Interval between prior SARS-CoV-2 infection and booster vaccination impacts magnitude and quality of antibody and B cell responses.

SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a 2-month period, we evaluated antibody and B cell responses to a third-dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies and memory B cells. Spike-specific B cell responses from recent infection (<180 days) were elevated at pre-boost but comparatively less so at 60 days post-boost compared with uninfected individuals, and these differences were linked to baseline frequencies of CD27lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B cell responses to booster vaccines are impeded by recent infection.

Emerging Pandemic Diseases: How We Got to COVID-19.

Infectious diseases prevalent in humans and animals are caused by pathogens that once emerged from other animal hosts. In addition to these established infections, new infectious diseases periodically emerge. In extreme cases they may cause pandemics such as COVID-19; in other cases, dead-end infections or smaller epidemics result. Established diseases may also re-emerge, for example by extending geographically or by becoming more transmissible or more pathogenic. Disease emergence reflects dynamic balances and imbalances, within complex globally distributed ecosystems comprising humans, animals, pathogens, and the environment. Understanding these variables is a necessary step in controlling future devastating disease emergences.

Proinflammatory IgG Fc structures in patients with severe COVID-19.

Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fcγ receptor FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1.

RNA vaccines: A transformational advance.

Vaccines have stemmed many infectious diseases, but when SARS-CoV-2 emerged, traditional vaccine development would not have been fast enough. This year's Nobel Prize in Physiology or Medicine recognizes work that enabled the rapid development of mRNA vaccines, which halted the COVID-19 pandemic. The feat was a product of basic biological insights coupled with technological innovations, which have transformed vaccine design.

From mRNA sensing to vaccines.

The 2005 Immunity paper by Karikó et al. has been hailed as a cornerstone insight that directly led to the design and delivery of the mRNA vaccines against COVID-19. We asked experts in pathogen sensing, vaccine development, and public health to provide their perspective on the study and its implications.

Country-specific net-zero strategies of the pulp and paper industry.

The pulp and paper industry is an important contributor to global greenhouse gas emissions1,2. Country-specific strategies are essential for the industry to achieve net-zero emissions by 2050, given its vast heterogeneities across countries3,4. Here we develop a comprehensive bottom-up assessment of net greenhouse gas emissions of the domestic paper-related sectors for 30 major countries from 1961 to 2019-about 3.2% of global anthropogenic greenhouse gas emissions from the same period5-and explore mitigation strategies through 2,160 scenarios covering key factors. Our results show substantial differences across countries in terms of historical emissions evolution trends and structure. All countries can achieve net-zero emissions for their pulp and paper industry by 2050, with a single measure for most developed countries and several measures for most developing countries. Except for energy-efficiency improvement and energy-system decarbonization, tropical developing countries with abundant forest resources should give priority to sustainable forest management, whereas other developing countries should pay more attention to enhancing methane capture rate and reducing recycling. These insights are crucial for developing net-zero strategies tailored to each country and achieving net-zero emissions by 2050 for the pulp and paper industry.

Suckling, Feeding, and Swallowing: Behaviors, Circuits, and Targets for Neurodevelopmental Pathology.

All mammals must suckle and swallow at birth, and subsequently chew and swallow solid foods, for optimal growth and health. These initially innate behaviors depend critically upon coordinated development of the mouth, tongue, pharynx, and larynx as well as the cranial nerves that control these structures. Disrupted suckling, feeding, and swallowing from birth onward-perinatal dysphagia-is often associated with several neurodevelopmental disorders that subsequently alter complex behaviors. Apparently, a broad range of neurodevelopmental pathologic mechanisms also target oropharyngeal and cranial nerve differentiation. These aberrant mechanisms, including altered patterning, progenitor specification, and neurite growth, prefigure dysphagia and may then compromise circuits for additional behavioral capacities. Thus, perinatal dysphagia may be an early indicator of disrupted genetic and developmental programs that compromise neural circuits and yield a broad range of behavioral deficits in neurodevelopmental disorders.

Combination anti-HIV antibodies provide sustained virological suppression.

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.

Long-Term Outcomes of Resynchronization-Defibrillation for Heart Failure.

BACKGROUND: The Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT) showed a greater benefit with respect to mortality at 5 years among patients who received cardiac-resynchronization therapy (CRT) than among those who received implantable cardioverter-defibrillators (ICDs). However, the effect of CRT on long-term survival is not known. METHODS: We randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more (or a paced QRS duration of 200 msec or more) to receive either an ICD alone or a CRT defibrillator (CRT-D). We assessed long-term outcomes among patients at the eight highest-enrolling participating sites. The primary outcome was death from any cause; the secondary outcome was a composite of death from any cause, heart transplantation, or implantation of a ventricular assist device. RESULTS: The trial enrolled 1798 patients, of whom 1050 were included in the long-term survival trial; the median duration of follow-up for the 1050 patients was 7.7 years (interquartile range, 3.9 to 12.8), and the median duration of follow-up for those who survived was 13.9 years (interquartile range, 12.8 to 15.7). Death occurred in 405 of 530 patients (76.4%) assigned to the ICD group and in 370 of 520 patients (71.2%) assigned to the CRT-D group. The time until death appeared to be longer for those assigned to receive a CRT-D than for those assigned to receive an ICD (acceleration factor, 0.80; 95% confidence interval, 0.69 to 0.92; P = 0.002). A secondary-outcome event occurred in 412 patients (77.7%) in the ICD group and in 392 (75.4%) in the CRT-D group. CONCLUSIONS: Among patients with a reduced ejection fraction, a widened QRS complex, and NYHA class II or III heart failure, the survival benefit associated with receipt of a CRT-D as compared with ICD appeared to be sustained during a median of nearly 14 years of follow-up. (RAFT ClinicalTrials.gov number, NCT00251251.).

HIV reservoirs as obstacles and opportunities for an HIV cure.

The persistence of HIV reservoirs remains a formidable obstacle to achieving sustained virologic remission in HIV-infected individuals after antiretroviral therapy (ART) is discontinued, even if plasma viremia has been successfully suppressed for prolonged periods of time. Numerous approaches aimed at eradicating the virus, as well as maintaining its prolonged suppression in the absence of ART, have had little success. A better understanding of the pathophysiologic nature of HIV reservoirs and the impact of various interventions on their persistence is essential for the development of successful therapeutic strategies against HIV or the long-term control of infection. Here, we discuss the persistent HIV reservoir as a barrier to cure as well as the current therapeutic strategies aimed at eliminating or controlling the virus in the absence of ART.

Evolution and Physiology of Amphibious Yeasts.

Since the emergence of the first fungi some 700 million years ago, unicellular yeast-like forms have emerged multiple times in independent lineages via convergent evolution. While tens to hundreds of millions of years separate the independent evolution of these unicellular organisms, they share remarkable phenotypic and metabolic similarities, and all have streamlined genomes. Yeasts occur in every aquatic environment yet examined. Many species are aquatic; perhaps most are amphibious. How these species have evolved to thrive in aquatic habitats is fundamental to understanding functions and evolutionary mechanisms in this unique group of fungi. Here we review the state of knowledge of the physiological and ecological diversity of amphibious yeasts and their key evolutionary adaptations enabling survival in aquatic habitats. We emphasize some genera previously thought to be exclusively terrestrial. Finally, we discuss the ability of many yeasts to survive in extreme habitats and how this might lend insight into ecological plasticity, including amphibious lifestyles.

The Pathway to a Universal Influenza Vaccine.

Development of a universal influenza vaccine is a research priority for the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. To facilitate this goal, we convened a workshop in Rockville, Maryland to identify knowledge gaps in influenza research and develop strategies to fill them.

Author Correction: A naturally occurring antiviral ribonucleotide encoded by the human genome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The researcher's guide to selecting biomarkers in mental health studies.

Clinical mental health researchers may understandably struggle with how to incorporate biological assessments in clinical research. The options are numerous and are described in a vast and complex body of literature. Here we provide guidelines to assist mental health researchers seeking to include biological measures in their studies. Apart from a focus on behavioral outcomes as measured via interviews or questionnaires, we advocate for a focus on biological pathways in clinical trials and epidemiological studies that may help clarify pathophysiology and mechanisms of action, delineate biological subgroups of participants, mediate treatment effects, and inform personalized treatment strategies. With this paper we aim to bridge the gap between clinical and biological mental health research by (1) discussing the clinical relevance, measurement reliability, and feasibility of relevant peripheral biomarkers; (2) addressing five types of biological tissues, namely blood, saliva, urine, stool and hair; and (3) providing information on how to control sources of measurement variability.

LPS-aggregating proteins GBP1 and GBP2 are each sufficient to enhance caspase-4 activation both in cellulo and in vitro.

The gamma-interferon (IFNγ)-inducible guanylate-binding proteins (GBPs) promote host defense against gram-negative cytosolic bacteria in part through the induction of an inflammatory cell death pathway called pyroptosis. To activate pyroptosis, GBPs facilitate sensing of the gram-negative bacterial outer membrane component lipopolysaccharide (LPS) by the noncanonical caspase-4 inflammasome. There are seven human GBP paralogs, and it is unclear how each GBP contributes to LPS sensing and pyroptosis induction. GBP1 forms a multimeric microcapsule on the surface of cytosolic bacteria through direct interactions with LPS. The GBP1 microcapsule recruits caspase-4 to bacteria, a process deemed essential for caspase-4 activation. In contrast to GBP1, closely related paralog GBP2 is unable to bind bacteria on its own but requires GBP1 for direct bacterial binding. Unexpectedly, we find that GBP2 overexpression can restore gram-negative-induced pyroptosis in GBP1KO cells, without GBP2 binding to the bacterial surface. A mutant of GBP1 that lacks the triple arginine motif required for microcapsule formation also rescues pyroptosis in GBP1KO cells, showing that binding to bacteria is dispensable for GBPs to promote pyroptosis. Instead, we find that GBP2, like GBP1, directly binds and aggregates "free" LPS through protein polymerization. We demonstrate that supplementation of either recombinant polymerized GBP1 or GBP2 to an in vitro reaction is sufficient to enhance LPS-induced caspase-4 activation. This provides a revised mechanistic framework for noncanonical inflammasome activation where GBP1 or GBP2 assembles cytosol-contaminating LPS into a protein-LPS interface for caspase-4 activation as part of a coordinated host response to gram-negative bacterial infections.

Increased neutralization potency and breadth elicited by a SARS-CoV-2 mRNA vaccine forming virus-like particles.

Vaccines have played a fundamental role in the control of infectious diseases. We previously developed a messenger RNA (mRNA) vaccine against HIV-1 that forms virus-like particles (VLPs) through coexpression of the viral envelope with Gag. Here, we applied the same principle to the design of a VLP-forming mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To promote cognate interaction with simian immunodeficiency virus (SIV) Gag, we engineered different chimeric proteins encompassing the ectodomain and the transmembrane region of the SARS-CoV-2 Spike protein from the Wuhan-Hu-1 strain fused to the gp41 cytoplasmic tail of either HIV-1 (strain WITO) or SIV (strain mac239) with or without a partial truncation at amino acid 745 to enhance membrane expression. Upon cotransfection with SIV gag mRNA, the Spike-SIVCT.745 (SSt) chimera yielded the highest level of cell-surface expression and extracellular VLP release. Immunization of BALB/c mice with SSt+gag mRNA at 0, 4, and 16 wk induced higher titers of Spike-binding and autologous neutralizing antibodies at all time points compared to SSt mRNA alone. Furthermore, mice immunized with SSt+gag mRNA developed neutralizing antibodies effective against different variants of concern. These data demonstrate that the Gag/VLP mRNA platform can be successfully applied to vaccines against different agents for the prevention of infectious diseases of global relevance.

Inflammasome-triggered IL-18 controls skin inflammation in the progression of Buruli ulcer.

Buruli ulcer is an emerging chronic infectious skin disease caused by Mycobacterium ulcerans. Mycolactone, an exotoxin produced by the bacterium, is the only identified virulence factor so far, but the functions of this toxin and the mechanisms of disease progression remain unclear. By interfering Sec61 translocon, mycolactone inhibits the Sec61-dependent co-translational translocation of newly synthesized proteins, such as induced cytokines and immune cell receptors, into the endoplasmic reticulum. However, in regard to IL-1ß, which is secreted by a Sec61-independent mechanism, mycolactone has been shown to induce IL-1ß secretion via activation of inflammasomes. In this study, we clarified that cytokine induction, including that of IL-1ß, in infected macrophages was suppressed by mycolactone produced by M. ulcerans subsp. shinshuense, despite the activation of caspase-1 through the inflammasome activation triggered in a manner independent of mycolactone. Intriguingly, mycolactone suppressed the expression of proIL-1ß as well as TNF-α at the transcriptional level, suggesting that mycolactone of M. ulcerans subsp. shinshuense may exert additional inhibitory effect on proIL-1ß expression. Remarkably, constitutively produced IL-18 was cleaved and mature IL-18 was actually released from macrophages infected with the causative mycobacterium. IL-18-deficient mice infected subcutaneously with M. ulcerans exhibited exacerbated skin inflammation during the course of disease progression. On the other hand, IL-1ß controls bacterial multiplication in skin tissues. These results provide information regarding the mechanisms and functions of the induced cytokines in the pathology of Buruli ulcer.

MAdCAM-1 costimulation in the presence of retinoic acid and TGF-ß promotes HIV infection and differentiation of CD4+ T cells into CCR5+ TRM-like cells.

CD4+ tissue resident memory T cells (TRMs) are implicated in the formation of persistent HIV reservoirs that are established during the very early stages of infection. The tissue-specific factors that direct T cells to establish tissue residency are not well defined, nor are the factors that establish viral latency. We report that costimulation via MAdCAM-1 and retinoic acid (RA), two constituents of gut tissues, together with TGF-ß, promote the differentiation of CD4+ T cells into a distinct subset α4ß7+CD69+CD103+ TRM-like cells. Among the costimulatory ligands we evaluated, MAdCAM-1 was unique in its capacity to upregulate both CCR5 and CCR9. MAdCAM-1 costimulation rendered cells susceptible to HIV infection. Differentiation of TRM-like cells was reduced by MAdCAM-1 antagonists developed to treat inflammatory bowel diseases. These finding provide a framework to better understand the contribution of CD4+ TRMs to persistent viral reservoirs and HIV pathogenesis.

HIV-AIDS: much accomplished, much to do.

As a result of decades of research-driven breakthroughs in basic and clinical science and recent advances in the broad-scale implementation of interventions for the prevention and treatment of infection with HIV, a turning point has been reached in the global HIV-AIDS pandemic. To end the pandemic and achieve the goal of an AIDS-free generation, researchers and clinicians must follow the dual pathway of optimizing the implementation of existing prevention and treatment interventions and discovering with basic and clinical research new and effective tools in both of these arenas.