Persistent fetal infection with bovine viral diarrhea virus differentially affects maternal blood cell signal transduction pathways

Abstract

The consequences of viral infection during pregnancy include impact on fetal and maternal immune responses and on fetal development. Transplacental infection in cattle with noncytopathic bovine viral diarrhea virus (ncpBVDV) during early gestation results in persistently infected (PI) fetuses with life-long viremia and susceptibility to infections. Infection of the fetus during the third trimester or after birth leads to a transient infection cleared by a competent immune system. We hypothesized that ncpBVDV infection and presence of an infected fetus would alter immune response and lead to downregulation of proinflammatory processes in pregnant dams. Naïve pregnant heifers were challenged with ncpBVDV2 on day 75 (PI fetus) and day 175 [transiently infected (TI) fetus] or kept uninfected (healthy control fetus). Maternal blood samples were collected up to day 190 of gestation. Genome-wide microarray analysis of gene expression in maternal peripheral white blood cells, performed on days 160 and 190 of gestation, revealed multiple signal transduction pathways affected by ncpBVDV infection. Acute infection and presence of a TI fetus caused upregulation of the type I interferon (IFN) pathway genes, including dsRNA sensors and IFN-stimulated genes. The presence of a PI fetus caused prolonged downregulation of chemokine receptor 4 (CXCR4) and T cell receptor (TCR) signaling in maternal blood cells. We conclude that: 1) infection with ncpBVDV induces a vigorous type I IFN response, and 2) presence of a PI fetus causes downregulation of important signaling pathways in the blood of the dam, which could have deleterious consequences on fetal development and the immune response.

Yield and characterization of subcutaneous human adipose-derived stem cells by flow cytometric and adipogenic mRNA analyzes

“…This approach, unlike stringent selection of microarray probes, allowed for a better accounting of interactive genes which may not be statistically significant considered separately, but add strength to each other as a group. Pathway analysis has been proven effective for the analysis of metastasis biomarker association with cancer (31, 32) and for signal transduction relationships with infectious disease (32). Ingenuity Pathway Analysis (Ingenuity Systems Inc., Redwood City, CA) of the induced microarray dataset identified specific metabolic pathways that could be associated with between 16 to 32 individual genes.…”

Bovine Viral Diarrhea Virus Infections

“…27 There is upregulation of type I IFN in maternal blood of calves infected with ncp BVDV at day 175 of gestation. 138 Leukocytes from these dams with a PI fetus showed downregulation of T-cell receptor signaling and of CXCR4 (the receptor for the lymphocyte chemoattractant, stromal cell-derived factor 1). 15,123,138 It is these features of the BVDV proteins E rns and N pro that are thought to enable the virus to avoid the innate immune system in the early gestation fetus.…”

“…Upregulation of interferon-stimulated gene 15kD (ISG15) has been observed in the blood of pregnant cattle during the early stage of ncp BVDV infection both in early and middle gestation. 137,138 By day 45 postinoculation, ISG15 had returned to baseline in both the PI and transiently infected (TI) cows in PI mothers, using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Further work has shown that ncp BVDV has effects on several families of chemokines.…”

Assessment of immune status using blood transcriptomics and potential implications for global health

“…Reproductive biology studies are also well represented (e.g. [101][102][103]), which was in comparison a very minor theme in human studies. As can be expected these themes are common to most species of economical relevance.…”