ESPID Education. Vissers M. 06/07/11; 7766
Mrs. Marloes Vissers
Mrs. Marloes Vissers

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Bacterial cell wall component muramyl dipeptide synergizes with respiratory syncytial virus in cytokine production
Vissers, M.E.P., de Jong, D.J., Hermans, P.W.M. and Ferwerda, G.

Hospitalizations due to respiratory syncytial virus (RSV) have been associated with respiratory bacterial co-infections. Research into how a viral and bacterial co-infection can enhance each other can therefore give insight and potential targets for therapeutical intervention strategies. However, not much is known about the mechanism behind this synergy.
Muramyl dipeptide (MDP) is a component of the cell wall of both Gram positive and Gram negative bacteria and is recognized by NOD2, an intracellular pattern recognition receptor. NOD2 is a modulator of signals transmitted through Toll Like Receptor 3 (TLR3) and TLR4. Literature shows that RSV can be recognized by TLR3 (dsRNA), TLR4 (F-protein) and TLR7/8 (ssRNA). Our hypothesis is that RSV induced TLR activation is enhanced by NOD2 stimulation.
Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers and Crohn patients homozygous for the 3020insC frameshift mutation (NOD2fs) were stimulated for 24hrs with RSV A2, MDP, LPS and RSV+MDP. Inhibitors of specific pathways (e.g. R.sphaeroides LPS (TLR4 inhibitor), IRAK ¼ (MyD88 dependent pathway inhibitor), luteolin (TRIF dependent pathway inhibitor) and piceatannol (NF-kB inhibitor) were used to find out which pathways are involved. Subsequently cytokines were measured and ratios were calculated as follows: [RSV+MDP]/[RSV]+[MDP].
Stimulation of human PBMCs with RSV A2 as well as MDP resulted in low cytokine responses. A combination of both stimuli resulted in high cytokine responses. The combination of both stimuli resulted in a 19.6±8.7 fold increase in TNF production and a 4.8±1.7 fold increase in IL-1beta production.
Stimulation of PBMCs from Crohn patients homozygous for the 3020insC mutation showed no synergy in contrast to the PBMCs from healthy volunteers. Therefore the synergy is NOD2 dependent.
Experiments with different pathway inhibitors showed that TLR4 inhibitor nor IRAK ¼ inhibitor inhibited the synergy between RSV and MDP. However, the synergy was TRIF and NF-kB dependent. Therefore, our hypothesis is that TLR3 is the TLR involved in the synergy seen between RSV and MDP.
RSV and MDP induce synergistic pro-inflammatory cytokine production in human PBMCs. This synergy in cytokine production is NOD2 dependent. RSV does not seem to induce TNF and IL-1beta through TLR4 dependent signaling. However, the synergy seems to be TRIF and NF-kB dependent. Ongoing experiments will have to show if TLR3 is involved, measurement of type I IFNs and the influence of the synergy on viral infection of PBMCs.
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