Wednesday, December 3, 2014

Is helminth infection sensed by latent virus?

During life time a human body is infected and re-infected with the same or the diverse types of infectious agents, sometimes simultaneously.

Since early 90's, an immune responses to infections were categorized into two major types: type 1, TH1 response, dominated by IFN-gamma (thought to be protective against viruses, intra-cellular pathogens, tumors) and type 2, TH2 response dominated by IL-4 (thought to to be protective against helminth infection). This division of labors, of course, is for simplicity purpose only.

Most importantly, since TH1 and TH2 responses thought to antagonize each other, it is clearly scientifically interesting to study and to know how immune system would deal with simultaneous presence of infections driving TH1 and TH2 responses.

The following Science paper has tried to answer this question. This study has examined the effect of an acute helminth infection on latent viral infection.

The authors has used a luciferase expression as a readout for latent viral reactivation. After initial viral infection and resting period (42 days), the mice were exposed to helminth or their eggs. Such exposure led to viral re-activation. 
It is of note, that very few peritoneal macrophages (< 0.02%) show sign of viral infection (RFP expression). Interestingly, the authors also observed that some of the virus infected macrophages expressed Arginase-1, a TH2 response signature molecule (though the numbers are so low that I am not sure whether it is real expression or an artifact). 
To understand the role of TH2 signature molecule, Arg1, in infected macrophages, the authors conducted the series of in vitro experiments with bone marrow derived macrophages infected with MHV86. These experiments showed that IL-4 and IL-13 (but not IL-5) were promoting viral infection of macrophages via STAT6 pathway.

This effect of IL-4 on MHV86 infection was antagonized by IFN-gamma.

Finally, in vivo experiments confirmed that IL-4 was promoting viral reactivation but only in absence of IFN-gamma signaling.
This effect was through STAT6. It should be noted here, however, that STAT6KO mice already showed high viral expression at day 0. This is unusual observation since IFN-gamma signaling should be more dominant in STAT6KO mice.
In summary, the authors proposed that in some situations, there is a competition between IL-4 and IFN-gamma responses on the level of viral promoters in infected cells.   

Few comments: First, a time has come to retire a simplified view of immune responses dominated either by IL-4 or IFN-gamma. Second, IL-4 was shown to not sufficient for viral reactivation. It requires inhibition of IFN-gamma signaling as well. No evidence is provided that helminth infection inhibits IFN-gamma signaling in latently infected macrophages. This study reminds me the story about in vitro TH17 induction that required the presence of anti-IFN-gamma and anti-IL-4 blocking antibodies to activate IL-17 program. Of course, this is a completely artificial system. Whether latent virus reactivation is IL-4 dependent in vivo is not clear either.

David Usharauli

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