT).
• Decreased sphingolipid synthesis is implicated in asthma pathogenesis, with reduced SPT activity linked to airway hyperreactivity.
• 17q21 asthma risk alleles are also associated with childhood rhinovirus (RV) infections.

Purpose of the Study:

• To investigate the interaction between RV infection and the de novo sphingolipid synthesis pathway.
• To evaluate the effects of concurrent SPT inhibition in SPT-deficient mice and human airway epithelial cells during RV infection.

Main Methods:

• Examined sphingolipid synthesis gene expression in RV-infected SPT-deficient mice and human airway epithelial cells.
• Analyzed SPTssa expression in lung epithelial (EpCAM+) and immune (CD45+) cells.
• Measured de novo sphingolipid species in mouse lungs, blood, and human airway cells.

Main Results:

• RV infection induced a sphingolipid synthesis gene expression pattern in mouse lungs resembling genetic SPT deficiency, particularly in EpCAM+ cells.
• RV increased de novo sphingolipid species in mouse lungs and human airway cells, but decreased them in the blood of infected wild-type mice.
• RV infection exacerbated SPT deficiency-associated airway hyperreactivity, while airway inflammation levels were comparable between infected wild-type and SPT-deficient mice.

Conclusions:

• RV infection significantly impacts the de novo sphingolipid synthesis pathway.
• This study provides a mechanistic link between 17q21 asthma risk alleles and rhinovirus infection, highlighting altered sphingolipid metabolism as a key factor in asthma pathogenesis.