Redefining the "carrier" state for foot-and-mouth disease from the dynamics of virus persistence in endemically affected cattle populations

The foot-and-mouth disease virus (FMDV) “carrier” state was defined by van Bekkum in 1959. It was based on the recovery of infectious virus 28 days or more post infection and has been a useful construct for experimental studies. Using historic data from 1,107 cattle, collected as part of a population based study of endemic FMD in 2000, we developed a mixed effects logistic regression model to predict the probability of recovering viable FMDV by probang and culture, conditional on the animal’s age and time since last reported outbreak. We constructed a second set of models to predict the probability of an animal being probang positive given its antibody response in three common non-structural protein (NSP) ELISAs and its age. We argue that, in natural ecological settings, the current definition of a ”carrier” fails to capture the dynamics of either persistence of the virus (as measured by recovery using probangs) or the uncertainty in transmission from such animals that the term implies. In these respects it is not particularly useful. We therefore propose the first predictive statistical models for identifying persistently infected cattle in an endemic setting that captures some of the dynamics of the probability of persistence. Furthermore, we provide a set of predictive tools to use alongside NSP ELISAs to help target persistently infected cattle

Implications for gene therapy-limiting expression of IL-2R gamma c delineate differences in signaling thresholds required for lymphocyte development and maintenance.

X-linked SCID patients are deficient in functional IL-2Rγc leading to the loss of IL-2/IL-4/IL-7/IL-9/IL-15/IL-21 signaling and a lack of NK and mature T cells. Patients treated with IL-2Rγc gene therapy have T cells develop; however, their NK cell numbers remain low, suggesting antiviral responses may be compromised. Similarly, IL-2Rγc−/− mice reconstituted with IL-2Rγc developed few NK cells, and reconstituted T cells exhibited defective proliferative responses suggesting incomplete recovery of IL-2Rγc signaling. Given the shift toward self-inactivating long terminal repeats with weaker promoters to control the risk of leukemia, we assessed NK and T cell numbers and function in IL-2Rγc−/− mice reconstituted with limiting amounts of IL-2Rγc. Reconstitution resulted in lower IL-2/-15–mediated STAT5 phosphorylation and proliferation in NK and T cells. However, TCR costimulation restored cytokine-driven T cell proliferation to wild-type levels. Vector modifications that improved IL-2Rγc levels increased cytokine-induced STAT5 phosphorylation in both populations and increased NK cell proliferation demonstrating that IL-2Rγc levels are limiting. In addition, although the half-lives of both NK and T cells expressing intermediate levels of IL-2Rγc are reduced compared with wild-type cells, the reduction in NK cell half-live is much more severe than in T cells. Collectively, these data indicate different IL-2Rγc signaling thresholds for lymphocyte development and proliferation making functional monitoring imperative during gene therapy. Further, our findings suggest that IL-2Rγc reconstituted T cells may persist more efficiently than NK cells due to compensation for suboptimal IL-2Rγc signaling by the TCR

LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells.

Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2-/- mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear β-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted in Lat2-/- DCs. Accordingly, Lat2-/- DCs directed reduced Th1 polarization in vitro and Lat2-/- mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-γ production in vivo/ex vivo. Thus our data define a novel link between LAB and β-catenin nuclear accumulation in DCs that facilitates IFN-γ responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-γ response for pathogen clearance