Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

Abstract

Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-γ (IFN-γ) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid.antiviral | innate immunity | respiratory epithelium R espiratory syncytial virus (RSV) is an important pathogen that infects 98% of children within the first 2 years of life, and also causes serious disease in elderly individuals and persons with chronic lung disease. In the 1980s, an estimated 100,000 children were hospitalized annually with RSV infection in the United States (1). Although RSV is commonly considered a pediatric disease, it is also highlighted as an opportunistic pathogen (2), with infections producing a mortality rate of 30-100% in immunosuppressed individuals (1). There is growing appreciation that RSV is an important pathogen in elderly and high-risk patients, and a cause of acute exacerbations of asthma (3, 4) and chronic obstructive pulmonary disease (COPD) (5). Over the period 1999-2003, RSV was responsible for hospitalization rates of 10.6% for pneumonia, 11.4% for COPD, 5.4% for congestive heart failure, and 7.2% for asthma (6).No vaccine is currently available for prevention of RSV infection. Several vaccine candidates have not only proved to be ineffective, but have also been shown to lead to vaccine-enhanced disease (7,8). Inhibitors directed against the RSV fusion protein (F protein) were abandoned partly because of the frequency of resistant mutations mapping to the F gene (9). A monoclonal antibody against F protein, Palivizumab, has restricted application and it is recommended for prophylactic use during the RSV season, for high-risk infants (1). Currently the onl...

Specific roles of phosphatidylglycerols in hosts and microbes

“…Regarding a potential role of surfactant PGs in anti-inflammatory response, it was observed that Palmitoyl-OleoylPhosphatidylGlycerol (POPG) alone, added to bronchial epithelial cells in culture inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by Rous Sarcoma Virus infection. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT (58). PG was shown also to inhibit inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2 (59).…”

Is phosphatidylglycerol essential for terrestrial life?

“…However, it can be isomerised to by alveolar macrophages [42]. There is also evidence that PG suppresses proliferation of respiratory viral infection [43,44,45]. Taken together, these data suggest that PG has one or more unique properties that are essential to lung function.…”

Lipidomics Analysis of Peroxisomal Disorders: Discovery of Deficits in Phosphatidyglycerol Levels in Rhizomelic Chondrodysplasia Type 1

“…ToF-SIMS studies have demonstrated that phosphatidylglycerols concentrate along the edges of the tubular proteolipids that form the tubular myelin of pulmonary surfactant and are dispersed throughout the interstitial space between the tubular networks [24]. Of further significance are the observations that phosphatidylglycerols regulate innate immunity against lung viral infections and the associated inflammatory processes [23][24][25][26][27][28][29][30][31]. Recent studies have also demonstrated in murine models that phosphatidylglycerol administration is effective both for postinfection treatment and for prophylaxis against respiratory syncytial viral infections [32], a predominant respiratory pathogen in young children.…”