Pattern recognition receptor MDA5 modulates CD8+ T cell- dependent clearance of west nile virus from the central nervous system

Many viruses induce type I interferon responses by activating cytoplasmic RNA sensors, including the RIG-I-like receptors (RLRs). Although two members of the RLR family, RIG-I and MDA5, have been implicated in host control of virus infection, the relative role of each RLR in restricting pathogenesis in vivo remains unclear. Recent studies have demonstrated that MAVS, the adaptor central to RLR signaling, is required to trigger innate immune defenses and program adaptive immune responses, which together restrict West Nile virus (WNV) infection in vivo. In this study, we examined the specific contribution of MDA5 in controlling WNV in animals. MDA5(−/−) mice exhibited enhanced susceptibility, as characterized by reduced survival and elevated viral burden in the central nervous system (CNS) at late times after infection, even though small effects on systemic type I interferon response or viral replication were observed in peripheral tissues. Intracranial inoculation studies and infection experiments with primary neurons ex vivo revealed that an absence of MDA5 did not impact viral infection in neurons directly. Rather, subtle defects were observed in CNS-specific CD8(+) T cells in MDA5(−/−) mice. Adoptive transfer into recipient MDA5(+/+) mice established that a non-cell-autonomous deficiency of MDA5 was associated with functional defects in CD8(+) T cells, which resulted in a failure to clear WNV efficiently from CNS tissues. Our studies suggest that MDA5 in the immune priming environment shapes optimal CD8(+) T cell activation and subsequent clearance of WNV from the CNS

The RIG-I-like Receptor LGP2 Controls CD8+ T Cell Survival and Fitness

SummaryThe RIG-I-like receptors (RLRs) signal innate immune defenses upon RNA virus infection, but their roles in adaptive immunity have not been clearly defined. Here, we showed that the RLR LGP2 was not essential for induction of innate immune defenses, but rather was required for controlling antigen-specific CD8+ T cell survival and fitness during peripheral T cell-number expansion in response to virus infection. Adoptive transfer and biochemical studies demonstrated that T cell-receptor signaling induced LGP2 expression wherein LGP2 operated to regulate death-receptor signaling and imparted sensitivity to CD95-mediated cell death. Thus, LGP2 promotes an essential prosurvival signal in response to antigen stimulation to confer CD8+ T cell-number expansion and effector functions against divergent RNA viruses, including West Nile virus and lymphocytic choriomeningitis virus

IL-1β Production through the NLRP3 Inflammasome by Hepatic Macrophages Links Hepatitis C Virus Infection with Liver Inflammation and Disease

Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease. Liver inflammation underlies infection-induced fibrosis, cirrhosis and liver cancer but the processes that promote hepatic inflammation by HCV are not defined. We provide a systems biology analysis with multiple lines of evidence to indicate that interleukin-1β (IL-1β) production by intrahepatic macrophages confers liver inflammation through HCV-induced inflammasome signaling. Chronic hepatitis C patients exhibited elevated levels of serum IL-1β compared to healthy controls. Immunohistochemical analysis of healthy control and chronic hepatitis C liver sections revealed that Kupffer cells, resident hepatic macrophages, are the primary cellular source of hepatic IL-1β during HCV infection. Accordingly, we found that both blood monocyte-derived primary human macrophages, and Kupffer cells recovered from normal donor liver, produce IL-1β after HCV exposure. Using the THP-1 macrophage cell-culture model, we found that HCV drives a rapid but transient caspase-1 activation to stimulate IL-1β secretion. HCV can enter macrophages through non-CD81 mediated phagocytic uptake that is independent of productive infection. Viral RNA triggers MyD88-mediated TLR7 signaling to induce IL-1β mRNA expression. HCV uptake concomitantly induces a potassium efflux that activates the NLRP3 inflammasome for IL-1β processing and secretion. RNA sequencing analysis comparing THP1 cells and chronic hepatitis C patient liver demonstrates that viral engagement of the NLRP3 inflammasome stimulates IL-1β production to drive proinflammatory cytokine, chemokine, and immune-regulatory gene expression networks linked with HCV disease severity. These studies identify intrahepatic IL-1β production as a central feature of liver inflammation during HCV infection. Thus, strategies to suppress NLRP3 or IL-1β activity could offer therapeutic actions to reduce hepatic inflammation and mitigate disease

Deficient IFN signaling by myeloid cells leads to MAVS-dependent virus-induced sepsis

The type I interferon (IFN) signaling response limits infection of many RNA and DNA viruses. To define key cell types that require type I IFN signaling to orchestrate immunity against West Nile virus (WNV), we infected mice with conditional deletions of the type I IFN receptor (IFNAR) gene. Deletion of the Ifnar gene in subsets of myeloid cells resulted in uncontrolled WNV replication, vasoactive cytokine production, sepsis, organ damage, and death that were remarkably similar to infection of Ifnar-/- mice completely lacking type I IFN signaling. In Mavs-/-×Ifnar-/- myeloid cells and mice lacking both Ifnar and the RIG-I-like receptor adaptor gene Mavs, cytokine production was muted despite high levels of WNV infection. Thus, in myeloid cells, viral infection triggers signaling through MAVS to induce proinflammatory cytokines that can result in sepsis and organ damage. Viral pathogenesis was caused in part by massive complement activation, as liver damage was minimized in animals lacking complement components C3 or factor B or treated with neutralizing anti-C5 antibodies. Disease in Ifnar-/- and CD11c Cre+Ifnarf/f mice also was facilitated by the proinflammatory cytokine TNF-α, as blocking antibodies diminished complement activation and prolonged survival without altering viral burden. Collectively, our findings establish the dominant role of type I IFN signaling in myeloid cells in restricting virus infection and controlling pathological inflammation and tissue injury

In support of the ICCAT ecosystem report card: advances in monitoring the impacts on and the state of the “foodweb and trophic relationships” ecosystem component.

In support of the development of the ICCAT Ecosystem Report Card, this paper addresses the “foodweb/trophic relationships” ecosystem component. Specifically, it contributes towards developing the following elements: (1) we describe what this component means in the context of ICCAT species and fisheries and the importance of monitoring it; (2) we describe the role of ecological indicators and ecosystem models in monitoring this ecosystem component; (3) we present a list of candidate ecological indicators that could be estimated to monitor this component; (4) we discuss the main challenges in monitoring this ecosystem component and indicator development; and finally (5), we draft a work plan to guide our future work. We invite the ICCAT community and others to contribute towards the development of ecological indicators and ecosystem models to monitor this ecosystem component. If interested, contact the corresponding authors to find out how you can contribute to this initiative.Versión del editor

In support of the IOTC ecosystem report card: Advances in monitoring the impacts on and the state of the “foodweb and trophic relationships” ecosystem component

In support of the development of the ICCAT Ecosystem Report Card, this paper addresses the “foodweb/trophic relationships” ecosystem component. Specifically, it contributes towards developing the following elements: (1) we describe what this component means in the context of ICCAT species and fisheries and the importance of monitoring it; (2) we describe the role of ecological indicators and ecosystem models in monitoring this ecosystem component; (3) we present a list of candidate ecological indicators that could be estimated to monitor this component; (4) we discuss the main challenges in monitoring this ecosystem component and indicator development; and finally (5), we draft a work plan to guide our future work. We invite the ICCAT community and others to contribute towards the development of ecological indicators and ecosystem models to monitor this ecosystem component. If interested, contact the corresponding authors to find out how you can contribute to this initiative

Best standards for data collection and reporting requirements on FOBs: towards a science-based FOB fishery management.

A major concern for tropical tunas, on these last years, has been the worldwide increasing use of drifting FOBs by purse seiners, which are equipped with satellite buoys and echo-sounders. The use of these floating objects has contributed to increase the catch of skipjack tuna, but also of juveniles of yellowfin and bigeye tunas. Moreover, it has increased the amount of by-catch (including some species classified as vulnerable or endangered) and has likely resulted in adverse effects on the ecology of fish and on vulnerable areas (e.g. beaching events on coral reef areas). Despite the increasing FOB use and concerns, little information is available on FOB use worldwide for an appropriate monitoring and management. Thus, FOB monitoring has become a priority in all tuna t-RFMOs. However, the data collection and reporting requirements around FOBs are not standardized and there are significant data gaps. The aim of this document is to review current requirements and procedures in place and propose standards for data collection and submission on FOBs to tRFMOs. The proposals included in this document are the result of a collaborative work between scientists and the fishing industry

Factors influencing terrestriality in primates of the Americas and Madagascar

Among mammals, the order Primates is exceptional in having a high taxonomic richness in which the taxa are arboreal, semiterrestrial, or terrestrial. Although habitual terrestriality is pervasive among the apes and African and Asian monkeys (catarrhines), it is largely absent among monkeys of the Americas (platyrrhines), as well as galagos, lemurs, and lorises (strepsirrhines), which are mostly arboreal. Numerous ecological drivers and species-specific factors are suggested to set the conditions for an evolutionary shift from arboreality to terrestriality, and current environmental conditions may provide analogous scenarios to those transitional periods. Therefore, we investigated predominantly arboreal, diurnal primate genera from the Americas and Madagascar that lack fully terrestrial taxa, to determine whether ecological drivers (habitat canopy cover, predation risk, maximum temperature, precipitation, primate species richness, human population density, and distance to roads) or species-specific traits (bodymass, group size, and degree of frugivory) associate with increased terrestriality. We collated 150,961 observation hours across 2,227 months from 47 species at 20 sites in Madagascar and 48 sites in the Americas. Multiple factors were associated with ground use in these otherwise arboreal species, including increased temperature, a decrease in canopy cover, a dietary shift away from frugivory, and larger group size. These factors mostly explain intraspecific differences in terrestriality. As humanity modifies habitats and causes climate change, our results suggest that species already inhabiting hot, sparsely canopied sites, and exhibiting more generalized diets, are more likely to shift toward greater ground use