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Respiratory syncytial virus (RSV) is among the most common causes of lower respiratory tract infection (LRTI) and hospitalization in infants. However, the mechanisms of immune control in infants remain incompletely understood. Antibody profiling against attachment (G) and fusion (F) proteins in children less than 2 years of age, with mild (outpatients) or severe (inpatients) RSV disease, indicated substantial age-dependent differences in RSV-specific immunity. Maternal antibodies were detectable for the first 3 months of life, followed by a long window of immune vulnerability between 3 and 6 months and a rapid evolution of FcγR-recruiting immunity after 6 months of age. Acutely ill hospitalized children exhibited lower G-specific antibodies compared with healthy controls. With disease resolution, RSV-infected infants generated broad functional RSV strain-specific G-responses and evolved cross-reactive F-responses, with minimal maternal imprinting. These data suggest an age-independent RSV G-specific functional humoral correlate of protection, and the evolution of RSV F-specific functional immunity with disease resolution.
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Anticuerpos Antivirales , Reacciones Cruzadas , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Humanos , Infecciones por Virus Sincitial Respiratorio/inmunología , Lactante , Anticuerpos Antivirales/inmunología , Reacciones Cruzadas/inmunología , Virus Sincitial Respiratorio Humano/inmunología , Femenino , Inmunidad Humoral/inmunología , Proteínas Virales de Fusión/inmunología , Estudios Longitudinales , Masculino , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Recién Nacido , Inmunidad Materno-AdquiridaRESUMEN
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a global health burden. While Mtb is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that leads to differential disease across organs. Attention has focused on differences in T cell responses in the control of Mtb in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood brain barrier, here we characterized the antibody profiles across the blood and brain compartments during TBM, and determined whether Mtb-specific humoral immune responses differed between Mtb infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different Mtb antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n=10) vs TBM (n=60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4), the capacity of Mtb-specific antibodies to bind to Fc receptors or C1q, and to activate innate immune effectors functions (complement and NK cells activation, monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against Mtb, characterized by an enrichment of Mtb-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited Mtb-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared to individuals with pulmonary TB, despite having lower IgG titers and Fcγ receptors (FcγR)-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs vs brain), and demonstrate a highly compartmentalized Mtb-specific antibody response within the CSF during TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease.
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Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the CNS, can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations and persistence of SARS-CoV-2 reservoirs. In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common coronaviruses: 229E, HKU1, NL63 and OC43) in the serum and CSF from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC compared with serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2, IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM). These data argue in favour of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected. Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 versus 66.5 years, respectively, P = 0.55; females 33% versus 44%, P = 0.52) but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common coronaviruses, including 229E, HKU1, NL63 and OC43. This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an 'original antigenic sin' (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to the current infection, as a key prognostic marker of neuroPASC disease. Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.
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COVID-19 , Femenino , Humanos , Anciano , SARS-CoV-2 , Síndrome Post Agudo de COVID-19 , Estudios Prospectivos , Inmunoglobulina G , Inmunoglobulina MRESUMEN
Molecular catch bonds are ubiquitous in biology and essential for processes like leucocyte extravasion1 and cellular mechanosensing2. Unlike normal (slip) bonds, catch bonds strengthen under tension. The current paradigm is that this feature provides 'strength on demand3', thus enabling cells to increase rigidity under stress1,4-6. However, catch bonds are often weaker than slip bonds because they have cryptic binding sites that are usually buried7,8. Here we show that catch bonds render reconstituted cytoskeletal actin networks stronger than slip bonds, even though the individual bonds are weaker. Simulations show that slip bonds remain trapped in stress-free areas, whereas weak binding allows catch bonds to mitigate crack initiation by moving to high-tension areas. This 'dissociation on demand' explains how cells combine mechanical strength with the adaptability required for shape change, and is relevant to diseases where catch bonding is compromised7,9, including focal segmental glomerulosclerosis10 caused by the α-actinin-4 mutant studied here. We surmise that catch bonds are the key to create life-like materials.
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Actinas , Unión ProteicaRESUMEN
Cells require mechanical forces for their physiological functions. The forces are generated mainly from molecular interactions between actin filaments, cross-linking proteins, and myosin motors in the actin cytoskeleton. To better understand the molecular interactions, many studies employed myosin motility assays with actin filaments propelled by myosin heads fixed on a surface. Various interesting behaviors of actin filaments have been observed in the motility assay experiments. Despite the popularity of the motility assays, there were only a few computational models designed for simulating the motility assay systems. Most of the previous models have limitations which precluded full understanding of molecular origins for behaviors of actin filaments. In this study, we used an agent-based computational model based on Brownian dynamics for simulating the motility assay system. Our model rigorously describes the mechanics, dynamics, and interactions of actin filaments, cross-linking proteins, and molecular motors. Using the model, we first investigated how properties of actin filaments and motors affect gliding motions of actin filaments without volume-exclusion effects as a base study. We found that actin filaments can continuously glide at relative fast speed only when they are sufficiently longer than the average spacing between neighboring motors and that the gliding speed of F-actins shows a biphasic dependence on processivity of motors. Then, we showed that volume-exclusion effects between actin filaments can induce diverse collective movements and alignment of actin filaments, thus creating thick bundles and ring-like structures in the absence of cross-linking proteins. Lastly, we demonstrated that cross-linking proteins can lead to distinct contractile behaviors of actin networks depending on the density and kinetics of the cross-linking proteins. Results from our study show the ability of our model to simulate the motility assay system under various conditions and provide insights into understanding of different behaviors of actin filaments.
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Citoesqueleto de Actina/química , Modelos Teóricos , Movimiento (Física) , Miosinas/químicaRESUMEN
Mechanical forces play an important role in various physiological processes, such as morphogenesis, cytokinesis, and migration. Thus, in order to illuminate mechanisms underlying these physiological processes, it is crucial to understand how cells deform and respond to external mechanical stimuli. During recent decades, the mechanical properties of cells have been studied extensively using diverse measurement techniques. A number of experimental studies have shown that cells are far from linear elastic materials. Cells exhibit a wide variety of nonlinear elastic and inelastic properties. Such complicated properties of cells are known to emerge from unique mechanical characteristics of cellular components. In this review, we introduce major cellular components that largely govern cell mechanical properties and provide brief explanations of several experimental techniques used for rheological measurements of cell mechanics. Then, we discuss the representative nonlinear elastic and inelastic properties of cells. Finally, continuum and discrete computational models of cell mechanics, which model both nonlinear elastic and inelastic properties of cells, will be described.
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Citoesqueleto , Elasticidad , Fenómenos Mecánicos , Mecanotransducción Celular , Microscopía de Fuerza AtómicaRESUMEN
Cells assemble numerous types of actomyosin bundles that generate contractile forces for biological processes, such as cytokinesis and cell migration. One example of contractile bundles is a transverse arc that forms via actomyosin-driven condensation of actin filaments in the lamellipodia of migrating cells and exerts significant forces on the surrounding environments. Structural reorganization of a network into a bundle facilitated by actomyosin contractility is a physiologically relevant and biophysically interesting process. Nevertheless, it remains elusive how actin filaments are reoriented, buckled, and bundled as well as undergo tension buildup during the structural reorganization. In this study, using an agent-based computational model, we demonstrated how the interplay between the density of myosin motors and cross-linking proteins and the rigidity, initial orientation, and turnover of actin filaments regulates the morphological transformation of a cross-linked actomyosin network into a bundle and the buildup of tension occurring during the transformation.
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Citoesqueleto de Actina/fisiología , Actomiosina/fisiología , Proteínas del Citoesqueleto/fisiología , Modelos Biológicos , Proteínas Motoras Moleculares/fisiología , Morfogénesis/fisiología , Citoesqueleto de Actina/ultraestructura , Animales , Simulación por Computador , Citoesqueleto/fisiología , Citoesqueleto/ultraestructura , Módulo de Elasticidad/fisiología , Humanos , Mecanotransducción Celular/fisiología , Estrés MecánicoRESUMEN
Mechanical forces play a crucial role in diverse physiological processes, such as cell migration, cytokinesis, and morphogenesis. The actin cytoskeleton generates a large fraction of the mechanical forces via molecular interactions between actin filaments (F-actins) and myosin motors. Recent studies have shown that the common tendency of actomyosin networks to contract into a smaller structure deeply involves F-actin buckling induced by motor activities, fragmentation of F-actins, and the force-dependent unbinding of cross-linkers that inter-connect F-actins. The fragmentation of F-actins was shown to originate from either buckling or tensile force from previous single-molecule experiments. While the role of buckling in network contraction has been studied extensively, to date, the role of tension-induced F-actin fragmentation in network contraction has not been investigated. In this study, we employed in vitro experiments and an agent-based computational model to illuminate when and how the tension-induced F-actin fragmentation facilitates network contraction. Our experiments demonstrated that F-actins can be fragmented due to tensile forces, immediately followed by catastrophic rupture and contraction of networks. Using the agent-based model, we showed that F-actin fragmentation by tension results in distinct rupture dynamics different from that observed in networks only with cross-linker unbinding. Moreover, we found that tension-induced F-actin fragmentation is particularly important for the contraction of networks with high connectivity. Results from our study shed light on an important regulator of the contraction of actomyosin networks which has been neglected. In addition, our results provide insights into the rupture mechanisms of polymeric network structures and bio-inspired materials.
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Antibodies represent a primary mediator of protection against respiratory viruses such as SARS-CoV-2. Serum neutralizing antibodies (NAbs) are often considered a primary correlate of protection. However, detailed antibody profiles including characterization of antibody functions in different anatomic compartments are not well understood. Here we show that antibody correlates of protection against SARS-CoV-2 challenge are different in systemic versus mucosal compartments in rhesus macaques. In serum, neutralizing antibodies were the strongest correlate of protection and were linked to Spike-specific binding antibodies and other extra-neutralizing antibody functions that create a larger protective network. In contrast, in bronchiolar lavage (BAL), antibody-dependent cellular phagocytosis (ADCP) proved the strongest correlate of protection rather than NAbs. Within BAL, ADCP was linked to mucosal Spike-specific IgG, IgA/secretory IgA, and Fcγ-receptor binding antibodies. Our results support a model in which antibodies with different functions mediate protection at different anatomic sites. The correlation of ADCP and other Fc functional antibody responses with protection in BAL suggests that these antibody responses may be critical for protection against SARS-CoV-2 Omicron challenge in mucosa.
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With the continued emergence of variants of concern, the global threat of COVID-19 persists, particularly in low- and middle-income countries with limited vaccine access. Protein-based vaccines, such as SCB-2019, can be produced on a large scale at a low cost while antigen design and adjuvant use can modulate efficacy and safety. While effective humoral immunity against SARS-CoV-2 variants has been shown to depend on both neutralization and Fc-mediated immunity, data on the effectiveness of protein-based vaccines with enhanced Fc-mediated immunity is limited. Here, we assess the humoral profile, including antibody isotypes, subclasses, and Fc receptor binding generated by a boosting with a recombinant trimer-tag protein vaccine SCB-2019. Individuals who were primed with 2 doses of the ChAdOx1 vaccine were equally divided into 4 groups and boosted with following formulations: Group 1: 9 µg SCB-2019 and Alhydrogel; Group 2: 9 µg SCB-2019, CpG 1018, and Alhydrogel; Group 3: 30 µg SCB-2019, CpG 1018, and Alhydrogel; Group 4: ChAdOx1. Group 3 showed enhanced antibody FcγR binding against wild-type and variants compared to Groups 1 and 2, showing a dose-dependent enhancement of immunity conferred by the SCB-2019 vaccine. Moreover, from day 15 after vaccination, Group 3 exhibited higher IgG3 and FcγR binding across variants of concerns, including Omicron and its subvariants, compared to the ChAdOx1-boosted individuals. Overall, this highlights the potential of SCB-2019 as a cost-efficient boosting regimen effective across variants of concerns.
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Actomyosin contractility originating from interactions between F-actin and myosin motors in the actin cytoskeleton generates mechanical forces and drives a wide range of cellular processes including cell migration and cytokinesis. To probe the interactions between F-actin and myosin motors, the myosin motility assay has been popularly employed, which consists of myosin heads attached to a glass surface and F-actins gliding on the surface via interactions with the heads. Several experiments have shown that F-actins move in a collective fashion due to volume-exclusion effects between neighboring F-actins. Furthermore, Computational models have shown how changes in key parameters lead to diverse pattern formation in motility assay. However, in most of the computational models, myosin motors were implicitly considered by applying a constant propulsion force to filaments to reduce computational cost. This simplification limits the physiological relevance of the insights provided by the models and potentially leads to artifacts. In this study, we employed an agent-based computational model for the motility assay with explicit immobile motors interacting with filaments. We rigorously account for the kinetics of myosin motors including the force-velocity relationship for walking and the binding and unbinding behaviors. We probed the effects of the length, rigidity, and concentration of filaments and repulsive strength on collective movements and pattern formation. It was found that four distinct types of structures-homogeneous networks, flocks, bands, and rings-emerged as a result of collisions between gliding filaments. We further analyzed the frequency and morphology of these structures and the curvature, alignment, and rotational motions of filaments. Our study provides better insights into the origin and properties of patterns formed by gliding filaments beyond what was shown before.
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The matrix (M) protein of rhabdoviruses locates between the inner line of the viral envelope and the nucleocapsids core and plays an important role in viral replication. In the present study, we aimed to rescue a mutant of VHSV genotype IVa that has artificial mutations in the M protein (M-D62A E181A). However, most rescued recombinant viruses unexpectedly showed non-targeted secondary mutations in the M protein. Therefore, this study was conducted to know whether the targeted artificial mutation can lead to specific non-targeted secondary mutations in the M protein and whether the secondary mutations are compensatory for the targeted artificial mutations. Experiments were conducted to rescue three kinds of M protein mutants (rVHSV-M-D62A, -E181A, and -D62A E181A), and rVHSV-M-E181A and rVHSV-M-D62A E181A without the secondary mutations were rescued only from IRF-9 gene-knockout EPC cells. Recombinant VHSVs having only targeted mutation(s) (rVHSV-M-D62A, -E181A, and -D62A E181A) showed slower CPE progression and retarded growth compared to rVHSV-wild. Although the sites of secondary mutations were changed in every transfection experiment to generate recombinant VHSVs, the positions of the secondary mutations were not random. Some amino acid residues in the M protein showed more frequent mutations than others, and the changed amino acid residues were always the same. EPC cells infected with rVHSV-M-D62A E181A showed significantly higher type I interferon response and NF-κB activity, and the inhibitory activity against type I interferon response and NF-κB activity in other recombinant VHSVs having secondary mutations in M gene were similar to those of rVHSV-wild. In conclusion, the present results showed that VHSV actively responded to the artificial mutation of M protein through the secondary mutations, and those secondary mutations occurred when the artificial mutations were deleterious to viral replication and protein stability. Furthermore, most secondary mutations in recombinant viruses compensated for the deleterious effect of the engineered mutations.
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Enfermedades de los Peces , Interferón Tipo I , Novirhabdovirus , Animales , Aminoácidos/genética , FN-kappa B/genética , Novirhabdovirus/genética , Mutación , Genotipo , Interferón Tipo I/genéticaRESUMEN
Gardasil® (Merck) and Cervarix® (GlaxoSmithKline) both provide protection against infection with Human Papillomavirus 16 (HPV16) and Human Papillomavirus 18 (HPV18), that account for around 70% of cervical cancers. Both vaccines have been shown to induce high levels of neutralizing antibodies and are known to protect against progression beyond cervical intraepithelial neoplasia grade 2 (CIN2+), although Cervarix® has been linked to enhanced protection from progression. However, beyond the transmission-blocking activity of neutralizing antibodies against HPV, no clear correlate of protection has been defined that may explain persistent control and clearance elicited by HPV vaccines. Beyond blocking, antibodies contribute to antiviral activity via the recruitment of the cytotoxic and opsonophagocytic power of the immune system. Thus, here, we used systems serology to comprehensively profile Gardasil®- and Cervarix®- induced antibody subclass, isotype, Fc-receptor binding, and Fc-effector functions against the HPV16 and HPV18 major capsid protein (L1). Overall, both vaccines induced robust functional humoral immune responses against both HPV16 and HPV18. However, Cervarix® elicited higher IgG3 and antibody-dependent complement activating responses, and an overall more coordinated response between HPV16 and 18 compared to Gardasil®, potentially related to the distinct adjuvants delivered with the vaccines. Thus, these data point to robust Fc-effector functions induced by both Gardasil® and Cervarix®, albeit with enhanced coordination observed with Cervarix®, potentially underlying immunological correlates of post-infection control of HPV.
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[This corrects the article DOI: 10.3389/fimmu.2022.856906.].
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Introduction: Placental transfer of maternal antibodies is essential for neonatal immunity over the first months of life. In the setting of maternal HIV infection, HIV-exposed uninfected (HEU) infants are at higher risk of developing severe infections, including active tuberculosis (TB). Given our emerging appreciation for the potential role of antibodies in the control of Mycobacterium tuberculosis (Mtb), the bacteria that causes TB, here we aimed to determine whether maternal HIV status altered the quality of Mtb-specific placental antibody transfer. Methods: Antigen-specific antibody systems serology was performed to comprehensively characterize the Mtb-specific humoral immune response in maternal and umbilical cord blood from HIV infected and uninfected pregnant people in Uganda. Results: Significant differences were noted in overall antibody profiles in HIV positive and negative maternal plasma, resulting in heterogeneous transfer of Mtb-specific antibodies. Altered antibody transfer in HIV infected dyads was associated with impaired binding to IgG Fc-receptors, which was directly linked to HIV viral loads and CD4 counts. Conclusions: These results highlight the importance of maternal HIV status on antibody transfer, providing clues related to alterations in transferred maternal immunity that may render HEU infants more vulnerable to TB than their HIV-unexposed peers.
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Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is an inflammatory demyelinating disease of the CNS. Although MOG is encephalitogenic in different mammalian species, the mechanisms by which human MOG-specific Abs contribute to MOGAD are poorly understood. Here, we use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral immune responses in 123 patients with MOGAD. We show that age is a major determinant for MOG-antibody-related immune signatures. Unsupervised clustering additionally identifies two dominant immunological endophenotypes of MOGAD. The pro-inflammatory endophenotype characterized by increased binding affinities for activating Fcγ receptors (FcγRs), capacity to activate innate immune cells, and decreased frequencies of galactosylated and sialylated immunoglobulin G (IgG) glycovariants is associated with clinically active disease. Our data support the concept that FcγR-mediated effector functions control the pathogenicity of MOG-specific IgG and suggest that FcγR-targeting therapies should be explored for their therapeutic potential in MOGAD.
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Inmunoglobulina G , Receptores de IgG , Animales , Humanos , Glicoproteína Mielina-Oligodendrócito/metabolismo , Mamíferos/metabolismoRESUMEN
People with HIV (PWH) appear to be at higher risk for suboptimal pathogen responses and for worse COVID-19 outcomes, but the effects of host factors and COVID-19 on the humoral repertoire remain unclear. We assessed the antibody isotype/subclass and Fc-receptor binding Luminex arrays of non-SARS-CoV-2 and SARS-CoV-2 humoral responses among antiretroviral therapy-treated (ART-treated) PWH. Among the entire cohort, COVID-19 infection was associated with higher cytomegalovirus (CMV) responses (vs. the COVID- cohort ), potentially signifying increased susceptibility or a consequence of persistent inflammation. Among the COVID+ participants, (a) higher BMI was associated with a striking amplification of SARS-CoV-2 responses, suggesting exaggerated inflammatory responses, and (b) lower nadir CD4 was associated with higher SARS-CoV-2 IgM and FcγRIIB binding capacity, indicating poorly functioning extrafollicular and inhibitory responses. Among the COVID-19- participants, female sex, older age, and lower nadir CD4 were associated with unique repertoire shifts. In this first comprehensive assessment of the humoral repertoire in a global cohort of PWH, we identify distinct SARS-CoV-2-specific humoral immune profiles among PWH with obesity or lower nadir CD4+ T cell count, underlining plausible mechanisms associated with worse COVID-19-related outcomes in this setting. Host factors associated with the humoral repertoire in the COVID-19- cohort enhance our understanding of these important shifts among PWH.
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COVID-19 , Femenino , Humanos , Antirretrovirales , Anticuerpos Antivirales , Linfocitos T CD4-Positivos , SARS-CoV-2 , Infecciones por VIH/tratamiento farmacológicoRESUMEN
Collective motion is a ubiquitous phenomenon in nature. The collective motion of cytoskeleton filaments results mainly from dynamic collisions and alignments; however, the detailed mechanism of pattern formation still needs to be clarified. In particular, the influence of persistence length, which is a measure of filament flexibility, on collective motion is still unclear and lacks experimental verifications although it is likely to directly affect the orientational flexibility of filaments. Here, we investigated the collective motion of microtubules with different persistence lengths using a microtubule-kinesin motility system. We showed that local interactions between microtubules significantly vary depending on their persistence length. We demonstrated that the bundling of microtubules is enhanced by more durable alignment, rather than by greater likelihood of alignment. An agent-based computational model confirmed that the rigidity-dependent durability of microtubule alignment dominates their collective behavior.
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Cinesinas , Microtúbulos , Citoesqueleto , Movimiento (Física) , Transición de FaseRESUMEN
Tuberculosis (TB) is among the leading causes of death worldwide from a single infectious agent, second only to COVID-19 in 2020. TB is caused by infection with Mycobacterium tuberculosis (Mtb), that results either in a latent or active form of disease, the latter associated with Mtb spread. In the absence of an effective vaccine, epidemiologic modeling suggests that aggressive treatment of individuals with active TB (ATB) may curb spread. Yet, clinical discrimination between latent (LTB) and ATB remains a challenge. While antibodies are widely used to diagnose many infections, the utility of antibody-based tests to diagnose ATB has only regained significant traction recently. Specifically, recent interest in the humoral immune response to TB has pointed to potential differences in both targeted antigens and antibody features that can discriminate latent and active TB. Here we aimed to integrate these observations and broadly profile the humoral immune response across individuals with LTB or ATB, with and without HIV co-infection, to define the most discriminatory humoral properties and diagnose TB disease more easily. Using 209 Mtb antigens, striking differences in antigen-recognition were observed across latently and actively infected individuals that was modulated by HIV serostatus. However, ATB and LTB could be discriminated, irrespective of HIV-status, based on a combination of both antibody levels and Fc receptor-binding characteristics targeting both well characterized (like lipoarabinomannan, 38 kDa or antigen 85) but also novel Mtb antigens (including Rv1792, Rv1528, Rv2435C or Rv1508). These data reveal new Mtb-specific immunologic markers that can improve the classification of ATB versus LTB.
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COVID-19 , Infecciones por VIH , Tuberculosis Latente , Tuberculosis , Anticuerpos , Infecciones por VIH/complicaciones , HumanosRESUMEN
During intracellular transport, cellular cargos, such as organelles, vesicles, and proteins, are transported within cells. Intracellular transport plays an important role in diverse cellular functions. Molecular motors walking on the cytoskeleton facilitate active intracellular transport, which is more efficient than diffusion-based passive transport. Active transport driven by kinesin and dynein walking on microtubules has been studied well during recent decades. However, mechanisms of active transport occurring in disorganized actin networks via myosin motors remain elusive. To provide physiologically relevant insights, we probed motions of myosin motors in actin networks under various conditions using our well-established computational model that rigorously accounts for the mechanical and dynamical behaviors of the actin cytoskeleton. We demonstrated that myosin motions can be confined due to three different reasons in the absence of F-actin turnover. We verified mechanisms of motor stalling using in vitro reconstituted actomyosin networks. We also found that with F-actin turnover, motors consistently move for a long time without significant confinement. Our study sheds light on the importance of F-actin turnover for effective active transport in the actin cytoskeleton.