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Analysis of Hepatitis in Murine Herpesvirus 68-Infected Mice Used As Epstein-Barr Virus Hepatitis Model

Murine herpesvirus 68 (MHV68) infection in mice causes hepatitis similar to Epstein-Barr virus (EBV) hepatitis in humans. Administration of antibiotics that reduce intestinal bacteria prevented MHV68 hepatitis in mice. Blocking toll-like receptor 4 (TLR4) signaling with an inhibitor or neutralizing antibody also prevented hepatitis. However, introducing additional intestinal bacteria aggravated hepatitis. These results suggest intestinal bacteria and TLR4 signaling play a role in MHV68 hepatitis through lipopolysaccharide (LPS) stimulation, and represent a model for studying EBV hepatitis.

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46 views9 pages

Analysis of Hepatitis in Murine Herpesvirus 68-Infected Mice Used As Epstein-Barr Virus Hepatitis Model

Murine herpesvirus 68 (MHV68) infection in mice causes hepatitis similar to Epstein-Barr virus (EBV) hepatitis in humans. Administration of antibiotics that reduce intestinal bacteria prevented MHV68 hepatitis in mice. Blocking toll-like receptor 4 (TLR4) signaling with an inhibitor or neutralizing antibody also prevented hepatitis. However, introducing additional intestinal bacteria aggravated hepatitis. These results suggest intestinal bacteria and TLR4 signaling play a role in MHV68 hepatitis through lipopolysaccharide (LPS) stimulation, and represent a model for studying EBV hepatitis.

Uploaded by

Rahmiati Lao
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Analysis of hepatitis in


Murine herpesvirus 68-infected mice



used as Epstein-Barr virus hepatitis model.


Kyosuke Kanai

Division of Virology, Tottori University
kkanai@tottori-u.ac.jp
Epstein-Barr virus (EBV) hepatitis


• EBV, Human Herpesvirus 4, is distributed in the world.

• Primary infection often causes infectious mononucleosis (IM).

• IM is usually self-limiting but is associated with hepatitis.


(Hara et al., J Clin Virol, 2006)
• EBV does not directly infect hepatocytes.

• The pathogenesis of EBV hepatitis is not still clear.

• EBV hepatitis is caused as a consequence of host immune responses.

(Adams et al., Am J Pathol, 2006)


https://basicmedicalkey.com/ 


Analysis of immune response is required.



Murine herpesvirus 68 (MHV68)

A. MHV68 infected mice lost weight
The average of body weight up to 12 dpi
110 %

Body Wight Ratio (%) 



100 %
http://molecularvirology.org/MHV-68.html

90 %

80 %
c57BL/6J 0 2 4 6 8 10 12
Days post inoculation (dpi) 


B. Lymphocytes infiltration in liver
 C. Increase of liver enzyme



H&E staining of liver tissue at 12 dpi Liver enzyme level in peripheral blood at 12dpi
MHV68-
 MHV68+
 AST
 ALT

*
 *


102 IU/dl

102 IU/dl
We found MHV68 infected mice also show hepatitis.

Hypothesis

CD8+T • CD8+T express CXCR3


NK
• CXCR3 ligand chemokines; CXCL9,
CXCL10, and CXCL11, are enhanced
Recruit Infiltrate
by co-stimulation with IFNγ and LPS
CD8+T
or PDG.
NK
IFNγ CXCR3 (Proost et al., J Leukoc Biol, 2004; Loos et al., Lab Invest, 2006;
Groom et al., Immunol Cell Biol, 2011) 

chemokines
e
nc • Intestinal bacterial products, LPS and
Attack

a
Enh
LPS
PDG, are delivered to liver via portal
PDG
vein.
+
EBV
B cells
• Intestinal bacteria may be involved in
Intestinal MHV68 hepatitis.
Bacteria
Reduction of intestinal microbiota by antibiotics

A. Neomycin ameliorated weight loss
 B. Decreased live enzyme

The average of body weight up to 12 dpi Liver enzyme level in peripheral blood at 12dpi

B. Decreased IFNγ+CD8+ T and NK cells
 D. Decreased CXCR3 ligand chemokine



ICS-FAC analysis of lymphocyte in liver at 14dpi Chemokine level in peripheral blood at 7dpi
C

(Kanai K., Ah-Mee Park 1, Teruhito Yasui 2, Hiroki Yoshida 3, Ikuo Tsunoda 1 and Osamu Yoshie 1,2. Journal of Immunology. 2018)

Intestinal microbiota may associate with hepatitis


Neutralizing of TLR4 or TLR2 by neutralizing antibody 

A. Anti-TLR4 Ab ameliorated weight loss
 B. Decreased live enzyme

The average of body weight up to 14 dpi Liver enzyme level in peripheral blood at 14dpi

C. Decreased IFNγ+CD8+ T and NK cells D. Decreased CXCR3 ligand chemokine


ICS-FAC analysis of lymphocyte in liver at 14dpi Chemokine level in peripheral blood at 7dpi
C

Anti-TLR4 Ab ameliorated hepatitis, but not TLR2



Inhibition of LPS-TLR4 using TLR4 inhibitor, C34

A. C34 ameliorated weight loss
 B. Decreased liver enzyme

The average of body weight up to 14 dpi Liver enzyme level in peripheral blood at 14dpi

C. Decreased IFNγ+CD8+ T and NK cells D. Decreased CXCR3 ligand chemokine


ICS-FAC analysis of lymphocyte in liver at 14dpi Chemokine level in peripheral blood at 7dpi
C

C34 ameliorated MHV68 hepatitis



Administration of Escherichia coli (E. coli) intrarectally

A. E. coli aggravated weight loss
 B. Increased liver enzyme

The average of body weight up to 14 dpi Liver enzyme level in peripheral blood at 14dpi

C. Increased IFNγ+CD8+ T and NK cells D. Increased CXCR3 ligand chemokine


ICS-FAC analysis of lymphocyte in liver at 14dpi Chemokine level in peripheral blood at 7dpi
C

Gram- bacteria, E. Coli aggravated MHV68 hepatitis



Conclusion

Kinetics of intestinal microbiota



• LPS may associate MHV68
hepatitis, but not PDG.

• TLR4 antagonist may be


therapeutically for EBV hepatitis.

• Gram- bacteria may associate with


EBV hepatitis.
Lactobacillus E. Coli • Increase of Gram- bacteria in gut
(Gram+)
 (Gram-)

LPS- LPS＋

with growth may be the reason why
PDG+
 PDG+
 IM occurs only in adults.

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