A balanced game: chicken macrophage response to ALV-J infection

Min Feng, Tingting Xie, Yuanfang Li, Nan Zhang, Qiuyuan Lu, Yaohong Zhou, Meiqing Shi, Jingchen Sun, Xiquan Zhang, Min Feng, Tingting Xie, Yuanfang Li, Nan Zhang, Qiuyuan Lu, Yaohong Zhou, Meiqing Shi, Jingchen Sun, Xiquan Zhang

Abstract

Avian leukosis virus subgroup J (ALV-J) infection can cause tumors and immunosuppression in infected chickens. Macrophages play a central role in host defense against invading pathogens. In this study, we discovered an interesting phenomenon: ALV-J replication is weakened from 3 hours post-infection (hpi) to 36 hpi, which was verified using Western blotting and RT-PCR. To further investigate the interaction between ALV-J and macrophages, transcriptome analysis was performed to analyze the host genes' function in chicken primary monocyte-derived macrophages (MDM). Compared to the uninfected control, 624 up-regulated differentially expressed genes (DEG) and 341 down-regulated DEG at 3 hpi, and 174 up-regulated DEG and 87 down-regulated DEG at 36 hpi were identified in chicken MDM, respectively. ALV-J infection induced strong innate immune responses in chicken MDM at 3 hpi, instead of 36 hpi, according to the analysis results of Gene Ontology and KEGG pathway. Importantly, the host factors, such as up-regulated MIP-3α, IL-1β, iNOS, K60, IRG1, CH25H, NFKBIZ, lysozyme and OASL were involved in the host defense response during the course of ALV-J infection. On the contrary, up-regulated EX-FABP, IL4I1, COX-2, NFKBIA, TNFAIP3 and the Jak STAT pathway inhibitors including CISH, SOCS1 and SOCS3 are beneficial to ALV-J survival in chicken macrophages. We speculated that ALV-J tropism for macrophages helps to establish a latent infection in chicken MDM from 6 to 36 hpi. The present study provides a comprehensive view of the interactions between macrophages and ALV-J. It suggests the mechanisms of defense of chicken macrophages against ALV-J invasion and how ALV-J escape the host innate immune responses.

Figures

Figure 1
Figure 1
Detection of ALV-J replication in chicken MDM from 3 hpi to 36 hpi. A PCR detection with DNA template and ALV-J specific primer. All samples extracted from 3 hpi to 36 hpi produced specific 545 bp fragment. B RT-PCR detection with cDNA template and ALV-J specific primer. C Western blotting analysis shows that samples extracted from 3 hpi produced obvious specific ALV-J envelope protein blots, but the protein blots became weaker at 6 hpi and tended to disappear at 12 to 36 hpi.
Figure 2
Figure 2
DEG in chicken MDM infected with ALV-J at 3 hpi and 36 hpi. Venn diagrams of up-regulated DEG (A) and down-regulated DEG (B) at 3 hpi and 36 hpi from chicken MDM. C Venn diagrams of up-regulated DEG at 3 hpi and down-regulated DEG at 36 hpi in chicken MDM. D Venn diagrams of down-regulated DEG at 3 hpi compared up-regulated DEG at 36 hpi in chicken MDM.
Figure 3
Figure 3
Gene ontology (GO) terms analysis of DEG expressed in ALV-J-infected MDM. Representative GO terms of up-regulated DEG in the ALV-J-infected MDM at A 3 hpi and B 36 hpi. Down-regulated DEG enriched in the representative GO terms of ALV-J-infected MDM at C 3 hpi and D 36 hpi.
Figure 4
Figure 4
KEGG pathways in ALV-J-infected MDM. KEGG pathways of up-regulated DEG expressed in ALV-J-infected MDM at A 3 hpi and B 36 hpi. C Down-regulated DEG enriched in KEGG pathways of ALV-J-infected MDM at 3 hpi.
Figure 5
Figure 5
Heatmap of immune-related DEG at different time points after ALV-J infection. DEG with similar expressed patterns were clustered and are displayed in a heatmap format. Color intensity corresponds to relative expression level normalized according to log2 fold change. A Selected immune-related DEG from 3 hpi and 36 hpi. Red, up-regulated DEG; blue, down-regulated DEG. B ISG expression in MDM at 3 hpi and 36 hpi. Red, up-regulated ISG; purple, down-regulated ISG.
Figure 6
Figure 6
Validation of RNA-Seq data by qPCR. DEG were selected at (A) 3 hpi and (B) 36 hpi. qPCR results were represented using relative expression value. RNA-seq value is log2(foldchange) values of DEG. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 7
Figure 7
Overexpression ofK60, IRG1, OASLandCH25Hcould inhibit ALV-J replication. MDM cells were transfected with pCMV-K60, pCMV-IRG1, pCMV-OASL, pCMV-CH25H and infected with ALV-J strain SCAU-HN06 at 24 post-transfection. MDM cells transfected with pCMV-EGFP as a control. A SCAU-HN06 strain envelop protein was measured by Western blot at 3 hpi. B The level of SCAU-HN06 strain envelop protein was analyzed by Image Studio Ver 5.2 (Odyssey Fc). C The expression of SCAU-HN06 env gene was measured by qPCR at 3 hpi. *p < 0.05, **p < 0.01.
Figure 8
Figure 8
Overexpression ofCISH, EX-FABP, IL4I1andSOCS3could enhance ALV-J replication. MDM cells were transfected with plasmids including EGFP, CISH, EX-FABP, IL4I1 and SOCS3 and infected with SCAU-HN06 at 24 post-transfection. A, B The level of SCAU-HN06 strain envelop protein was detected by Western blot at 3 hpi and analyzed by Image Studio Ver 5.2 (Odyssey Fc). (C) The expression of SCAU-HN06 env gene was detected by qPCR at 3 hpi. *p < 0.05, **p < 0.01.

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