Memory-Like Responses of Brain Microglia Are Controlled by Developmental State and Pathogen Dose

Microglia, the innate immune cells of the central nervous system, feature adaptive immune memory with implications for brain homeostasis and pathologies. However, factors involved in the emergence and regulation of these opposing responses in microglia have not been fully addressed. Recently, we showed that microglia from the newborn brain display features of trained immunity and immune tolerance after repeated contact with pathogens in a dose-dependent manner. Here, we evaluate the impact of developmental stage on adaptive immune responses of brain microglia after repeated challenge with ultra-low (1 fg/ml) and high (100 ng/ml) doses of the endotoxin LPS in vitro. We find that priming of naïve microglia derived from newborn but not mature and aged murine brain with ultra-low LPS significantly increased levels of pro-inflammatory mediators TNF-α, IL-6, IL-1β, MMP-9, and iNOS as well as neurotrophic factors indicating induction of trained immunity (p \u3c 0.05). In contrast, stimulation with high doses of LPS led to a robust downregulation of pro-inflammatory cytokines and iNOS independent of the developmental state, indicating induced immune tolerance. Furthermore, high-dose priming with LPS upregulated anti-inflammatory mediators IL-10, Arg-1, TGF- β, MSR1, and IL-4 in newborn microglia (p \u3c 0.05). Our data indicate pronounced plasticity of the immune response of neonate microglia compared with microglia derived from mature and aged mouse brain. Induced trained immunity after priming with ultra-low LPS doses may be responsible for enhanced neuro-inflammatory susceptibility of immature brain. In contrast, the immunosuppressed phenotype following high-dose LPS priming might be prone to attenuate excessive damage after recurrent systemic inflammation

PKA regulatory subunits mediate synergy among conserved G-protein-coupled receptor cascades

G-protein-coupled receptors sense extracellular chemical or physical stimuli and transmit these signals to distinct trimeric G-proteins. Activated Gα-proteins route signals to interconnected effector cascades, thus regulating thresholds, amplitudes and durations of signalling. Gαs- or Gαi-coupled receptor cascades are mechanistically conserved and mediate many sensory processes, including synaptic transmission, cell proliferation and chemotaxis. Here we show that a central, conserved component of Gαs-coupled receptor cascades, the regulatory subunit type-II (RII) of protein kinase A undergoes adenosine 3′-5′-cyclic monophosphate (cAMP)-dependent binding to Gαi. Stimulation of a mammalian Gαi-coupled receptor and concomitant cAMP-RII binding to Gαi, augments the sensitivity, amplitude and duration of Gαi:βγ activity and downstream mitogen-activated protein kinase signalling, independent of protein kinase A kinase activity. The mechanism is conserved in budding yeast, causing nutrient-dependent modulation of a pheromone response. These findings suggest a direct mechanism by which coincident activation of Gαs-coupled receptors controls the precision of adaptive responses of activated Gαi-coupled receptor cascades

Public health risk communication through the lens of a quarantined community: Insights from a coronavirus hotspot in Germany.

BackgroundQuarantine is one of the most effective interventions to contain an infectious disease outbreak, yet it is one of the most disruptive. We investigated the quarantine of an entire village to better understand risk communication requirements for groups.MethodsWe conducted a cross-sectional, mixed-methods survey study on a single cohort of adult residents in Neustadt am Rennsteig, Germany, six weeks after the removal of a 14-day mandatory community quarantine. The survey response rate was 33% (289/883 residents).FindingsSurvey participants reported a lack of information on the quarantine implementation process. What authorities communicated was not necessarily what residents desired to know. While inhabitants used social media and telephones to communicate with each other, the official information sources were regional radio, television, newspapers and official websites. Public health authorities did not employ social media communication to engage with their communities. Despite a lack of information, the majority of respondents stated that they had complied with the quarantine and they expressed little sympathy for those who violated the quarantine. After lifting the quarantine, many respondents continued to avoid places where they suspected a significant risk of infection, such as family and friends' homes, doctor's offices and grocery stores.InterpretationThe survey participants utilised existing social networks to disseminate vital information and stabilise its group identity and behaviour (quarantine compliance). The authorities communicated sparsely in a unidirectional, top-down manner, without engaging the community. Despite the lack of official information, the social coherency of the group contributed to considerate and compliant conduct, but participants expressed dissatisfaction with official leadership and asked for more attention.ConclusionPublic health risk communication must engage with communities more effectively. This necessitates a deeper comprehension of groups, their modes of communication and their social needs

Persistent avoidance of places and people.

BackgroundQuarantine is one of the most effective interventions to contain an infectious disease outbreak, yet it is one of the most disruptive. We investigated the quarantine of an entire village to better understand risk communication requirements for groups.MethodsWe conducted a cross-sectional, mixed-methods survey study on a single cohort of adult residents in Neustadt am Rennsteig, Germany, six weeks after the removal of a 14-day mandatory community quarantine. The survey response rate was 33% (289/883 residents).FindingsSurvey participants reported a lack of information on the quarantine implementation process. What authorities communicated was not necessarily what residents desired to know. While inhabitants used social media and telephones to communicate with each other, the official information sources were regional radio, television, newspapers and official websites. Public health authorities did not employ social media communication to engage with their communities. Despite a lack of information, the majority of respondents stated that they had complied with the quarantine and they expressed little sympathy for those who violated the quarantine. After lifting the quarantine, many respondents continued to avoid places where they suspected a significant risk of infection, such as family and friends’ homes, doctor’s offices and grocery stores.InterpretationThe survey participants utilised existing social networks to disseminate vital information and stabilise its group identity and behaviour (quarantine compliance). The authorities communicated sparsely in a unidirectional, top-down manner, without engaging the community. Despite the lack of official information, the social coherency of the group contributed to considerate and compliant conduct, but participants expressed dissatisfaction with official leadership and asked for more attention.ConclusionPublic health risk communication must engage with communities more effectively. This necessitates a deeper comprehension of groups, their modes of communication and their social needs.</div

Reasons given for quarantine non-compliance.

BackgroundQuarantine is one of the most effective interventions to contain an infectious disease outbreak, yet it is one of the most disruptive. We investigated the quarantine of an entire village to better understand risk communication requirements for groups.MethodsWe conducted a cross-sectional, mixed-methods survey study on a single cohort of adult residents in Neustadt am Rennsteig, Germany, six weeks after the removal of a 14-day mandatory community quarantine. The survey response rate was 33% (289/883 residents).FindingsSurvey participants reported a lack of information on the quarantine implementation process. What authorities communicated was not necessarily what residents desired to know. While inhabitants used social media and telephones to communicate with each other, the official information sources were regional radio, television, newspapers and official websites. Public health authorities did not employ social media communication to engage with their communities. Despite a lack of information, the majority of respondents stated that they had complied with the quarantine and they expressed little sympathy for those who violated the quarantine. After lifting the quarantine, many respondents continued to avoid places where they suspected a significant risk of infection, such as family and friends’ homes, doctor’s offices and grocery stores.InterpretationThe survey participants utilised existing social networks to disseminate vital information and stabilise its group identity and behaviour (quarantine compliance). The authorities communicated sparsely in a unidirectional, top-down manner, without engaging the community. Despite the lack of official information, the social coherency of the group contributed to considerate and compliant conduct, but participants expressed dissatisfaction with official leadership and asked for more attention.ConclusionPublic health risk communication must engage with communities more effectively. This necessitates a deeper comprehension of groups, their modes of communication and their social needs.</div

Recommended topics to communicate during quarantine.

Recommended topics to communicate during quarantine.</p

Information needs of participants.

BackgroundQuarantine is one of the most effective interventions to contain an infectious disease outbreak, yet it is one of the most disruptive. We investigated the quarantine of an entire village to better understand risk communication requirements for groups.MethodsWe conducted a cross-sectional, mixed-methods survey study on a single cohort of adult residents in Neustadt am Rennsteig, Germany, six weeks after the removal of a 14-day mandatory community quarantine. The survey response rate was 33% (289/883 residents).FindingsSurvey participants reported a lack of information on the quarantine implementation process. What authorities communicated was not necessarily what residents desired to know. While inhabitants used social media and telephones to communicate with each other, the official information sources were regional radio, television, newspapers and official websites. Public health authorities did not employ social media communication to engage with their communities. Despite a lack of information, the majority of respondents stated that they had complied with the quarantine and they expressed little sympathy for those who violated the quarantine. After lifting the quarantine, many respondents continued to avoid places where they suspected a significant risk of infection, such as family and friends’ homes, doctor’s offices and grocery stores.InterpretationThe survey participants utilised existing social networks to disseminate vital information and stabilise its group identity and behaviour (quarantine compliance). The authorities communicated sparsely in a unidirectional, top-down manner, without engaging the community. Despite the lack of official information, the social coherency of the group contributed to considerate and compliant conduct, but participants expressed dissatisfaction with official leadership and asked for more attention.ConclusionPublic health risk communication must engage with communities more effectively. This necessitates a deeper comprehension of groups, their modes of communication and their social needs.</div

S1 File -

BackgroundQuarantine is one of the most effective interventions to contain an infectious disease outbreak, yet it is one of the most disruptive. We investigated the quarantine of an entire village to better understand risk communication requirements for groups.MethodsWe conducted a cross-sectional, mixed-methods survey study on a single cohort of adult residents in Neustadt am Rennsteig, Germany, six weeks after the removal of a 14-day mandatory community quarantine. The survey response rate was 33% (289/883 residents).FindingsSurvey participants reported a lack of information on the quarantine implementation process. What authorities communicated was not necessarily what residents desired to know. While inhabitants used social media and telephones to communicate with each other, the official information sources were regional radio, television, newspapers and official websites. Public health authorities did not employ social media communication to engage with their communities. Despite a lack of information, the majority of respondents stated that they had complied with the quarantine and they expressed little sympathy for those who violated the quarantine. After lifting the quarantine, many respondents continued to avoid places where they suspected a significant risk of infection, such as family and friends’ homes, doctor’s offices and grocery stores.InterpretationThe survey participants utilised existing social networks to disseminate vital information and stabilise its group identity and behaviour (quarantine compliance). The authorities communicated sparsely in a unidirectional, top-down manner, without engaging the community. Despite the lack of official information, the social coherency of the group contributed to considerate and compliant conduct, but participants expressed dissatisfaction with official leadership and asked for more attention.ConclusionPublic health risk communication must engage with communities more effectively. This necessitates a deeper comprehension of groups, their modes of communication and their social needs.</div