Effect of Foot-and-Mouth Disease Virus Infection on the Frequency, Phenotype and Function of Circulating Dendritic Cells in Cattle

Abstract

Foot-and-mouth disease virus (FMDV) is a highly contagious virus that causes one of the most devastating diseases in cloven-hoofed animals. Disease symptoms develop within 2 to 3 days of exposure and include fever and vesicular lesions on the tongue and hooves. Dendritic cells (DC) play an essential role in protective immune responses against pathogens. Therefore, investigating their role during FMDV infection would lead to a better understanding of host-pathogen interactions. In this study, following infection of cattle with FMDV, we investigated the frequency and function of conventional (cDC) and plasmacytoid DC (pDC) in blood by using multi-color flow cytometry. We show that the frequency of cDC and pDC increased following FMDV infection and peaked 3 to 4 days post-infection. During peak viremia, the cattle became lymphopenic, the expression of MHC class II molecules on cDC and pDC was dramatically down-regulated, the processing of exogenous antigen by cDC and pDC was impaired, and there was an increase in IL-10 production by DC and monocytes. Notably, after clearance of FMDV from the blood, MHC class II expression returned to pre-infection levels. Altogether, our study demonstrates that in cattle, FMDV inhibits the function of DC, thereby retarding the initiation of adaptive immune responses, potentially enhancing virus shedding during the acute phase of infection.

The Different Tactics of Foot-and-Mouth Disease Virus to Evade Innate Immunity

“…Implications of these observations favor a model in which Mφ act as transporters and disseminators of viable virions to distant sites of the body where the virus can infect and replicate in other cells. On the other hand, in cattle, CD14+ monocyte frequency increases following inoculation with FMDV ( Sei et al, 2016 ), consistently with previous reports demonstrating that the number of blood monocytes augment following vaccination and challenge with FMDV ( Sigal et al, 1992 ). In this case, blood monocytes may function as cDCs, in which the reduced levels of MHC-II compromise antigen presentation.…”

“…It is worth mentioning that DC functionality is affected upon FMDV infection. During acute infection, the virus stimulates swine and cattle cDCs to produce IL-10, a cytokine that directs the immune response toward a stronger humoral rather than a T-cell mediated adaptive response ( Díaz-San Segundo et al, 2009 ; Sei et al, 2016 ). FMDV also blocks the ability of porcine DCs to differentiate into mature cDCs ( Díaz-San Segundo et al, 2009 ) and impairs the response to stimulation by TLR ligands ( Nfon et al, 2008 ).…”

“…FMDV also blocks the ability of porcine DCs to differentiate into mature cDCs ( Díaz-San Segundo et al, 2009 ) and impairs the response to stimulation by TLR ligands ( Nfon et al, 2008 ). Similarly, during FDMV infection in cattle, the number of bovine CD11c- cDCs, but not CD11c+ cDCs, is significantly decreased during the peak of viremia, the expression of MHC-II molecules on all bovine cDC populations is dramatically downregulated and the processing of exogenous antigen is impaired ( Sei et al, 2016 ).…”

“…In contrast, high levels of type I IFN are produced after ex vivo stimulation of bovine pDCs with TLR9 agonist CpG and FMDV immune complexes ( Reid et al, 2011 ). Furthermore, a robust systemic in vivo type I IFN response is detected in cattle infected with FMDV ( Stenfeldt et al, 2011 ; Perez-Martin et al, 2012 ) and the number of systemic mature bovine CD4+ MHC-II+ pDCs is increased during FMDV infection, while levels of MHC-II and immature CD4+ MHC-II- pDCs are declined ( Sei et al, 2016 ).…”

“…In vivo cytokine profile analysis during the 1st week of infection shows a systemic decrease of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), while an increase of the anti-inflammatory cytokine IL-10 and IFNα is detected ( Nfon et al, 2010 ; Diaz-San Segundo et al, 2012 , 2013 ; Perez-Martin et al, 2012 ; Sei et al, 2016 ). Most likely, these changes are related with the early T cell unresponsiveness and lymphopenia described in swine and cattle during FMDV infection ( Bautista et al, 2005 ; Díaz-San Segundo et al, 2006 ; Perez-Martin et al, 2012 ; Sei et al, 2016 ). Indeed, it has been reported that, IL-10, inhibits a broad spectrum of cellular responses, and causes immunosuppression and persistence in vivo for other viruses ( Brooks et al, 2006 ).…”