Genetic Susceptibility to Life-threatening Respiratory Syncytial Virus Infection in Previously Healthy Infants

Background: Genetic background may be an important host determinant of respiratory syncytial virus (RSV) disease severity, but full characterization of susceptibility genes remains unclear. This study aimed to assess the presence of specific single-nucleotide polymorphisms (SNPs) in selected genes codifying for different components of the antiviral innate immune response, to determine their role for developing RSV life-threatening disease (LTD). Methods: Prospective cohort study including previously healthy full-term infants hospitalized with a first RSV infection during 2017-2018. RSV detection, quantification and subgroup determination, and genotyping for SNPs inToll-like receptor 4(TLR4rs4986790, rs4986791),Toll-like receptor 8(TLR8rs3761624),macrophage receptor with collagenous structure(MARCOrs1318645)and myxovirus resistance 1(MX1rs469390) were performed by real-time polymerase chain reaction in nasopharyngeal aspirates obtained on admission. Patients with LTD were those admitted to the intensive care unit requiring ventilatory support. Results: Seventy-five patients were studied, 15 (20%) developed LTD. Infants with concurrent SNPs inMX1andTLR8, MARCOandTLR8orMARCO, MX1andTLR8had an increased risk of developing LTD. Multivariable logistic regression analysis confirmed this significant association (odds ratio [OR] = 3.75,P= 0.046; OR = 3.92,P= 0.040; OR = 5.56,P= 0.010, respectively). No differences were seen in viral load of patients with LTD compared with those with better outcome (P= 0.737). In addition, no differences in viral load were seen in patients with the described high-risk SNPs compared with those without these polymorphisms. Conclusions: Life-threatening RSV infection in previously healthy infants was significantly associated with the presence of combined SNPs inMARCO, MX1andTLR8.