Friday, 11 October 2013

Does MERS-CoV delay the antiviral response against it?

Lau and colleagues from the University of Hong King recently wrote about MERS-CoV's ability to delay the induction of proinflammatory cytokines in human cells. These are potent defensive chemicals that cause and accelerate an inflammatory response to viral infection.

While inflammation is part of kicking out the virus, it can get out of control, especially with more "foreign" viruses, like those that are still zoonotic and not as co-evolved with humans. Excessive inflammation can lead to tissue remodelling and damage.

In their paper in the Journal of General Virology, the authors compared the results of growing viruses in 2 different cell systems, which was need to account for differences in tropism by the different viruses. Key findings include:
  • The lower airway cell-line, CaLu-3 was used for MERS-CoV and SARS-CoV because they produce good titres
    • IL-1β, IL-6, IL-8, TNF-α, IFN-β & IP-10 mRNA levels were increased by MERS-CoV and SARS-CoV compared to uninfected cells
    • Proinflammatory cytokines shown in bold above were induced more by MERS-CoV infection than by SARS-CoV
    • Innate antiviral cytokines TNF-α, IFN-β & IP-10  were induced more by SARS-CoV infection
    • MCP-1 (a chemokine) and TGF-β (anti-inflammatory cytokine) remained unimpressed by infection
    • At 48-hours, MERS-CoV infection induced less IL-8 or IFN-β protein than did SARS-CoV
  • Embryonal lung fibroblasts (HFL) to grow MERS-CoV and compare it to HCoV-229E (which does not grow well in CaLu-3 cells), an infrequently identified but well characterised "common cold" CoV.
    • The CaLu-3 results suggested MERS-CoV generates an attenuated innate immune response  the response which induces inflammation. SO HCoV-229E was added as it produces a strong innate response through IFN-β
    • IL-1βIL-6IL-8TNF-αIFN-β & IP-10 mRNA levels were increased by MERS-CoV and HCoV-229E
    • HCoV-229E was a stronger inducer than MERS-CoV of all but TNF-α, which triggered more by MERS-CoV
    • MCP-1 and TGF-β again remained unchanged
The authors conclude a delayed innate immune response by MERS-CoV infection compared to SARS-CoV. 

This study contrasted with that by Kindler and colleagues which I reviewed earlier. The reason may be because Kindler only sampled for immune analyses up to 12-hours, rather than the 30-hours used by Lau. This would certainly lend weight to claims of a "delayed" induction by MERS-CoV infection since in this study no IFN-β was produced either virus at 12-hour, the first rise in mRNA was apparent at 24-hour post-infection (Lau's protein data suggest there may have been a tiny amount of IFN-β translation at 12-hours, but Kindler did not measure protein).