The antagonistic transcription factors, EspM and EspN, regulate the ESX-1 secretion system in .

Bacterial pathogens use protein secretion systems to transport virulence factors and regulate gene expression. Among pathogenic mycobacteria, including and , the ESAT-6 system 1 (ESX-1) secretion is crucial for host interaction. Secretion of protein substrates by the ESX-1 secretion system disrupts phagosomes, allowing mycobacteria cytoplasmic access during macrophage infections.

The Many Hosts of Mycobacteria 9 (MHM9): A conference report.

The Many Hosts of Mycobacteria (MHM) meeting series brings together basic scientists, clinicians and veterinarians to promote robust discussion and dissemination of recent advances in our knowledge of numerous mycobacterial diseases, including human and bovine tuberculosis (TB), nontuberculous mycobacteria (NTM) infection, Hansen's disease (leprosy), Buruli ulcer and Johne's disease. The 9th MHM conference (MHM9) was held in July 2022 at The Ohio State University (OSU) and centered around the theme of "Confounders of Mycobacterial Disease." Confounders can and often do drive the transmission of mycobacterial diseases, as well as impact surveillance and treatment outcomes.

The EspN transcription factor is an infection-dependent regulator of the ESX-1 system in .

Unlabelled: Bacterial pathogens use protein secretion systems to translocate virulence factors into the host and to control bacterial gene expression. The ESX-1 (ESAT-6 system 1) secretion system facilitates disruption of the macrophage phagosome during infection, enabling access to the cytoplasm, and regulates widespread gene expression in the mycobacterial cell. The transcription factors contributing to the ESX-1 transcriptional network during mycobacterial infection are not known.

Macrophage NFATC2 mediates angiogenic signaling during mycobacterial infection.

During mycobacterial infections, pathogenic mycobacteria manipulate both host immune and stromal cells to establish and maintain a productive infection. In humans, non-human primates, and zebrafish models of infection, pathogenic mycobacteria produce and modify the specialized lipid trehalose 6,6'-dimycolate (TDM) in the bacterial cell envelope to drive host angiogenesis toward the site of forming granulomas, leading to enhanced bacterial growth. Here, we use the zebrafish-Mycobacterium marinum infection model to define the signaling basis of the host angiogenic response.

An ancestral mycobacterial effector promotes dissemination of infection.

The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak presenting with unusually high rates of extrapulmonary dissemination and bone disease.

mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity.

Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis.

Modelling infectious disease to support human health.

During the current COVID-19 pandemic, there has been renewed scientific and public focus on understanding the pathogenesis of infectious diseases and investigating vaccines and therapies to combat them. In addition to the tragic toll of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we also recognize increased threats from antibiotic-resistant bacterial strains, the effects of climate change on the prevalence and spread of human pathogens, and the recalcitrance of other infectious diseases - including tuberculosis, malaria, human immunodeficiency virus (HIV) and fungal infections - that continue to cause millions of deaths annually. Large amounts of funding have rightly been redirected toward vaccine development and clinical trials for COVID-19, but we must continue to pursue fundamental and translational research on other pathogens and host immunity.

Decoding the tuberculous granuloma.

In this issue of Immunity,Gideon et al. (2022) couple sophisticated single-cell analyses with detailed in vivo measurements of Mycobacterium tuberculosis granulomas to define the cellular and transcriptional properties of a successful host immune response during tuberculosis.

Inhibition of infection-induced vascular permeability modulates host leukocyte recruitment to Mycobacterium marinum granulomas in zebrafish.

Mycobacterial granuloma formation involves significant stromal remodeling including the growth of leaky, granuloma-associated vasculature. These permeable blood vessels aid mycobacterial growth, as antiangiogenic or vascular normalizing therapies are beneficial host-directed therapies in preclinical models of tuberculosis across host-mycobacterial pairings. Using the zebrafish-Mycobacterium marinum infection model, we demonstrate that vascular normalization by inhibition of vascular endothelial protein tyrosine phosphatase (VE-PTP) decreases granuloma hypoxia, the opposite effect of hypoxia-inducing antiangiogenic therapy.

Consequential drug combinations for tuberculosis treatments.

Improved therapies for tuberculosis will require the careful revision of complex, multi-drug regimens. In this issue of Cell Systems, Larkins-Ford et al. integrate extensive dose-response measurements of drug combinations, in vivo animal data, and computational analysis to provide a new predictive framework for the prioritization of specific antitubercular drug regimens.

A non-canonical type 2 immune response coordinates tuberculous granuloma formation and epithelialization.

The central pathogen-immune interface in tuberculosis is the granuloma, a complex host immune structure that dictates infection trajectory and physiology. Granuloma macrophages undergo a dramatic transition in which entire epithelial modules are induced and define granuloma architecture. In tuberculosis, relatively little is known about the host signals that trigger this transition.

A robust and flexible CRISPR/Cas9-based system for neutrophil-specific gene inactivation in zebrafish.

CRISPR/Cas9-based tissue-specific knockout techniques are essential for probing the functions of genes in embryonic development and disease using zebrafish. However, the lack of capacity to perform gene-specific rescue or live imaging in the tissue-specific knockout background has limited the utility of this approach. Here, we report a robust and flexible gateway system for tissue-specific gene inactivation in neutrophils.

Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone.

Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in (), which regulates expression of the proinflammatory mediator leukotriene B (LTB). TT homozygotes, with increased expression of , have the highest survival when treated with dexamethasone and the lowest survival without.

Visualizing the dynamics of tuberculosis pathology using molecular imaging.

Nearly 140 years after Robert Koch discovered Mycobacterium tuberculosis, tuberculosis (TB) remains a global threat and a deadly human pathogen. M. tuberculosis is notable for complex host-pathogen interactions that lead to poorly understood disease states ranging from latent infection to active disease.

A Cluster of Nontuberculous Mycobacterial Tenosynovitis Following Hurricane Relief Efforts.

Background: Nontuberculous mycobacteria (NTM) are a rare cause of infectious tenosynovitis of the upper extremity. Using molecular methods, clinical microbiology laboratories are increasingly reporting identification down to the species level. Improved methods for speciation are revealing new insights into the clinical and epidemiologic features of rare NTM infections.

Early cell-autonomous accumulation of neutral lipids during infection promotes mycobacterial growth.

Lipids represent an important source of nutrition for infecting mycobacteria, accumulating within the necrotic core of granulomas and present in foamy macrophages associated with mycobacterial infection. In order to better understand the timing, process and importance of lipid accumulation, we developed methods for direct in vivo visualization and quantification of this process using the zebrafish-M. marinum larval model of infection.

Macrophage ACKRobatics: An atypical Cxcr3 keeps macrophages in check.

Discussion on an unusual role for a cxcr3 receptor, in which it antagonizes a paralogous receptor to limit macrophage migration.

Epithelial delamination is protective during pharmaceutical-induced enteropathy.

Intestinal epithelial cell (IEC) shedding is a fundamental response to intestinal damage, yet underlying mechanisms and functions have been difficult to define. Here we model chronic intestinal damage in zebrafish larvae using the nonsteroidal antiinflammatory drug (NSAID) Glafenine. Glafenine induced the unfolded protein response (UPR) and inflammatory pathways in IECs, leading to delamination.

Mycobacterial Evolution Intersects With Host Tolerance.

Over the past 200 years, tuberculosis (TB) has caused more deaths than any other infectious disease, likely infecting more people than it has at any other time in human history. (), the etiologic agent of TB, is an obligate human pathogen that has evolved through the millennia to become an archetypal human-adapted pathogen. This review focuses on the evolutionary framework by which emerged as a specialized human pathogen and applies this perspective to the emergence of specific lineages that drive global TB burden.

Thrombocyte Inhibition Restores Protective Immunity to Mycobacterial Infection in Zebrafish.

Background: Infection-induced thrombocytosis is a clinically important complication of tuberculosis infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action.

Methods: In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas.

Spotlight on zebrafish: the next wave of translational research.

Five years after the launch of the Disease Models & Mechanisms (DMM) Special Issue on zebrafish as a disease model, the field has progressed significantly. Zebrafish have been used to precisely model human genetic variants, to unpick the mechanisms of metabolic and other diseases, to study infection, inflammation and cancer, and to develop and test new therapeutic approaches. In this Editorial, we highlight recent research published in DMM that uses zebrafish to develop new experimental tools and to provide new insight into disease mechanism and therapy.

Intestinal Serum amyloid A suppresses systemic neutrophil activation and bactericidal activity in response to microbiota colonization.

The intestinal microbiota influences the development and function of myeloid lineages such as neutrophils, but the underlying molecular mechanisms are unresolved. Using gnotobiotic zebrafish, we identified the immune effector Serum amyloid A (Saa) as one of the most highly induced transcripts in digestive tissues following microbiota colonization. Saa is a conserved secreted protein produced in the intestine and liver with described effects on neutrophils in vitro, however its in vivo functions remain poorly defined.