Human Toll‐Like Receptor 4 Mutations but Not CD14 Polymorphisms Are Associated with an Increased Risk of Gram‐Negative Infections

Abstract

Human toll-like receptor 4 (hTLR4) and CD14 are known to be components of the lipopolysaccharide receptor complex. Our study investigated the association between TLR4 mutations (Asp299Gly and Thr399Ile) and CD14 polymorphism(s) with outcome in an intensive care unit (ICU) population at risk for sepsis. By use of a polymerase chain reaction-based restriction fragment-length polymorphism analysis technique, the hTLR4 gene was altered in 14 (18%) of 77 ICU patients (all positive for systemic inflammatory response syndrome) and in 5 (13%) of 39 volunteers. There was a significantly higher incidence of gram-negative infection among patients with the mutations (11 [79%] of 14), compared with that in the wild-type population (11 [17%] of 63; P=.004). No association between CD14 polymorphism(s) and the incidence of infection or outcome was observed. These findings indicate that hTLR4 mutations are associated with an increased incidence of gram-negative infections in critically ill patients in a surgical setting.

Incremental expression of Tlr4 correlates with mouse resistance to Salmonella infection and fine regulation of relevant immune genes

“…Gram-negative infection 31 or septic shock due to Gram-negative organisms, 32 severe malaria, 33 brucellosis, 34 Crohn's disease 35 and severe sepsis following burn injury. 36 On the other hand, the same alleles have shown protective effects against various diseases such as atherosclerosis, 37 Legionnaire's disease 38 and late-onset Alzheimer's disease.…”

The TLR4 +896 polymorphism is not associated with lipopolysaccharide hypo-responsiveness in leukocytes

“…Two groups have observed associations among the TLR4 þ 896G/ þ 1196T variant and the incidence of Gram negative infections and septic shock in ICU patients. 17,18 These clinical studies suffer from small sample size and the absence of correlating biologic data such as in vivo cytokine or cell signaling. Furthermore, other clinical and basic science investigations have failed to demonstrate a role for TLR4 in altering the inflammatory response.…”

“…Carriers have been reported to have an impaired response to bacterial endotoxin exposure compared to wild-type controls, [13][14][15][16] and they may be at increased risk for Gram negative infections and septic shock, and mortality from systemic inflammatory response syndrome (SIRS). [17][18][19] However, other in vivo and clinical studies have shown inconsistencies in the link between coding SNPs in the TLR4 gene and the inflammatory response. [20][21][22] We sought to determine the effect of the A þ 896G polymorphism within the TLR4 gene on the response to LPS in a population of healthy donors.…”

CD14 promoter polymorphism −159C>T is associated with susceptibility to chronic Chlamydia pneumoniae infection in peripheral blood monocytes

“…Previously, enhanced frequencies of the Arg753Gln TLR2 and Asp299Gly TLR4 polymorphisms were found in patients with staphylococcal sepsis or Gram-negative infections in critically ill patients. 9,10 We thus examined whether the chronic C. pneumoniae infection in coronary artery disease (CAD) patients is related to the prevalence of these genetic variations in TLR2, TLR4 or CD14. We focused on 78 CAD patients determined to be chronically infected with C. pneumoniae as defined by consistent detection of C. pneumoniae DNA in their PBMC fraction up to 1 year.…”