Phosphatidylglycerol provides short-term prophylaxis against respiratory syncytial virus infection

Abstract

Respiratory syncytial virus (RSV) causes respiratory tract infections in young children, and significant morbidity and mortality in the elderly, immunosuppressed, and immunocompromised patients and in patients with chronic lung diseases. Recently, we reported that the pulmonary surfactant phospholipid palmitoyl-oleoyl-phosphatidylglycerol (POPG) inhibited RSV infection in vitro and in vivo by blocking viral attachment to epithelial cells. Simultaneous application of POPG along with an RSV challenge to mice markedly attenuated infection and associated inflammatory responses. Based on these findings, we expanded our studies to determine whether POPG is effective for prophylaxis and postinfection treatment for RSV infection. In vitro application of POPG at concentrations of 0.2–1.0 mg/ml at 24 h after RSV infection of HEp-2 cells suppressed interleukin-8 production up to 80% and reduced viral plaque formation by 2–6 log units. In vivo, the turnover of POPG in mice is relatively rapid, making postinfection application impractical. Intranasal administration of POPG (0.8–3.0 mg), 45 min before RSV inoculation in mice reduced viral infection by 1 log unit, suppressed inflammatory cell appearance in the lung, and suppressed virus-elicited interferon-γ production. These findings demonstrate that POPG is effective for short-term protection of mice against subsequent RSV infection and that it has potential for application in humans. Respiratory syncytial virus (RSV) causes respiratory tract infections in young children, and significant morbidity and mortality in the elderly, immunosuppressed, and immunocompromised patients and in patients with chronic lung diseases. Recently, we reported that the pulmonary surfactant phospholipid palmitoyl-oleoyl-phosphatidylglycerol (POPG) inhibited RSV infection in vitro and in vivo by blocking viral attachment to epithelial cells. Simultaneous application of POPG along with an RSV challenge to mice markedly attenuated infection and associated inflammatory responses. Based on these findings, we expanded our studies to determine whether POPG is effective for prophylaxis and postinfection treatment for RSV infection. In vitro application of POPG at concentrations of 0.2–1.0 mg/ml at 24 h after RSV infection of HEp-2 cells suppressed interleukin-8 production up to 80% and reduced viral plaque formation by 2–6 log units. In vivo, the turnover of POPG in mice is relatively rapid, making postinfection application impractical. Intranasal administration of POPG (0.8–3.0 mg), 45 min before RSV inoculation in mice reduced viral infection by 1 log unit, suppressed inflammatory cell appearance in the lung, and suppressed virus-elicited interferon-γ production. These findings demonstrate that POPG is effective for short-term protection of mice against subsequent RSV infection and that it has potential for application in humans. Respiratory syncytial virus (RSV) infects nearly 90% of children under age 2. Immunity to the virus is incomplete, and reinfection of adults, especially the elderly, patients with chronic lung disease, and those with impaired immunity (1Hall C.B. Respiratory syncytial virus and parainfluenza virus.N. Engl. J. Med. 2001; 344: 1917-1928Crossref PubMed Scopus (922) Google Scholar, 2Collins P.L. Graham B.S. Viral and host factors in human respiratory syncytial virus pathogenesis.J. Virol. 2008; 82: 2040-2055Crossref PubMed Scopus (344) Google Scholar, 3Whimbey E. Ghosh S. Respiratory syncytial virus infections in immunocompromised adults.Curr. Clin. Top. Infect. Dis. 2000; 20: 232-255PubMed Google Scholar–4Falsey A.R. Hennessey P.A. Formica M.A. Cox C. Walsh E.E. 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PubMed Scopus Google Scholar), in a of the from of the with of for and the The with an of and with a of 1 The at a rate of for and a from to in by from to 100% in The of the an at 100% for this the from min and from phospholipid The to the of a and of the and the in in The the for for for for for for for for for for for for and for of The in the for the an of a potential of and a of of in the turnover a with a of of with the the the of the and and the of to demonstrate in this reported that of POPG and RSV to human epithelial cells cells or of human epithelial the virus-elicited production of the inflammatory and M. H.W. A. surfactant respiratory syncytial and 2010; PubMed Scopus Google Scholar). 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A. surfactant respiratory syncytial and 2010; PubMed Scopus Google Scholar). these we the of POPG prophylaxis against RSV infection in with concentrations of POPG and 45 min prior to RSV inoculation and with mice or treatment of POPG and the mice and the for plaque and on and the to cell inflammatory cell and production. The results in that RSV infection cell in by and that the prophylaxis suppressed the of inflammatory cells with the of POPG the cell in to nearly the that in or in virus and POPG inflammatory cell populations in the and and the prophylaxis treatment with POPG suppressed the of of these cell the The from is a of the of the RSV infection M. H.W. A. surfactant respiratory syncytial and 2010; PubMed Scopus Google Scholar). RSV infection a in and there no production in or those with RSV and POPG In with there a of and of of phospholipid from or to RSV and the viral of RSV by plaque M. H.W. A. surfactant respiratory syncytial and 2010; PubMed Scopus Google Scholar, plaque for respiratory syncytial of Virol. PubMed Scopus Google Scholar). Simultaneous treatment with RSV and POPG attenuated viral plaque by a of treatment with POPG inhibited RSV in the lung in a with the of the plaque by a of in treatment with POPG The of and N. D. and application of a for an model of pulmonary PubMed Scopus Google Scholar). The in from the in The in the and the and and of the in of POPG with the RSV protection from the RSV infection. of mice with or POPG of protection against of inflammatory reduced in and The in of the from demonstrate the phospholipid protection of the mice from RSV infection. The of protection with the of POPG from that by treatment with these we that POPG significant short-term prophylaxis against RSV infection and in the surfactant protein of in to infection and POPG treatment RSV after of infection reduced by and this with of POPG in the of mice with of POPG before RSV infection the in by with the of POPG prior to infection a in The treatment of mice with of POPG reduced the of after In the of this we for POPG prophylaxis against RSV infection. of or h at POPG reduced RSV plaque by In the 45 min in significant protection from infection. These results that there a relatively in the of the against the the turnover of POPG by the and of of the from The results from this that there at to the turnover of by the there is a in and and the at a with approximately 30% of the in the at the of the for turnover min for the and min for the of the appearance of of in the there is for a of with the appearance of a of that for of and at the and for min and the of and In at and and is an C. of in of lung J. 1997; Google Scholar, Mason and characterization of a in PubMed Scopus Google Scholar). of that the is up by the and to the the to the and of to determine of this is up by the and the of the turnover of is to of this POPG is a of pulmonary surfactant that is and cells and at the of the M. and in and Scholar, M.A. of surfactant in J. PubMed Scopus Google Scholar). The phospholipid the that the is and to mg/ml M. and in and Scholar, M. P. pulmonary surfactant of Med. PubMed Scopus Google Scholar, and the respiratory Dis. 1993; PubMed Scopus Google Scholar). The of the phospholipid the is approximately with POPG the The concentrations of in the to the no epithelial or has reported to of POPG a of and and an inhibitor of RSV and infection in the lung M. H.W. A. surfactant respiratory syncytial and 2010; PubMed Scopus Google Scholar, M. P. J. K. D. virus J. PubMed Scopus Google Scholar). The of the against with an that to of inflammatory to that in of POPG to of a for chronic of the In to the in to and in the to RSV Walsh E.E. M.W. L.J. et and to respiratory syncytial 2000; PubMed Scopus Google Scholar), the by this is studies that treatment of mice with RSV and POPG viral infection. These studies the that POPG in the short-term and treatment for RSV infection in humans. In this we demonstrate that the of POPG at 24 h in vitro viral infection of cells production. In POPG 24 h after RSV infection the of in plaque by 2–6 log in a POPG for RSV that the POPG the and of viral These demonstrate POPG concentrations at infections can These in vitro results that POPG can the lung in vivo, the an effective for has POPG it is the of in human pulmonary whether the of POPG with RSV is we the of with the virus by the of production and the to These studies that and and production with The for production of RSV and in with for and and for The in by a of and and These demonstrate that there is no to the a of the of the the of RSV to HEp-2 and by In these we and of the RSV to the of epithelial cells at to the virus and the POPG at or inhibited the by These that RSV attachment to the cell to determine whether the activity of POPG against RSV to of the from patients with antigenic RSV and in HEp-2 and the POPG and of viral infection in vitro plaque These studies demonstrate that POPG the infection by from POPG effective against of RSV to in mice C. D.C. K. et of respiratory syncytial virus (RSV) with the fusion protein of RSV viral and Virol. 2009; PubMed Scopus Google Scholar). These studies that of RSV infection is to to human of to for prophylaxis and postinfection treatment for RSV with of these studies that short-term prophylaxis studies to the of efficacy for a of inoculation with POPG 45 min prior to challenge with we to a significant of protection from the The POPG reduced the of and the to suppressed the host to and reduced the of from the lung by a of The of POPG in the of and the the of the of The that the effective for POPG in mice is relatively and of the for is in mice for The turnover of pulmonary surfactant is by the respiratory In the respiratory rate is in adults and in In the respiratory rate can and a turnover of surfactant is in pulmonary surfactant to human has to a of h M. K. The of surfactant in with respiratory PubMed Scopus Google Scholar). These that to human effective against RSV for a of the factors in the of the results in the that POPG has significant potential for use in after an RSV infection is The efficacy of POPG is by for and of by the lung the of the POPG there is for of of this to and these to in and the and to The of phospholipid and C. of in of lung J. 1997; Google Scholar, Mason and characterization of a in PubMed Scopus Google Scholar). cells the of surfactant M. and in and Scholar, M.A. of surfactant in J. PubMed Scopus Google Scholar, P. of lung from the to the 2005; PubMed Scopus Google Scholar), and it is that the POPG and these cells. In our that POPG is effective in the infection of epithelial cells by RSV and the of RSV infections in POPG is effective in vivo in the efficacy for the is These findings that POPG in for short-term prophylaxis against RSV and that POPG has significant potential for treatment of with RSV of infection palmitoyl-oleoyl-phosphatidylglycerol respiratory syncytial virus surfactant protein