publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Article Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough Graphical Abstract Highlights d An Mtb organic extract activates nociceptive neurons and induces cough in guinea pigs d Mtb sulfolipid-1 is necessary and sufficient to trigger neuronal activation and cough d Guinea pigs infected with an SL-1-deficient Mtb mutant do not coughMycobacterium tuberculosis produces a glycolipid called sulfolipid-1 (SL-1) that triggers cough by activating nociceptive neurons.

Summary The prevailing paradigm is that tuberculosis infection is initiated when patrolling alveolar macrophages and dendritic cells within the terminal alveolus ingest inhaled M. tuberculosis (Mtb). However, definitive data for this model are lacking. Among the epithelial cells of the upper airway a specialized epithelial cell known as a microfold cell (M-cell) overlies various components of mucosa associated lymphatic tissue. Here we show using multiple mouse models that Mtb invades via M-cells to initiate infection. Intranasal Mtb infection in mice lacking M-cells either genetically or by antibody depletion resulted in reduced invasion and dissemination to draining lymph nodes. M-cell depleted mice infected via aerosol also had delayed dissemination to lymph nodes and reduced mortality. Translocation of Mtb across two M-cell transwell models was rapid and transcellular. Thus, M-cell translocation is a vital entry mechanism that contributes to the pathogenesis of Mtb.

Kinetoplastid-based infections are neglected diseases that represent a significant human health issue. Chemotherapeutic options are limited due to toxicity, parasite susceptibility, and poor patient compliance. In response, we studied a molecular target-directed approach involving intervention of hexokinase activity – a pivotal enzyme in parasite metabolism. A benzamidobenzoic acid hit with modest biochemical inhibition of T. brucei hexokinase 1 (TbHK1, IC50 = 9.1 μM), low mammalian cytotoxicity (IMR-90, EC50 > 25 μM), and no appreciable activity on whole BSF parasites was optimized to afford probe 4f with improved TbHK1 potency and, significantly, efficacy against whole BSF parasites (TbHK1, IC50 = 0.28 μM, BSF LD50 = 1.9 μM). Compound 4f and analogs also inhibited the hexokinase enzyme from Leishmania major (LmHK1), albeit with less potency compared to TbHK1, suggesting that inhibition of the glycolytic pathway may be a promising opportunity to target multiple, disease-causing trypanosomatid protozoa.

Mycobacterium tuberculosis (Mtb) can enter the body through multiple routes, including via specialized transcytotic cells called microfold cells (M cell). However, the mechanistic basis for M cell entry remains undefined. Here, we show that M cell transcytosis depends on the Mtb Type VII secretion machine and its major virulence factor EsxA. We identify scavenger receptor B1 (SR-B1) as an EsxA receptor on airway M cells. SR-B1 is required for Mtb binding to and translocation across M cells in mouse and human tissue. Together, our data demonstrate a previously undescribed role for Mtb EsxA in mucosal invasion and identify SR-B1 as the airway M cell receptor for Mtb.

BackgroundA hallmark symptom of active pulmonary tuberculosis vital for disease transmission is cough. The current paradigm for tuberculosis-related cough is that it results from airway damage or irritation. However, there is limited experimental data to support this theory, and whether Mycobacterium tuberculosis (Mtb) induces cough to facilitate its own transmission has not been explored. The cough reflex is a complex and coordinated event involving both the nervous and musculoskeletal systems initiated by particulate or chemical molecules activating nociceptive neurons, which sense pain or irritation. This activation induces a signaling cascade ultimately resulting in a cough. Respiratory nociceptive neurons innervate the airway of humans and most mammals, and thus are poised to respond to noxious molecules to help protect the lung from damage. Because Mtb is a lung pathogen, cough is a primary mechanism of Mtb transmission, and respiratory nociceptive neurons activate cough, we hypothesized that Mtb produces molecules that stimulate cough, thereby facilitating its spread from infected to uninfected individuals.MethodsWe used an in vitro neuronal activation bioassay to fractionate, identify, and characterize Mtb cough-inducing molecules. We also measured cough in vivo in response to pure Mtb-derived cough molecules and during Mtb infection using a guinea pig model.ResultsWe found that an acellular organic extract of Mtb triggers and activates nociceptive neurons in vitro with a neuronal response that is as robust as the response to capsaicin, an established nociceptive and cough-inducing molecule. Using analytical chemistry and our neuronal bioassay, we then isolated 2 molecules produced by Mtb that activate nociceptive neurons. Both the organic Mtb extract and purified molecules alone were sufficient to induce cough in a conscious guinea pig cough model. Finally guinea pigs infected with wild-type Mtb cough much more frequently than guinea pigs infected with Mtb strains unable to produce nociceptive molecules.ConclusionWe conclude that Mtb produces molecules that activate nociceptive neurons and induce cough. These findings have significant implications for our understanding of Mtb transmission.Disclosures All authors: No reported disclosures.

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Study Design: A case report with 2 year follow up. Objective: The aim of this paper is to present a case of bilateral TMJ ankylosis with coexisting dentofacial deformity and occlusal cant, and 2 years follow-up evaluation for changes and relapse in the facial skeletal and airway. Methods: The patient was planned preoperatively by computer simulation for bilateral interposition arthroplasty and surgical jigs, coronoidectomy, detachment of masseter and medial pterygoid muscles from ramus, LeFort 1 osteotomy, temporary maxillomandibular fixation, counter-clockwise rotation of the maxillomandibular complex, maxillary fixation and iliac crest graft, reconstruction of bilateral TMJ with custom-made total joint prosthesis, dermal fat interposition in the joint, reattachment of muscles, maxillomandibular fixation, and active physiotherapy. Results: Average ramal length improved by 28.35 mm (81%) in the immediate postoperative and 25.6 mm (73.45%) at 2 years, showing 2.75 mm (4.4%) vertical bone resorption at the angle region. Point A advanced by 1.3 mm, but showed 4.5% horizontal relapse; Point B advanced by 10.2 mm, but showed 9.5% relapse at 2 years. Pogonion advanced by 26.3 mm (70%) but presented 7 mm (10.9%) horizontal relapse; and menton by 28.6 mm (89%) with 5.4 mm (8.9%) relapse at 2 years. The mean mandibular plane angle decreased by 33.5° (42%) after surgery and by 32° (40%) at 2 years. Pharyngeal airway increased by 49% after surgery and by 75.6% at 2 years follow-up. Conclusion: This computer simulated approach for the management of bilateral TMJ ankylosis with facial deformity and occlusal cant improves aesthetics, function and airway in a single surgery, thereby reducing the management cost and time, and deliver precise results.