Interleukin-10-Mediated Lymphopenia Caused by Acute Infection with Foot-and-Mouth Disease Virus in Mice

Guo, Zijing; Zhao, Yin; Zhang, Zhidong; Li, Yanmin

doi:10.3390/v13122358

Cited by 5 publications

(17 citation statements)

References 63 publications

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“…On this regard, similar levels of IL-10 were detected in the animals infected with WT and A12-L H138L viruses consistent with equivalent levels of detectable neutralizing antibodies by 21 days post infection. Our results are consistent with previous studies with other FMDV mutants ( 27 ) and further support the concept of IL-10 as key regulatory cytokine during FMD ( 60 ).…”

Section: Discussionsupporting

confidence: 93%

Mutation of FMDV Lpro H138 residue drives viral attenuation in cell culture and in vivo in swine

Azzinaro

Medina²,

Rai³

et al. 2022

Front. Vet. Sci.

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The foot-and-mouth disease virus (FMDV) leader proteinase (Lpro) is a papain like protease that cleaves the viral polyprotein and several host factors affecting host cell translation and induction of innate immunity. Introduction of Lpro mutations ablating catalytic activity is not tolerated by the virus, however, complete coding sequence deletion or introduction of targeted amino acid substitutions can render viable progeny. In proof-of-concept studies, we have previously identified and characterized FMDV Lpro mutants that are attenuated in cell culture and in animals, while retaining their capacity for inducing a strong adaptive immunity. By using molecular modeling, we have now identified a His residue (H138), that resides outside the substrate binding and catalytic domain, and is highly conserved across serotypes. Mutation of H138 renders possible FMDV variants of reduced virulence in vitro and in vivo. Kinetics studies showed that FMDV A12-LH138L mutant replicates similarly to FMDV A12-wild type (WT) virus in cells that do not offer immune selective pressure, but attenuation is observed upon infection of primary or low passage porcine epithelial cells. Western blot analysis on protein extracts from these cells, revealed that while processing of translation initiation factor eIF-4G was slightly delayed, no degradation of innate sensors or effector molecules such as NF-κB or G3BP2 was observed, and higher levels of interferon (IFN) and IFN-stimulated genes (ISGs) were induced after infection with A12-LH138L as compared to WT FMDV. Consistent with the results in porcine cells, inoculation of swine with this mutant resulted in a mild, or in some cases, no clinical disease but induction of a strong serological adaptive immune response. These results further support previous evidence that Lpro is a reliable target to derive numerous viable FMDV strains that alone or in combination could be exploited for the development of novel FMD vaccine platforms.

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Section: Discussionsupporting

confidence: 93%

Mutation of FMDV Lpro H138 residue drives viral attenuation in cell culture and in vivo in swine

Azzinaro

Medina²,

Rai³

et al. 2022

Front. Vet. Sci.

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“…In particular, IL-2, IL-10, and TGFβ showed a strong correlation with the age-dependent dynamics of MDAs, suggesting that in the presence of MDA, TCR-mediated B cell activation was likely to be inhibited by T regs . Recently, as IL-10 was shown to induce immunosuppression-related lymphophenia in mice with acute FMD infection, blocking IL-10/IL-10R signaling was suggested as a new therapeutic approach [ 50 ]. In contrast to the possibility that MDAs may temporarily exhibit protective effects in young individuals, IL-10 promotes lymphophenia, potentially causing severe clinical symptoms.…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Dynamics of Maternally Derived Antibodies (MDAs) and Understanding MDA-Mediated Immune Tolerance in Foot-and-Mouth Disease-Vaccinated Pigs

Shin

Park

et al. 2022

Vaccines

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Vaccine-induced active immunity in young animals may be compromised via interference caused by maternally derived antibodies (MDAs). Since the level, titer, and half-life of MDAs vary per individual, it is difficult to determine the appropriate timing of foot-and-mouth disease (FMD) vaccination in the field. In order to better understand the age-dependent characteristics of MDA in sows and piglets as well as the phenomenon of reduced vaccine-mediated active immunity due to MDAs, this study sought to determine antibody titers through structural protein (SP) O, A ELISA analyses, and virus-neutralizing (VN) antibody titers as well as their half-lives in the sera of sows and piglets derived from FMD-vaccinated mother. Furthermore, immunoglobulin (Ig) subtypes, such as IgG, IgM, and IgA, in serum were also evaluated. To understand the correlation between the inhibition of vaccine-mediated active immunity by MDA-mediated passive immunity and regulatory T (Treg) cells, Treg-related cytokine levels were explored. Our findings will help to predict the optimal timing of vaccination for overcoming MDAs and inducing a robust vaccine-mediated immune response in young individuals vaccinated against FMD. They also add to our understanding of MDA characteristics and interference, providing insight for the development of innovative strategies and novel FMD vaccine for overcoming such interference.

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“…Lymphopenia refers to lymphocyte depletion in the peripheral blood, and it is associated with immune suppression during FMDV infection. Our recent study found that interleukin-10 (IL-10) and CXCL13 were obviously elevated in sera from mice infected with FMDV and were related to lymphopenia and the progression and severity of the disease [ 18 ]. It was noted that IL-10 mediated lymphopenia in mice infected with FMDV [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Our recent study found that interleukin-10 (IL-10) and CXCL13 were obviously elevated in sera from mice infected with FMDV and were related to lymphopenia and the progression and severity of the disease [ 18 ]. It was noted that IL-10 mediated lymphopenia in mice infected with FMDV [ 18 ]. However, it is still unclear whether IL-10 regulates CXCL13 during FMDV infection and which cells are involved in producing CXCL13.…”

Section: Introductionmentioning

confidence: 99%

IL-10 Promotes CXCL13 Expression in Macrophages Following Foot-and-Mouth Disease Virus Infection

Guo

Chen

Zhao

et al. 2023

IJMS

Self Cite

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Foot-and-mouth disease (FMD) is one of the most contagious livestock diseases in the world, posing a constant global threat to the animal trade and national economies. The chemokine C-X-C motif chemokine ligand 13 (CXCL13), a biomarker for predicting disease progression in some diseases, was recently found to be increased in sera from mice infected with FMD virus (FMDV) and to be associated with the progression and severity of the disease. However, it has not yet been determined which cells are involved in producing CXCL13 and the signaling pathways controlling CXCL13 expression in these cells. In this study, the expression of CXCL13 was found in macrophages and T cells from mice infected with FMDV, and CXCL13 was produced in bone-marrow-derived macrophages (BMDMs) by activating the nuclear factor-kappaB (NF-κB) and JAK/STAT pathways following FMDV infection. Interestingly, CXCL13 concentration was decreased in sera from interleukin-10 knock out (IL-10-/-) mice or mice blocked IL-10/IL-10R signaling in vivo after FMDV infection. Furthermore, CXCL13 was also decreased in IL-10-/- BMDMs and BMDMs treated with anti-IL-10R antibody following FMDV infection in vitro. Lastly, it was demonstrated that IL-10 regulated CXCL13 expression via JAK/STAT rather than the NF-κB pathway. In conclusion, the study demonstrated for the first time that macrophages and T cells were the cellular sources of CXCL13 in mice infected with FMDV; CXCL13 was produced in BMDMs via NF-κB and JAK/STAT pathways; and IL-10 promoted CXCL13 expression in BMDMs via the JAK/STAT pathway.

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Interleukin-10-Mediated Lymphopenia Caused by Acute Infection with Foot-and-Mouth Disease Virus in Mice

Cited by 5 publications

References 63 publications

Mutation of FMDV Lpro H138 residue drives viral attenuation in cell culture and in vivo in swine

Mutation of FMDV Lpro H138 residue drives viral attenuation in cell culture and in vivo in swine

Age-Dependent Dynamics of Maternally Derived Antibodies (MDAs) and Understanding MDA-Mediated Immune Tolerance in Foot-and-Mouth Disease-Vaccinated Pigs

IL-10 Promotes CXCL13 Expression in Macrophages Following Foot-and-Mouth Disease Virus Infection

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