Murine γ-Herpesvirus 68 Induces Severe Lung Inflammation in IL-27–Deficient Mice with Liver Dysfunction Preventable by Oral Neomycin

Abstract

IL-27 is an immunoregulatory cytokine consisting of p28 and EBI3. Its receptor also has two subunits, WSX1 and gp130. Although IL-27 promotes Th1 differentiation in naive T cells, it also induces IL-10 expression in effector Th1 cells to curtail excessive immune responses. By using p28-deficient mice and WSX1-deficient mice (collectively called IL-27-deficient mice), we examined the role of IL-27 in primary infection by murine γ-herpesvirus 68 (MHV68), a murine model of EBV. Upon airway infection with MHV68, IL-27-deficient mice had more aggravated lung inflammation than wild-type mice, although MHV68 infection per se was better controlled in IL-27-deficient mice. Although epithelial cells and alveolar macrophages were primarily infected by MHV68, interstitial macrophages and dendritic cells were the major producers of IL-27. The lung inflammation of IL-27-deficient mice was characterized by more IFN-γ-producing CD8 T cells and fewer IL-10-producing CD8 T cells than that of wild-type mice. An infectious mononucleosis-like disease was also aggravated in IL-27-deficient mice, with prominent splenomegaly and severe hepatitis. Infiltration of IFN-γ-producing effector cells and upregulation of the CXCR3 ligand chemokines CXCL9, CXCL10, and CXCL11 were noted in the liver of MHV68-infected mice. Oral neomycin effectively ameliorated hepatitis, with decreased production of these chemokines in the liver, suggesting that the intestinal microbiota plays a role in liver inflammation through upregulation of these chemokines. Collectively, IL-27 is essential for the generation of IL-10-producing effector cells in primary infection by MHV68. Our findings may also provide new insight into the mechanism of hepatitis associated with infectious mononucleosis.

Conquering the Host: Determinants of Pathogenesis Learned from Murine Gammaherpesvirus 68

“…Examination of viral mutants and host factors has revealed key virus-host interactions that promote fibrosis, vasculitis, pneumonia, and arthritis ( 111 , 130 , 131 ). Interestingly, the gut microbiome differentially influences MHV68-driven pathologies ( 132 , 133 ). Such models serve as a foundation to explore therapeutics that impair virus-driven inflammatory processes in the specific tissues that relate to human disease ( 127 , 132 ).…”

Immune protection is dependent on the gut microbiome in a lethal mouse gammaherpesviral infection

“…68 persistent infection 33 leads to severe hemorrhagic and consolidating pulmonary pathology [34][35][36] . Hence, we investigated whether the pulmonary pathology induced by MHV-68 infection reflected the antibiotic-dependent exacerbation we observed in survival analysis.…”

“…Quantitative PCR (qPCR) was undertaken to investigate relative viral load using the following reaction per sample: 10 µL SsoAdvanced Universal SYBR Green Supermix (Bio-rad Laboratories Inc., USA), 0.4 µl each of the primers 65 F (5′-GTCAGGGCCCAGTCCGTA-3′) and 65 R (5′-TGGCCCTCTACCTTCTGTTGA-3′), 200 ng of DNA and water up to 20 µL total volume. Reactions were run in triplicate with controls, and a standard curve using pCR2.1 Topo plasmid (Thermo Fisher Scientific, USA) containing the cloned target MHV region 35 . The following cycling conditions used on a CFX96 (Bio-rad Laboratories, Inc., USA) instrument: 95 °C for 20 sec, 40 cycles (95 °C for 15 sec, 60 °C for 20 sec), followed by a melt curve analysis.…”