2017-06-27
Modeling infection and antiviral therapy of enteric viruses using primary intestinal organoids
Publication
Publication
Modeleren van infectie en antivirale therapie van enterische virussen met primaire intestinale organoiden
In this thesis, we first highlighted important clinical complications
associated with rotavirus infection in setting of orthotopic organ
transplantation, I then analyzed the incidence of rotavirus infection, its
diagnosis, its pathogenesis, how to rationally use of immunosuppressive
agents in patients at risk for rotavirus infection, especially by studying
the interactions of rotavirus with specific immunosuppressants, and also
how to manage rotavirus infection in organ recipients. I also found 3%
incidence of rotavirus infections among 6176 transplantations. I conclude
that rotavirus infections occurring in transplantation patients remain
clinically largely not diagnosed, and thus more attention should be paid
to this pathogen.
The situation might be improved through the development of new
superior model systems allowing new directions of research. I
demonstrated that primary intestinal organoids can support infection
with both laboratory rotavirus strains and with patient-derived rotavirus
isolates. Thus, the organoid model might become exceedingly useful for
obtaining new scientific insights but may also become important for
individualized assessment of the efficacy of different antivirals in a
particular patient, next to their potential for developing new and
effective medicines against rotavirus. In support for this notion I found
that the broadly used antivirals including interferon a and ribavirin
inhibit rotavirus replication utilizing the organoid model. I thus propose
that organoids provide a promising novel avenue for investigating
rotavirus-host interactions and the evaluation of medicines against
rotavirus.
I profiled common used immunosuppressive medicines on enteric
rotavirus and norovirus infections. I found that CsA moderately inhibits
rotavirus and norovirus infections, and that MPA is very in this respect
for both viruses and also with high barrier towards the development of
d.rug resistance. Mechanistically, the antiviral effects of MPA are
mediated through inhibition of its canonical cellular target IMPDH and
depend on the resulting guanosine nucleotide depletion. I also found
that 6-TG potently inhibits rotavirus via blocking the formation of the
active form of Rael {GTP-Racl), again with high barrier towards the
development of drug resistance. I hope my findings will become an
important reference for clinicians to design optimal immunosuppressive
therapy for rotavirus infected transplantation patients and aid the
development of novel antiviral medicines against rotavirus.
I also demonstrated that Pl3K-Akt-mTOR signaling pathway sustains
rotavirus infection and that the clinically used mTOR inhibitor rapamycin
significantly inhibits rotavirus infection. Rapamycin induces autophagy
via 4E-BP1, and induction of autophagy exerted antiviral effect on
rotavirus, suggesting that this is the mechanistic explanation of this
finding.
Although I perceive that the findings presented in this thesis contributed
to a better understanding of the complex nature of enteric viruses
including rotavirus and norovirus, I also have to acknowledge that more
work is needed to reduce the burden of rotavirus and norovirus infection
and hence there is plenty of opportunities for my successors either at the
Erasmus MC or elsewhere to further contribute to such efforts.
Additional Metadata | |
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, , | |
M.P. Peppelenbosch (Maikel) , Q. Pan (Qiuwei) | |
Erasmus University Rotterdam | |
hdl.handle.net/1765/100324 | |
Organisation | Department of Gastroenterology & Hepatology |
Yin, Y. (2017, June 27). Modeling infection and antiviral therapy of enteric viruses using primary intestinal organoids. Retrieved from http://hdl.handle.net/1765/100324 |
Additional Files | |
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propositions-Yuebang-Yin-27-05-2017-Final.pdf , 35kb | |
4732_Yin-Yuebang.jpg Cover Image , 1mb |