RESUMEN
Mycobacterium tuberculosis (Mtb) infects cells in multiple lung myeloid cell subsets and causes chronic infection despite innate and adaptive immune responses. However, the mechanisms allowing Mtb to evade elimination are not fully understood. Here, using new methods, we determined that after T cell responses have developed, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb compared to alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Bulk RNA sequencing of sorted cells revealed that the lysosome biogenesis pathway is underexpressed in MNC1. Functional assays confirmed that Mtb-permissive MNC1 have less lysosome content, acidification, and proteolytic activity than AM, and less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in MNC1 in vivo. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these cell subsets as a virulence mechanism that requires the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome function of primary macrophages in vitro and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results indicate that Mtb exploits lysosome-poor monocyte-derived cells for in vivo persistence, suggesting a potential target for host-directed tuberculosis therapy.
RESUMEN
INTRODUCTION: Multiple sclerosis (MS) is a chronic disease state that affects and disables many people each year. The most common clinical presentation is relapsing-remitting MS (RRMS). In the past 7 years, new medications have been approved for the treatment of RRMS, thereby providing more treatment options for patients and providers. The purpose of this article is to provide an update on medications for the treatment of MS that have been approved since January 2010. METHODS: A review was performed utilizing CenterWatch to search for medications approved by the US Food and Drug Administration for the treatment of RRMS between January 2010 and April 2017. The package inserts of medications indicated for RRMS were analyzed, and key points were summarized. PubMed and EBSCOhost were utilized to identify articles relevant to RRMS background and treatment. RESULTS: Seven medications with varying mechanisms of action have been approved to treat RRMS since 2010. Pharmacotherapy options include oral and injectable formulations. Efficacy across the agents is comparable, and each agent has safety data from clinical trials. The safety profile varies between oral and injectable agents, but potential adverse effects are important to consider before initiation. Therapeutic selection is based on patient preference, dosing (frequency and route), and safety considerations. DISCUSSION: Multiple therapeutic options are available for the treatment of RRMS. Health care practitioners should be cognizant of the adverse effects, dosing route, and frequency in order to optimally tailor therapy to meet individual patient needs.