Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease.
BACKGROUND
The clinical spectrum of respiratory syncytial virus (RSV) bronchiolitis in previously healthy infants is extremely variable. Thus, it is likely that factors such as genetic heterogeneity contribute to disease severity. Toll-like receptor 4 (TLR4) and CD14 are part of a receptor complex involved in the innate immune response to RSV.


METHODS
The association of the TLR4 mutations (Asp299Gly and Thr399Ile) and the CD14/-159 polymorphism were analyzed in 99 infants hospitalized with severe RSV bronchiolitis (group I). Eighty-two ambulatory infants with mild RSV bronchiolitis (group II) and 90 healthy adults (group III) composed the 2 control groups. The TLR4 mutations and the CD14/-159 polymorphism were genotyped by use of reverse-transcriptase polymerase chain reaction and restriction fragment-length polymorphism analysis, respectively.


RESULTS
Each of the TLR4 mutations, either alone or in cosegregation, were associated with severe RSV bronchiolitis: the Asp299Gly and Thr399Ile mutations were significantly overrepresented in group I, compared with groups II and III. No association between the CD14/-159 polymorphism and RSV bronchiolitis was found.


CONCLUSIONS
These findings suggest that TLR4 mutations, but not the CD14/-159 polymorphism, are associated with an increased risk of severe RSV bronchiolitis in previously healthy infants.
Tal
Guy
G
Pediatric Pulmonary Unit, Edith Wolfson Medical Center, Tel-Aviv University, Holon, Israel.
Mandelberg
Avigdor
A
Dalal
Ilan
I
Cesar
Karine
K
Somekh
Eli
E
Tal
Asher
A
Oron
Anat
A
Itskovich
Svetlana
S
Ballin
Ami
A
Houri
Sion
S
Beigelman
Avraham
A
Lider
Ofer
O
Rechavi
Gideon
G
Amariglio
Ninette
N
D000328:Adult; D001988:Bronchiolitis / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology*; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics / Q000276:immunology; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology*; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D012367:RNA, Viral; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors