Sunday, February 3, 2013

microbiota with retro taste

This is a really good paper to understand how we can be mistaken to rely on knock-out mice models without taking into account indirect effects of the mutations (1).

Published in journal Nature in November 2012, this study from Kassiotis Lab looked at the expression of retroviruses in immune-deficient B6 mice. Under  normal situation, B6 have replication-defective endogenous murine leukaemia viruses that can't produce infectious particles. However, as shown in paper, under certain immune-deficient conditions, like RAG-KO, Ighm-KO, MyD88-KO, TLR7-KO, but not in T cell-deficient mice, mouse starts to produce infectious retroviral particles by recombining eMLV with other retroviruses. In this conditions many immune cells started to express MLV surface glycoprotein. This, in turn, can promote formation of viral-induced lymphomas in aged mice. Anyone who has worked  with RAG-KO mice can attest to this observation. The author showed that MLV was transmitted from mother to offspring.

Next, the authors thought to understand the mechanism of this retroviral re-activation. It has been known that inflammatory stimuli can re-activate MLV expression in mouse cells. Indeed LPS and Poly(I:C), but not Pam3CSK4, could increase MLV expression in mouse bone marrow-derived dendritic cells.

Lastly, based on this observations, the authors reasoned that changes in commensal microbiota in Antibody-deficient mice contributed to the reactivation of retroviruses. This was confirmed by the absence of MLV in germ-free RAG-KO mice. In addition, giving to mice acidified drinking water  to reduce bacterial colonization and number in the gut dramatically cut MLV expression.

The conclusion of the paper is following: natural antibody produced in normal mice in a MyD88 and TLR7-dependent manners prevents commensal bacterial translocation and re-activation of MLV. Very similar observations regarding microbiota and viruses infectivity were made by two other research groups that was reported in journal Science in 2011 (23).

Why these results are relevant: first, it can explain how retroviral-induced tumors can develop. Secondly, many studies in immune-deficient mice may require re-evaluation to avoid erroneous conclusions because of the unintended presence of MLV.


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