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The aim of candidate universal influenza vaccines is to provide broad protection against influenza A and B viruses. Studies have demonstrated that broadly reactive antibodies require Fc–Fc gamma receptor interactions for optimal protection; however, the innate effector cells responsible for mediating this protection remain largely unknown. Here, we examine the roles of alveolar macrophages, natural killer cells, and neutrophils in antibody-mediated protection. We demonstrate that alveolar macrophages play a dominant role in conferring protection provided by both broadly neutralizing and non-neutralizing antibodies in mice. Our data also reveal the potential mechanisms by which alveolar macrophages mediate protection in vivo, namely antibody-induced inflammation and antibody-dependent cellular phagocytosis. This study highlights the importance of innate effector cells in establishing a broad-spectrum antiviral state, as well as providing a better understanding of how multiple arms of the immune system cooperate to achieve an optimal antiviral response following influenza virus infection or immunization. Broadly reactive antibodies that recognize influenza A virus HA can be protective, but the mechanism is not completely understood. Here, He et al. show that the inflammatory response and phagocytosis mediated by the interaction between protective antibodies and macrophages are essential for protection.

Purpose: Suicidal ideation and attempts in youth are a growing health concern, and more data are needed regarding their biological underpinnings. Asthma is a common chronic inflammatory disorder in youth and has been associated with suicidal ideation and attempts in adolescent and adult populations, but data in younger children and early adolescents are lacking. We wished to study associations of asthma with childhood suicidality considering asthma’s potential as a clinically relevant model for childhood chronic immune dysregulation. Methods: Using data from the Adolescent Brain Cognitive Development (ABCD) Study (n = 11,876, 47.8% female, mean age 9.9 years at baseline assessment and 12.0 years at two-year follow-up), we assessed associations between asthma and suicidal ideation and attempts through baseline to two-year follow-up. Results: Asthma history as defined by parent report (n = 2282, 19.2% of study population) was associated with suicide attempts (SA) (odds ratio (OR) = 1.44, p = 0.01), and this association remained significant even when controlling for demographics, socioeconomic factors, and environmental factors (OR = 1.46, p = 0.028). History of asthma attacks was associated with both suicidal ideation (SI) and SA when controlling for demographics, socioeconomic factors, and environmental factors (OR = 1.27, p = 0.042; OR = 1.83, p = 0.004, respectively). The association of asthma attack with SA remained significant when controlling for self-reported psychopathology (OR = 1.92, p = 0.004). The total number of asthma attacks was associated with both SI and SA (OR = 1.03, p = 0.043; OR = 1.06, p = 0.05, respectively). Conclusions: Findings suggest an association between asthma and suicidality in early adolescence. Further research is needed to investigate mechanisms underlying this relationship.

ABSTRACT West Nile virus (WNV) infection outcomes vary among individuals, with most infections resulting in asymptomatic or mild flu-like symptoms. We previously reported an association between early cytokine production and symptom outcome following WNV infection in US blood donors. In this meta-analysis, we found that WNV-infected females reported more symptoms than WNV-infected males, despite similar initial viremia and type I interferon responses. As the infection progressed, males exhibited a protracted cytokine response—marked by sustained CCL2 (MCP-1), CCL11 (eotaxin-1), CXCL10 (IP-10) and IL-15—that was absent in females. Our results suggest that sex differences may be a factor in sustaining WNV immunity. Sex may play a role in regulating the host cytokine response to West Nile virus infection in humans.

Adolescent depression rates increased during the COVID-19 pandemic globally. Data on risk and resilience factors can inform prevention and intervention strategies during a major adversity. To characterize depression symptom trajectories from before, during, and after the lockdown stages of the pandemic and to identify prospective risk and resilience factors. This cohort study followed participants from the Adolescent Brain Cognitive Development Study ascertained through 21 sites across the US from before March 2020 to February 2022. The design and hypotheses were preregistered in March 2024. Analyses were conducted from April to November 2024. Prepandemic risk and resilience factors spanning developmental stage, household environment, peer relationships, and depression polygenic risk. The primary outcome was depression-susceptible symptom trajectory of low prepandemic and high postpandemic symptoms. Trajectories of depression symptom score (6 symptoms: depressed mood, anhedonia, guilt or worthlessness, fatigue, sleep, and concentration impairments) were modeled using logistic regression models with prepandemic factors (independent variables) explaining trajectory class (dependent variable; resilient, 0; depression susceptible, 1), adjusting for sex and age at the pandemic onset. In the sample of 3512 participants included in the analyses (mean [SD] age in March 2020, 12.05 [0.85] years; 1672 [47.6%] female), a 3-class trajectory model identified resilient (low symptoms throughout follow-up, 3027 participants [86.2%]), depression-susceptible (low symptoms before the pandemic and high symptoms after the pandemic, 326 participants [9.3%]), and chronically high (159 participants [4.5%]) symptom trajectory classes. Girls were overrepresented in the depression-susceptible vs the resilient group (240 girls [73.6%] vs 1327 girls [43.8%]). The depression-susceptible trajectory, compared with the resilient trajectory, was associated with late pubertal or postpubertal stage before the pandemic (odds ratio [OR], 1.46; 95% CI, 1.08-1.96; P = .01), prepandemic family conflict (OR, 1.23; 95% CI, 1.10-1.38; P < .001), peer bullying (OR, 1.71; 95% CI, 1.11-2.65; P = .02), cyberbullying (OR, 2.28; 95% CI, 1.45-3.59; P < .001), maternal history of depression (OR, 1.52; 95% CI, 1.16-1.99; P = .002), polyenvironmental adversity exposure (OR, 1.28; 95% CI, 1.13-1.45; P < .001), and polygenic risk of depression (OR, 1.28; 95% CI, 1.03-1.59; P = .02 among those of European-like genetic ancestry, but not those of African-like ancestry). Greater prepandemic parental monitoring (OR, 0.81; 95% CI, 0.73-0.91; P < .001) and problem-solving skills (OR, 0.80; 95% CI, 0.66-0.97; P = .02) were associated with lower depression susceptibility. In this cohort study of adolescent depression trajectories throughout COVID-19, girls, teens in later puberty, and those with experiences of peer bullying, cyberbullying, and greater family conflict before the pandemic were more susceptible to developing depressive symptoms that persisted after the pandemic, whereas prepandemic parental monitoring and problem-solving skills were identified as prospective modifiable resilience factors.

Background. West Nile virus (WNV) is an emerging cause of meningitis and encephalitis in the United States. Although severe neuroinvasive disease and death can occur in rare instances, the majority of infected individuals remain asymptomatic or present with a range of clinical manifestations associated with West Nile fever. Methods. To better understand the interindividual variability associated with the majority of WNV infections, we evaluated the association of cytokine/chemokine production and outcome of infection among 115 WNV-positive US blood donors identified in 2008-2011. All subjects self-reported symptoms as having occurred during the 2 weeks following blood donation, using a standardized questionnaire. Results. We discovered that, prior to seroconversion, an early potent, largely type I interferon-mediated response correlated with development of a greater number of symptoms in WNV-infected individuals. Interestingly, individuals who developed fewer symptoms had not only a more modest type I interferon response initially, but also a protracted cytokine response after seroconversion, marked by the production of monocyte and T-cell-associated chemokines. Conclusions. Collectively, our data suggest that, although an early type I interferon response appears to be crucial to control WNV infection, successful immunity may require a modest early response that is maintained during the course of infection.

Allostatic load (AL) is the cumulative ‘wear and tear’ on the body due to chronic adversity. We tested the poly-environmental (exposomic) and polygenic contributions to AL and their combined contribution to adolescent mental health. In this cohort study of N = 5,036 diverse youth (mean age 12 years) from the Adolescent Brain Cognitive Development Study, we calculated a latent AL score, childhood exposomic risk and genetic risk. We tested the associations of exposomic and polygenic risks with AL using linear mixed-effects models, and tested the mediating role of AL on the pathway from exposomic/polygenic risk to mental health. AL was significantly lower among non-Hispanic white youth compared to Hispanic and non-Hispanic black youth. Childhood exposomic burden was associated with AL in adolescence (β = 0.25, 95% CI 0.22–0.29, P < 0.001). In subset analysis of participants of European-like genetic ancestry (n = 2,928), the type 2 diabetes polygenic risk score (T2D-PRS; β = 0.11, 95% CI 0.07–0.14, P < 0.001) and major depressive disorder (MDD)-PRS (β = 0.05, 95% CI 0.02–0.09, P = 0.003) were associated with AL. Both PRSs showed significant gene–environment interactions such that, with greater polygenic risk, associations between exposome and AL were stronger. AL significantly mediated the indirect path from exposomic risk at age 11 years, and from both MDD-PRS and T2D-PRS to psychopathology at age 12 years. Our findings show that AL can be quantified in youth and is associated with exposomic and polygenic burden, supporting the diathesis–stress model.Using a large US cohort of adolescents, the authors examine exposomic and polygenic contributions to allostatic load and a mediating role of allostatic load on the path from exposomic and polygenic risks to psychopathology.

West Nile virus (WNV) is a mosquito-transmitted flavivirus that is the leading cause of epidemic encephalitis in the United States. Currently there are no vaccines or specific antiviral therapies available for WNV in humans, and thus understanding viral pathogenesis is an important research goal. Following infection through a mosquito bite, the draining lymph node is one of the earliest sites of viral replication. However, very little is known about the early immune events that occur in the draining lymph node and how these early events might shape disease outcomes in humans. We hypothesize that early infection in the draining lymph node and the subsequent host inflammatory response impact WNV pathogenesis in humans. To address this hypothesis, we 1) established an ex vivo model of WNV infection using whole human lymph nodes, and 2) studied the inflammatory response to WNV in blood donors identified very early following infection. In human lymph nodes infected with WNV ex vivo, we found that WNV infection induces a strong T cell and myeloid associated cytokine response, with stronger cytokine network induction by neuroinvasive compared to non-neuroinvasive strains of WNV (Chapter 2). We also sought to identify the WNV-infected cells in human lymph nodes, which have not yet been identified. Using immunofluorescent co-staining techniques as well as cell-type restricted WNV strains, we identified T cells as the primary WNV-infected cell type in the lymph node (Chapter 3). By evaluating the cytokines/chemokines produced in a cohort of WNV infected blood donors, we found that early immune responses differed between individuals who remained asymptomatic versus those who developed symptoms, with WNV-infected individuals with better outcomes having a sustained immune response (Chapter 4). Taken together, our findings show that early infection events involving T cell and myeloid mediated responses are important in shaping the course of WNV pathogenesis in humans.

HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated pro-inflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. A human ex vivo human tonsil histo-culture infection model was developed to support HIV-1 productive infection and stimulated inflammatory cytokine interleukin-1 beta (IL-1 ) and immunosuppressive cytokine, interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. The purinergic P2X1 receptor antagonist, NF449, the purinergic P2X7 receptor antagonists, A438079, and azidothymidine (AZT) were tested in HIV-1 infected human tonsil explants to compare inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection but P2X-selective antagonists (NF449, and A438079) significantly lowered HIV-stimulated IL-10 and IL-1 . We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood as compared to lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.

HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated pro-inflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. A human ex vivo human tonsil histo-culture infection model was developed to support HIV-1 productive infection and stimulated inflammatory cytokine interleukin-1 beta (IL-1β) and immunosuppressive cytokine, interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. The purinergic P2X1 receptor antagonist, NF449, the purinergic P2X7 receptor antagonists, A438079, and azidothymidine (AZT) were tested in HIV-1 infected human tonsil explants to compare inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection but P2X-selective antagonists (NF449, and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood as compared to lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation. Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here we describe a class of drugs that target the P2X pro-inflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to both block HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.

1. Plant traits can provide unique insights into plant performance at the community scale. Functional composition, defined by both functional diversity and community-weighted trait means (CWMs), can affect the stability of above-ground net primary production (ANPP) in response to climate extremes. Further complexity arises, however, when functional composition itself responds to environmental change. The duration of climate extremes, such as drought, is expected to increase with rising global temperatures; thus, understanding the impacts of long-term drought on functional composition and the corresponding effect that has on ecosystem function could improve predictions of ecosystem sensitivity to climate change. 2. We experimentally reduced growing season precipitation by 66% across six temperate grasslands for 4 years and measured changes in three indices of functional diversity (functional dispersion, richness and evenness), community-weighted trait means and phylogenetic diversity (PD). Specific leaf area (SLA), leaf nitrogen content (LNC) and (at most sites) leaf turgor loss point (πTLP) were measured for species cumulatively representing ~90% plant cover at each site. 3. Long-term drought led to increased community functional dispersion in three sites, with negligible effects on the remaining sites. Species re-ordering following the mortality/senescence of dominant species was the main driver of increased functional dispersion. The response of functional diversity was not consistently matched by changes in phylogenetic diversity. Community-level drought strategies (assessed as CWMs) largely shifted from drought tolerance to drought avoidance and/or escape strategies, as evidenced by higher community-weighted , πTLP, SLA and LNC. Lastly, ecosystem drought sensitivity (i.e. relative reduction in ANPP in drought plots) was positively correlated with community-weighted SLA and negatively correlated with functional diversity. 4. Synthesis. Increased functional diversity following long-term drought may stabilize ecosystem functioning in response to future drought. However, shifts in community-scale drought strategies may increase ecosystem drought sensitivity, depending on the nature and timing of drought. Thus, our results highlight the importance of considering both functional diversity and abundance-weighted traits means of plant communities as their collective effect may either stabilize or enhance ecosystem sensitivity to drought.