Dichotomy between T Cell and B Cell Tolerance to Neonatal Retroviral Infection Permits T Cell Therapy.

Elucidation of the immune requirements for control or elimination of retroviral infection remains an important aim. We studied the induction of adaptive immunity to neonatal infection with a murine retrovirus, under conditions leading to immunological tolerance. We found that the absence of either maternal or offspring adaptive immunity permitted efficient vertical transmission of the retrovirus. Maternal immunodeficiency allowed the retrovirus to induce central Th cell tolerance in the infected offspring. In turn, this compromised the offspring's ability to mount a protective Th cell-dependent B cell response. However, in contrast to T cells, offspring B cells were not centrally tolerized and retained their ability to respond to the infection when provided with T cell help. Thus, escape of retrovirus-specific B cells from deletional tolerance offers the opportunity to induce protective retroviral immunity by restoration of retrovirus-specific T cell help, suggesting similar T cell immunotherapies for persistent viral infections.

Exposure to environmental stressors result in increased viral load and further reduction of production parameters in pigs experimentally infected with PCV2b.

Porcine circovirus type 2 (PCV2) has been identified as the essential, but not sole, underlying infectious component for PCV-associated diseases (PCVAD). Several co-factors have been suggested to convert an infection with PCV2 into the clinical signs of PCVAD, including co-infection with a secondary pathogen and the genetic background of the pig. In the present study, we investigated the role of environmental stressors in the form of changes in environmental temperature and increased stocking-density on viral load in serum and tissue, average daily weight gain (ADG) and food conversion rate (FCR) of pigs experimentally infected with a defined PCV2b strain over an eight week period. These stressors were identified recently as risk factors leading to the occurrence of severe PCVAD on a farm level. In the current study, PCV2-free pigs were housed in separate, environmentally controlled rooms, and the experiment was performed in a 2×2 factorial design. In general, PCV2b infection reduced ADG and increased FCR, and these were further impacted on by the environmental stressors. Furthermore, all stressors led to an increased viral load in serum and tissue as assessed by qPCR, although levels did not reach statistical significance. Our data suggest that there is no need for an additional pathogen to develop PCVAD in conventional status pigs, and growth retardation and clinical signs can be induced in PCV2 infected pigs that are exposed to environmental stressors alone.

Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes.

BACKGROUND: A substantial proportion of both the mouse and human genomes comprise of endogenous retroelements (REs), which include endogenous retroviruses. Over evolutionary time, REs accumulate inactivating mutations or deletions and thus lose the ability to replicate. Additionally, REs can be transcriptionally repressed by dedicated mechanisms of the host. Nevertheless, many of them still possess and express intact open reading frames, and their transcriptional activity has been associated with many physiological and pathological processes of the host. However, this association remains tenuous due to incomplete understanding of the mechanism by which RE transcription is regulated. Here, we use a bioinformatics tool to examine RE transcriptional activity, measured by microarrays, in murine and human immune cells responding to microbial stimulation. RESULTS: Immune cell activation by microbial signals in vitro caused extensive changes in the transcription not only of the host genes involved in the immune response, but also of numerous REs. Modulated REs were frequently found near or embedded within similarly-modulated host genes. Focusing on probes reporting single-integration, intergenic REs, revealed extensive transcriptional responsiveness of these elements to microbial signals. Microbial stimulation modulated RE expression in a cell-intrinsic manner. In line with these results, the transcriptional activity of numerous REs followed characteristics in different tissues according to exposure to environmental microbes and was further heavily altered during viral infection or imbalances with intestinal microbiota, both in mice and humans. CONCLUSIONS: Together, these results highlight the utility of improved methodologies in assessing RE transcription profiles in both archived and new microarray data sets. More importantly, application of this methodology suggests that immune activation, as a result of infection with pathogens or dysbiosis with commensal microbes, causes global modulation of RE transcription. RE responsiveness to external stimuli should, therefore, be considered in any association between RE transcription and disease.

Global gene expression profiling of myeloid immune cell subsets in response to in vitro challenge with porcine circovirus 2b.

Compelling evidence suggests that the early interaction between porcine circovirus 2 (PCV-2) and the innate immune system is the key event in the pathogenesis of Post-Weaning Multisystemic Wasting Syndrome (PMWS). Furthermore, PCV2 has been detected in bone-marrow samples, potentially enabling an easy spread and reservoir for the virus. To assess the gene-expression differences induced by an in-vitro PCV2b infection in different three different myeloid innate immune cell subsets generated from the same animal, we used the Agilent Porcine Gene Expression Microarray (V2). Alveolar macrophages (AMØs), monocyte-derived dendritic cells (MoDCs) and bone-marrow cells (BMCs) were generated from each animal, and challenged with a UK-isolate of a PCV2 genotype b-strain at a MOI of 0.5. Remarkably, analysis showed a highly distinct and cell-type dependent response to PCV2b challenge. Overall, MoDCs showed the most marked response to PCV2b challenge in vitro and revealed a key role for TNF in the interaction with PCV2b, whereas only few genes were affected in BMCs and AMØs. These observations were further supported by an enrichment of genes in the downstream NF-κB Signalling pathway as well as an up regulation of genes with pro-apoptotic functions post-challenge. PCV2b challenge increases the expression of a large number of immune-related and pro-apoptotic genes mainly in MoDC, which possibly explain the increased inflammation, granulomatous inflammation and lymphocyte depletion seen in PMWS-affected pigs.

Counterpoise between the microbiome, host immune activation and pathology.

The role of the mammalian intestinal microbiota in health and disease of the host has long been recognized and extensively studied. Largely, these studies have focused on the bacterial component of the microbiota. However, recent technological advances have shed new light on the microbiome at distinct anatomical locations and uncovered the role of additional microbial symbionts, including the virome and endogenous retroelements. Together, they have revealed interactions more intricate than previously recognized. Here, we review recent advances in our knowledge of this collective microbiome and the interactions with the immune system of their host.