Sunday, October 5, 2014

High Five to inactivated Flu vaccine

Here is another Immunity paper about microbiota with interesting twist. This paper came from Bali Pulendran's lab in Emory. His lab focuses on systems biology approach to immunology. The systems biology is a basically an algorithm-driven science with minimal involvement of human experience and intuition.

In this paper (1), the authors made initial observation TLR5-deficient mice immunized with FDA-approved inactivated Flu vaccine, TIV, mounted impaired antibody response compared to wild-type mice. 

Reduced antibody response was more apparent at early stage, at day 7, but not at day 28. Correspondingly, number of TIV-specific antibody-secreting cells in draining lymph nodes was reduced at day 7. However, interestingly, serum level of TIV-specific IgG at day 84 in TLR5-deficient mice was again lower compared to wild-type mice suggesting that both early and long-term antibody production were affected by absence of TLR5.

Since TIV itself does not interact with TLR5 directly, 

the authors tried to understand how absence of TLR5 impacted response to TIV. Interestingly, the authors found that germ-free mice or mice treated with broad-spectrum antibiotics showed similar impaired response to TIV, similar to TLR5-deficient mice. 

Germ-free mice inoculated with gut microbiota showed restored response to TIV.

In addition, the authors showed that supplementation of TIV with flagellin (TLR5 agonist) improved TIV-specific antibody response in antibiotic-treated mice.

Further experiments showed that TLR5 signaling in hematopoietic cells (specifically, in macrophages) were critical to TIV antibody response.

Finally, the authors showed that dependency on TLR5 for TIV-specific antibody response was not unique for TIV. IPOL, another inactivated vaccine consisting of polio virus subunits, also required TLR5 for full response. However, live-attenuated vaccine or alum-adjuvanted vaccines did not require TLR5 for full response.

In summary, this study indicates that even vaccine efficacy is depended on gut microbiota.

Why specifically, TLR5 plays such important role is not clear. Earlier research showed that TLR5 had a protective role against development of metabolic syndrome and radiation-induced toxicity. If those mechanisms also responsible for improved antibody response is to be seen. Or is it possible that an absence of TLR5 affects the composition of gut microbiota in such manner to impact the magnitude of TIV response?


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