The rockefeller university

In 2014, a child with broad combined immunodeficiency (CID) who was homozygous for a private BCL10 allele was reported to have complete inherited human BCL10 deficiency. In the present study, we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986). The mutant allele was a loss-of-expression and loss-of-function allele. As with the previously reported patient, this patient had complete BCL10 deficiency. The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis. Cellular and immunological phenotypes were similar to those of the previous patient. TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected. Autosomal-recessive BCL10 deficiency should therefore be considered in children with CID.

The mammalian gastrointestinal tract harbors a large reservoir of tissue macrophages, which, in concert with other immune cells, help to maintain a delicate balance between tolerance to commensal microbes and food antigens, and resistance to potentially harmful microbes or toxins. Beyond their roles in resistance and tolerance, recent studies have uncovered novel roles played by tissue-resident, including intestinal-resident macrophages in organ physiology. Here, we will discuss recent advances in the understanding of the origin, phenotype and function of macrophages residing in the different layers of the intestine during homeostasis and under pathological conditions.

T cell responses specific for HIV-1 Gag peptides increased in HIV-positive recipients of two broadly neutralizing antibodies with prolonged suppression of blood viremia during antiretroviral treatment interruption. Combination antiretroviral therapy (ART) is highly effective in controlling human immunodeficiency virus (HIV)-1 but requires lifelong medication due to the existence of a latent viral reservoir(1,2). Potent broadly neutralizing antibodies (bNAbs) represent a potential alternative or adjuvant to ART. In addition to suppressing viremia, bNAbs may have T cell immunomodulatory effects as seen for other forms of immunotherapy(3). However, this has not been established in individuals who are infected with HIV-1. Here, we document increased HIV-1 Gag-specific CD8(+) T cell responses in the peripheral blood of all nine study participants who were infected with HIV-1 with suppressed blood viremia, while receiving bNAb therapy during ART interruption(4). Increased CD4(+) T cell responses were detected in eight individuals. The increased T cell responses were due both to newly detectable reactivity to HIV-1 Gag epitopes and the expansion of pre-existing measurable responses. These data demonstrate that bNAb therapy during ART interruption is associated with enhanced HIV-1-specific T cell responses. Whether these augmented T cell responses can contribute to bNAb-mediated viral control remains to be determined.

Interferon gamma (IFN-gamma) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-gamma immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD). MSMD is characterized by genetic predisposition to disease caused by weakly virulent mycobacterial species. Paradoxically, macrophages from patients with MSMD were little tested. Here, we report a disease modeling platform for studying IFN-gamma related pathologies using macrophages derived from patient specific induced pluripotent stem cells (iPSCs). We used iPSCs from patients with autosomal recessive complete- and partial IFN-gamma R2 deficiency, partial IFN-gamma R1 deficiency and complete STAT1 deficiency. Macrophages from all patient iPSCs showed normal morphology and IFN-gamma-independent functionality like phagocytic uptake of bioparticles and internalization of cytokines. For the IFN-gamma-dependent functionalities, we observed that the deficiencies played out at various stages of the IFN-gamma pathway, with the complete IFN-gamma R2 and complete STAT1 deficient cells showing the most severe phenotypes, in terms of upregulation of surface markers and induction of downstream targets. Although iPSC-derived macrophages with partial IFN-gamma R1 and IFN-gamma R2 deficiency still showed residual induction of downstream targets, they did not reduce the mycobacterial growth when challenged with Bacillus Calmette-Guerin. Taken together, we report a disease modeling platform to study the role of macrophages in patients with inborn errors of IFN-gamma immunity.

Antillean manatees produce vocalizations reported to be important for communication, but their vocal behavior throughout their geographic range is poorly understood. A SoundTrap recorder (sample rates: 288/576kHz) was deployed in Belize to record vocalizations of wild manatees in a seagrass channel and of a young rehabilitated and released manatee in a shallow lagoon. Spectral analysis revealed broadband vocalizations with frequencies up to 150kHz and a high proportion of calls with ultrasonic components. Ultrasonic frequency components appear prevalent in their vocal repertoire and may be important to manatee communication. (C) 2020 Acoustical Society of America

Staphylococcal bi-component pore-forming toxins, also known as leukocidins, target and lyse human phagocytes in a receptor-dependent manner. S-components of the leukocidins Panton-Valentine leukocidin (PVL), gamma-haemolysin (HlgAB) and CB (HlgCB), and leukocidin ED (LukED) specifically employ receptors that belong to the class of G-protein coupled receptors (GPCRs). Although these receptors share a common structural architecture, little is known about the conserved characteristics of the interaction between leukocidins and GPCRs. In this study, we investigated host cellular pathways contributing to susceptibility towards S. aureus leukocidin cytotoxicity. We performed a genome-wide CRISPR/Cas9 library screen for toxin-resistance in U937 cells sensitized to leukocidins by ectopic expression of different GPCRs. Our screen identifies post-translational modification (PTM) pathways involved in the sulfation and sialylation of the leukocidin-receptors. Subsequent validation experiments show differences in the impact of PTM moieties on leukocidin toxicity, highlighting an additional layer of refinement and divergence in the staphylococcal host-pathogen interface. Leukocidin receptors may serve as targets for anti-staphylococcal interventions and understanding toxin-receptor interactions will facilitate the development of innovative therapeutics. Variations in the genes encoding PTM pathways could provide insight into observed differences in susceptibility of humans to infections with S. aureus.

Implicit in the RNA world hypothesis is that prebiotic RNA synthesis, despite occurring in an environment without biochemical catalysts, produced the long RNA polymers which are essential to the formation of life. In order to investigate the prebiotic formation of long RNA polymers, we consider a general solution of functionally identical monomer units that are capable of bonding to form linear polymers by a step-growth process. Under the assumptions that (1) the solution is well-mixed and (2) bonding/unbonding rates are independent of polymerization state, the concentration of each length of polymer follows the geometric Flory-Schulz distribution. We consider the rate dynamics that produce this equilibrium; connect the rate dynamics, Gibbs free energy of bond formation, and the bonding probability; solve the dynamics in closed form for the representative special case of a Flory-Schulz initial condition; and demonstrate the effects of imposing a maximum polymer length. Afterwards, we derive a lower bound on the error introduced by truncation and compare this lower bound to the actual error found in our simulation. Finally, we suggest methods to connect these theoretical predictions to experimental results.

The surface and lining tissues of our body are exposed to the external environment, and as such these epithelial tissues must form structural barriers able to defend against microbes, environmental toxins, and mechanical stress. Their cells are equipped to detect a diverse array of surface perturbations, and then launch signaling relays to the immune system. The aim of these liaisons is to coordinate the requisite immune cell response needed to preserve and/or restore barrier integrity and defend the host. It has been recently appreciated that epithelial cells learn from these experiences. Following inflammatory exposure, long-lived stem cells within the tissue retain an epigenetic memory that endows them with heightened responsiveness to subsequent encounters with stress. Here, we review the recent literature on how epithelial cells sense signals from microbes, allergens, and injury at the tissue surface, and transmit this information to immune cells, while embedding a memory of the experience within their chromatin.