Bovine leukemia virus reduces anti‐viral cytokine activities and NK cytotoxicity by inducing TGF‐β secretion from regulatory T cells

Ohira, Kosuke; Nakahara, Ayako; Konnai, Satoru; Okagawa, Tomohiro; Nishimori, Asami; Maekawa, Naoya; Ikebuchi, Ryoyo; Kohara, Junko; Shiro, Motoo; Ohashi, Kazuhiko

doi:10.1002/iid3.93

Cited by 34 publications

(34 citation statements)

References 46 publications

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“…In the advanced stages of BLV infection, BLV-specific Th1 responses are downregulated, leading to further disease progression and possible EBL (31). Several previous studies have demonstrated that loss of BLV-specific Th1 responses is mediated by upregulation of immunoinhibitory molecules such as PD-1 and PD-L1, as well as by expansion of regulatory T cells (15,16,24). Similarly, our previous study revealed that PGE 2 suppresses Th1 responses, such as T cell proliferation and Th1 cytokine production, and induces the expression of PD-L1 (22).…”

Section: Discussionmentioning

confidence: 99%

“…Infection was confirmed by detection of the provirus using nested PCR targeting the viral long terminal repeat (16) and by detection of the anti-BLV Ab using a commercial ELISA (JNC, Tokyo, Japan). The leukocyte numbers in BLVinfected cattle were counted using a Celltac a MEK-6450 automatic hematology analyzer (Nihon Kohden, Tokyo, Japan), and animals were classified as AL or PL as described previously (24). PBMCs derived from these blood samples were purified by density gradient centrifugation on Percoll (GE Healthcare, Buckinghamshire, U.K.) and cultured in RPMI 1640 (Sigma-Aldrich, St. Louis, MO) supplemented with 10% heat-inactivated FCS (Thermo Fisher Scientific, Waltham, MA), 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM L-glutamine (Thermo Fisher Scientific).…”

Section: Cell Preparationmentioning

confidence: 99%

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Prostaglandin E2–Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti–PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection

Sajiki

Konnai

Okagawa

et al. 2019

The Journal of Immunology

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Bovine leukemia virus (BLV) infection is a chronic viral infection of cattle and endemic in many countries, including Japan. Our previous study demonstrated that PGE 2 , a product of cyclooxygenase (COX) 2, suppresses Th1 responses in cattle and contributes to the progression of Johne disease, a chronic bacterial infection in cattle. However, little information is available on the association of PGE 2 with chronic viral infection. Thus, we analyzed the changes in plasma PGE 2 concentration during BLV infection and its effects on proviral load, viral gene transcription, Th1 responses, and disease progression. Both COX2 expression by PBMCs and plasma PGE 2 concentration were higher in the infected cattle compared with uninfected cattle, and plasma PGE 2 concentration was positively correlated with the proviral load. BLV Ag exposure also directly enhanced PGE 2 production by PBMCs. Transcription of BLV genes was activated via PGE 2 receptors EP2 and EP4, further suggesting that PGE 2 contributes to disease progression. In contrast, inhibition of PGE 2 production using a COX-2 inhibitor activated BLV-specific Th1 responses in vitro, as evidenced by enhanced T cell proliferation and Th1 cytokine production, and reduced BLV proviral load in vivo. Combined treatment with the COX-2 inhibitor meloxicam and anti-programmed death-ligand 1 Ab significantly reduced the BLV proviral load, suggesting a potential as a novel control method against BLV infection. Further studies using a larger number of animals are required to support the efficacy of this treatment for clinical application.

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Section: Discussionmentioning

confidence: 99%

Section: Cell Preparationmentioning

confidence: 99%

Prostaglandin E2–Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti–PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection

Sajiki

Konnai

Okagawa

et al. 2019

The Journal of Immunology

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“…In some cases, no synthesis of the corresponding antibodies is revealed in BLV-infected animals, despite the presence of the integrated proviral DNA [17]. BLV infection is shown to inhibit the regulatory function of T-lymphocytes subpopulation (CD4 + CD25 high Foxp3+) resulting in suppression of antiviral activity, particularly in NK-cells [18].…”

Section: Introductionmentioning

confidence: 99%

The Infection Hazard of Carriers of Proviral Bovine Leukemia Virus and Its Evaluation With Regard to Leukocytosis

Kosovskii¹,

Glazko²,

Andreichenko³

et al. 2016

S-h. biol.

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A b s t r a c tThe spread of the bovine leukemia virus (BLV) brings significant economic damage to dairy and beef cattle still due to the problems to develop the optimal methods for its prevention. The situation is compounded by the fact that the clinical manifestation of lymphocytic leukemia has been observed in animals during 5 to 10 years after infection in approximately 5-7 % of animals. Subdivision of BLV infected B cells on the producers of mature viral particles and precursors of the formation of lymphomas necessitates of separately consideration of the risk of infecting animals and forecast for development of lymphocytic leukemia. Testing antibodies to viral antigens, or provirus DNA insertion into the host genomes does not allow to reveal the most dangerous animals in view of their role in the infection spread, which is most essential for its control. In this regard, the particular urgency is the method development to assess the infection hazard from carriers of provirus DNA of bovine leukemia virus, associated with a large number of B lymphocytes, producing mature viral particles. In order to evaluate the possibility of using in these purposes not only testing individual animals on the quantity of viral RNA in blood samples, but the proliferative activity of leucocytes, these two characteristics were compared in the present work. The presence or absence of genome integrated provirus DNA in Black-and-White Holstein cows (n = 57, commercial herd) was evaluated and the group of infected animals was revealed when using primers designed by us for BLV gag and pol genes (G.Yu. Kosovoskii et al., 2013). The relative quantity expression of provirus in individual infected cows using RT-PCR analysis and primers to the fragment of the BLV pol gene were assessed. The counting of leukocytes in blood samples of all cows, included in the analysis, was performed. The number of leucocytes in cows free from infection, with the exception of one cow, was less than 1210 9 cells/l. This indicator in infected animals divided the investigated cows into two subgroupsin the first subgroup the leucocyte values did not exceed 1710 9 cells/l, in the second subgroup the number of leukocytes was significantly higher, reaching 2810 9 cells/l in some animals. It was important to note, that the amount (above 2010 9 cells/l) of BLV RNA, sufficient to detect by RT-PCR, was revealed only in the second subgroup. The coincidence of the increased leucocyte amount and the BLV RNA in blood of infected animals indicates that particular these cows represent the greatest infection hazard and suggests that the combination of estimates of the number of leukocytes and RNA BLV can be quite a reliable approach for the herd recovery by priority of their liquidation.

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“…The proportion of Treg cells positively correlates with the number of lymphocytes, the virus titer and viral load in BLV infected cattle. There is experimental data showing that suppression of antiviral activity and cytotoxicity of NK-cells is due to activation of the secretion of growth-transforming beta factor (TGF-β) by Treg cells [22]. It should be emphasized that one of the effects of BLV proviral gene tax on host genes is an increase in the expression of tumor necrosis factor TNF- [23,24], which, in turn, activates Treg cells [25,26].…”

Section: Expression Of Genes Nk-lysin Blvr Ifn- In Peripheral Bloomentioning

confidence: 99%

EXPRESSION of NK-lysin, blvr, ifn-a AND BLOOD CELL POPULATIONS IN COWS INFECTED BY BOVINE LEUKEMIA VIRUS

Kosovskii¹,

Glazko²,

Kovalchuk³

et al. 2017

S-h. biol.

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At now, it is impossible to prevent or control the spread of retroviral infections, in particular, bovine leukemia virus (BLV). The existing methods of vaccination and detection of infected animals remain insufficient (G. Gutiérrez et al., 2014; M. Nishiike et al., 2016) which necessitates further investigations of the interactions between pathogen and host organism. Previously, we obtained evidence that a common characteristic for BLV infected animals with moderate and high leukocytosis was the increase in platelets, and in cows with a pronounced leukocytosis the decrease in the number of neutrophils (G.Yu. Kosovovskii et al. 2017). In order to assess the relationship between BLV infection in animals, the ratio of cell populations in the peripheral blood and the expression of the genes, encoding the BLV receptor (blvr gene), a comparative analysis of antivirus protection protein, interferon alpha (INFΑ), and effector protein of innate immunity, NK-lysine, was carried out in two groups of cows that differed in origin and farm conditions. In result, the evidences were obtained that cows from two farms differed mainly in the amount of peripheral blood neutrophils and platelets. However, in both farms the BLV infected animals had the reduced gene expression of NK-lysine and an increased number of platelets compared to cows free from infection. Relatively increased expression of blvr was observed in BLV infected cows, reflecting, apparently, the increase in the proportion of the young forms of B-lymphocytes (M. Lavanya et al., 2008). On the basis of the own obtained findings and literature data the scheme is proposed of the influence of BLV on the expression of NK-lysine and the suppression of apoptosis. As per the scheme, viral protein TAX (a transcription activator) induces the expression of host tnf- gene (M. Arainga et al., 2012) which, in turn, activates the Treg regulators of immune homeostasis (L.Y. Chang et al., 2015); Treg produces TGF-β (transforming growth factor beta), TGF-β inhibits the proliferation and activity of T-killers and NK-cells, the producers of NK-lysine, and increases the number and activity of platelets which inhibits the apoptosis (K. Ohira et al., 2016; S.C. Tao et al., 2016). The proposed scheme suggested that the key event in pathogenesis, induced by BLV, is the effect on the innate immune system.

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Bovine leukemia virus reduces anti‐viral cytokine activities and NK cytotoxicity by inducing TGF‐β secretion from regulatory T cells

Cited by 34 publications

References 46 publications

Prostaglandin E2–Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti–PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection

Prostaglandin E2–Induced Immune Exhaustion and Enhancement of Antiviral Effects by Anti–PD-L1 Antibody Combined with COX-2 Inhibitor in Bovine Leukemia Virus Infection

The Infection Hazard of Carriers of Proviral Bovine Leukemia Virus and Its Evaluation With Regard to Leukocytosis

EXPRESSION of NK-lysin, blvr, ifn-a AND BLOOD CELL POPULATIONS IN COWS INFECTED BY BOVINE LEUKEMIA VIRUS

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