Recent advances in the development and deployment of antituberculosis drugs have been underpinned by an improved understanding of their pharmacokinetic-pharmacodynamic behavior in the complex context of tuberculosis disease in the host. New information from novel technologies has helped to clarify aspects of drug distribution and action, which contribute to the critical clinical phenomena of persistence and resistance in Mycobacterium tuberculosis (Mtb), while effective integration of these data through quantitative pharmacology tools has facilitated more rational decision-making in preclinical and clinical drug development. This new framework permits a much more extensive and efficient evaluation of the space of novel and repurposed multidrug regimens in tuberculosis with the expectation of accelerating the arrival of even shorter, safer, and more effective treatments in the clinic.
Post-tuberculosis lung disease (PTLD) is an increasingly recognized consequence of pulmonary tuberculosis (TB) disease, affecting millions of survivors worldwide and imposing substantial clinical, functional, and socioeconomic burdens. This narrative review synthesizes current evidence across epidemiology, definitions, clinical phenotypes, assessment, and management, with dedicated consideration of children and adolescents. PTLD is common: Studies report abnormal spirometry in ∼60% of TB survivors and persistent, activity-limiting dyspnea in a sizeable minority. Outcomes are generally worse in low- and middle-income settings. The 2019 international consensus definition-"evidence of chronic respiratory abnormality attributable at least in part to prior TB"-has catalyzed research and service development; a newer research definition proposes a structured, three-domain approach (symptoms, radiology, lung function) and introduces "post-TB lung abnormality" for single-domain findings. PTLD encompasses heterogeneous patterns, including fibrosis, cavitation with chronic pulmonary aspergillosis risk, bronchiectasis, airflow obstruction, tracheobronchial stenosis, pleural disease, vascular complications, and pulmonary hypertension. Assessment should integrate symptom review, exercise capacity, oximetry, spirometry (with Global Lung Initiative [GLI] reference standards), and context-appropriate imaging, alongside targeted microbiology and echocardiography where indicated. Evidence for disease-modifying therapy remains limited; however, pulmonary rehabilitation improves function and symptoms, and selected patients may benefit from inhaled bronchodilators or surgical interventions. A "treatable traits" framework-spanning pulmonary, extrapulmonary, and behavioral risk domains-offers a pragmatic, person-centered strategy while high-quality trials mature. In children, TB during critical periods of lung development confers lasting functional and growth impacts, underscoring the need for age-specific screening and follow-up. We outline key research priorities: embedding PTLD outcomes in TB trials, standardizing measurement, elucidating mechanisms, evaluating host-directed therapies, and integrating post-TB care into routine health services.
Tuberculosis (TB) care and prevention have long relied on the assumption that individuals with the disease will seek care once they become aware of symptoms. However, national prevalence surveys show that nearly half of bacteriologically confirmed TB cases report no symptoms at screening, challenging this paradigm. The World Health Organization (WHO) now recognizes asymptomatic TB as part of the disease spectrum and promotes symptom-agnostic screening strategies to identify and treat these individuals. Evidence suggests that asymptomatic TB could be contributing to transmission, although further research is needed. While defining symptom status remains imprecise, individuals with asymptomatic TB present distinct diagnostic and treatment challenges. Asymptomatic pulmonary TB typically involves more limited disease, lower bacillary burden, and difficulty producing sputum, reducing the sensitivity of current sputum-based tests. Novel diagnostic approaches, including alternative sampling and molecular tools, are under development. Treatment uptake and adherence are another concern, as individuals feel well and derive no immediate symptomatic benefit, increasing the risk of poor initiation and completion. Addressing these gaps through improved diagnostics, shorter and better-tolerated regimens, and enhanced treatment support is essential. Recognizing and targeting asymptomatic TB is critical to interrupt transmission and accelerate progress toward global TB elimination.
Although the airborne route of Mycobacterium tuberculosis has been known for more than 60 years, and suspected long before that, there remains controversy over exactly how transmission occurs and how to prevent it. From an infectious particle perspective, the Wells-Riley equation simplifies understanding the interrelationship of some but not all relevant factors, and many assumptions are made that we know are untrue, like steady-state, well-mixed conditions, uniform virulence of infectious particles, and uniform susceptibility of exposed hosts. The source strength of infectious individuals is an important unknown factor. Retrospectively, the infection rate is used to calculate the infectious dose generation rate (quanta/h). A recent controversy is the importance of presymptomatic tuberculosis (TB) and quiet breathing as opposed to cough-generated aerosol. Early effective treatment rapidly reduces infectiousness from known and presymptomatic cases but requires active screening of high-risk populations. Environmental controls are essential for reducing transmission from presymptomatic and unsuspected cases. While masks for patients and respirators for healthcare workers are valuable in high-risk situations before appropriate treatment begins, their effectiveness is limited.
Malaria prevention is key for protecting high-risk groups, such as children and pregnant women. Existing approaches, including insecticide-based vector control, infant vaccination, and targeted chemoprevention are successful in some contexts. However, new tools are needed to broaden the scope and enhance the effectiveness of preventive strategies, particularly in high transmission areas. This paper examines emerging modalities for malaria chemoprevention beyond vaccination, illustrating advances toward long-acting interventions that can provide sustained protection with fewer doses. The pharmacological rationale and essential considerations for the clinical development and deployment of monoclonal antibodies, long-acting oral agents, and long-acting injectable small-molecule formulations are explored with examples. These innovations represent a step-change in malaria prevention, improving operational feasibility and long-term impact in endemic settings. They also have the potential to transform malaria prevention from a disease control tool in high-burden settings to a strategy capable of accelerating malaria elimination.
The Plasmodium liver stages of infection-initiated when mosquito-transmitted sporozoites invade hepatocytes-are asymptomatic and essential for initial parasite replication and progression to blood stage infection. This paper provides an overview of liver stage biology, from sporozoite invasion mechanisms and host hepatocyte remodeling to intracellular development, nutrient acquisition, and evasion of host defenses. We highlight recent insights into cellular and molecular host-parasite interactions, and innate immune pathways that mediate liver stage clearance. The paper also reviews the evolution and clinical progress of pre-erythrocytic whole parasite vaccines, which are deeply rooted in an understanding of liver stage biology. As they constitute the initial phase of infection, the liver stages are a critical target for malaria prevention and a focal point for next-generation interventions that aim at malaria elimination.
Tuberculosis (TB) is usually a preventable and curable disease, yet it remains the leading cause of death due to an infectious agent. Diabetes mellitus (DM) is a chronic metabolic disorder with ∼589 million adults living with it worldwide. Although the two diseases differ in etiology, pathophysiology, and socioeconomic burden, there is a significant link between them. Individuals with diabetes have a 1.9 times higher risk of developing TB. The co-occurrence of DM with TB compromises adaptive and innate immune responses, thereby increasing susceptibility to infections. The clinical indicators of TB in patients with DM are severe and show atypical radiological findings. World Health Organization (WHO) recommends that TB screening for DM individuals be conducted in settings where the TB prevalence in the general population is 100/100,000 population. TB treatment regimen in people with DM is in accordance with WHO guidelines and includes an initial intensive phase followed by a continuation phase. TB-DM co-occurrence is a significant global health challenge.
The global imperative for malaria eradication demands innovative strategies for antimalarial drug discovery, particularly in the face of growing drug resistance. This article describes how biological insights into Plasmodium parasites and their interactions with the human host are transforming the antimalarial drug discovery landscape. We examine the parasite's complex life cycle and its unique metabolic pathways and organelles as potential sources of drug targets. We demonstrate how advances in omics technologies and gene-editing tools are revolutionizing our understanding of parasite biology and accelerating target identification. Novel approaches to overcoming existing resistance mechanisms, with improved methods for predicting and preventing drug resistance, are presented, while promising new drug targets are discussed, as well as emerging approaches to target dormant forms of the parasite. The potential of host-directed therapies is explored together with notable case studies that highlight recent successes in biologically driven drug discovery efforts. The future of the field must embrace artificial intelligence, pharmacogenomics, and collaborative innovation anchored in ethical and equitable frameworks, to maximize global health impact.
Tuberculosis (TB) infection remains the largest reservoir sustaining the global TB epidemic and a critical target for TB elimination. Contemporary evidence has fundamentally reframed TB infection from a static latent state to a dynamic spectrum encompassing early clearance, contained infection, incipient disease, and asymptomatic TB, with heterogeneous risks of progression. This review synthesizes evidence on the natural history, epidemiology, diagnosis, treatment, and programmatic management of TB infection. It reviews World Health Organization (WHO)-recommended diagnostic tools, including interferon-γ release assays and antigen-specific skin tests, and highlights the limitations of current tests in predicting individual progression. Advances in TB preventive treatment, particularly short-course rifamycin-based regimens and evidence-based preventive therapy for drug-resistant TB exposure, are examined alongside persistent implementation gaps across the prevention cascade. The article also addresses priority populations, ethical considerations, and emerging research directions, including prognostic biomarkers, postexposure vaccines, and digital innovations. Effective TB infection management is presented as a central, integrated pillar of future TB elimination strategies.
The practice of malaria parasite genomics has evolved due to changing technology, expanded capacity, shifting funding, and broader applications. What began as a descriptive, discovery-focused field has grown into a global system for routine surveillance that informs public health decisions. This shift is supported by wider access to sequencing and new, cost-effective targeted sequencing methods. These changes, however, introduce new needs for standardizing data formats, analysis pipelines, sharing practices, and approaches for translating genomic insights into action. This review examines the progressive decentralization and diversification of malaria genomic data generation, highlights emerging applications enabled by these trends, and outlines key development needs and growth opportunities for this maturing field.
Human immunodeficiency virus (HIV)-associated tuberculosis (TB) is a leading cause of morbidity and mortality, and HIV fuels the TB epidemic in many countries. While there is overlap, there are also critical differences in the diagnosis and management of HIV-associated TB, compared to TB in HIV-uninfected patients. To prevent deaths, the diagnosis and treatment of TB in people with HIV (PWH) needs to occur without delay. Non-sputum-based samples are important to fill the diagnostic yield gap created by challenges obtaining sputum, and reduced sensitivity of sputum diagnostics in PWH. Management of rifampicin-susceptible HIV-associated TB remains a 6month regimen initially with four drugs; an alternative 4month rifapentine and moxifloxacin containing regimen cannot be used in certain PWH (those with CD4 count <100 cells/mm3) and is currently not widely available. Management of rifampicin-resistant TB now involves a 6month all-oral regimen for most patients, including PWH. While significant gains have recently been made toward decreasing mortality from HIV-associated TB, there are many ongoing challenges, some of which are being addressed in active clinical trials.
We are witnessing a sea change in the epidemiology of dermatophytosis. While commonly perceived as a mild infection of skin, hair, or nails, new human pathogens have emerged from the zoophilic Trichophyton mentagrophytes complex-Trichophyton indotineae and T. mentagrophytes internal transcribed spacer (ITS) genotype VII-that has caused a paradigm shift in management. Trichophyton indotineae has become the main etiological agent in the Indian subcontinent, characterized by widespread, sometimes severe, infection in immunocompetent individuals, and resistance to one or multiple standard antifungals. The evolution of terbinafine resistance has significant healthcare implications worldwide, while itraconazole resistance is also being reported. On the other hand, outbreaks of sexually transmissible T. mentagrophytes ITS genotype VII has changed our understanding of dermatophyte transmission. Healthcare providers are often challenged by the lack of testing capacity to diagnose and inform treatment decision-making. Continued advocacy and collaboration efforts are warranted.
Research in the 1970s showed that while retroviruses had been a key to identification of oncogenes, they were not actually a major cause of human cancer. Moreover, cells contained additional proto-oncogenes that did not necessarily have viral oncogene counterparts. In this excerpt from his forthcoming book, Joe Lipsick remembers the groundbreaking work on DNA transfection, chromosomal rearrangements, and gene amplification that identified the smoking guns responsible for activation of oncogenes such as RAS and revealed how translocations in immune cells produce cancer drivers like the Philadelphia chromosome.
Tuberculosis (TB) remains a critical global health challenge, disproportionately affecting populations in resource-limited settings and vulnerable groups such as children, pregnant individuals, and people living with human immunodeficiency virus (HIV). Despite significant progress in TB treatment and drug development, challenges, including antimicrobial resistance, drug-drug interaction, toxicity, and limited data in special populations, persist. This work explores the transformative advancements in TB therapeutics and the strategic priorities for improving outcomes, overcoming emerging resistance, and ameliorating tolerability.
Tuberculosis (TB) and acquired immunodeficiency syndrome (AIDS) are the leading causes of death from single infectious agents in low- and middle-income countries. Moreover, in the individual host, the two pathogens, Mycobacterium tuberculosis and human immunodeficiency virus (HIV), potentiate one another, accelerating the deterioration of immunological functions. In high-burden settings, HIV coinfection is the most important risk factor for TB disease, due to reactivation. Susceptibility to primary TB infection, or reinfection, is also elevated in people living with HIV (PLWH). TB disease also has a negative impact in PLWH not receiving antiretroviral therapy (ART), accelerating the progression to AIDS. The clinical management of HIV-associated TB includes the integration of effective TB treatment, use of concurrent ART, prevention of HIV-related comorbidities, management of drug cytotoxicity, and prevention/treatment of immune reconstitution inflammatory syndrome.
Tuberculosis (TB) remains a major global health challenge, with increasing prevalence of multidrug-resistant and extrapulmonary forms complicating diagnosis and management. Imaging plays a pivotal role in the early detection, characterization, and treatment monitoring of TB, particularly when clinical or microbiological findings are inconclusive. Modalities such as chest radiography, computed tomography (CT), ultrasound, magnetic resonance imaging (MRI), and 18F-fluorodeoxyglucose positron emission tomography combined with CT (18F-fluorodeoxyglucose [18F-FDG PET-CT]) provide critical insights into pulmonary, extrapulmonary, and disseminated TB. While chest X-ray is a first-line tool, CT and MRI offer superior anatomical detail, and PET-CT adds metabolic evaluation, aiding differentiation of active versus inactive disease and monitoring therapeutic response. Imaging is especially valuable in TB involving the central nervous system (CNS), musculoskeletal system, abdomen, and genitourinary tract. Advanced techniques and artificial intelligence (AI)-driven tools hold promise for enhancing diagnostic accuracy and guiding personalized treatment. This review comprehensively reviews the imaging spectrum of TB, underscoring its evolving role across the disease continuum.
Tuberculosis is an airborne infectious disease treated with combination therapeutic regimens. Adherence to long-term antituberculosis therapy is crucial to maintain adequate blood drug level. The emergence and spread of drug-resistant Mycobacterium tuberculosis strains is mainly favored by the inadequate medical management of patients. The therapeutic approach for drug-resistant tuberculosis is cumbersome, because of the poor, expensive, less effective, and toxic alternatives to the first-line drugs. New antituberculosis regimens have been recently approved by the health authorities shortening the duration of treatment for both drug-susceptible and drug-resistant tuberculosis drugs, including new drugs such as bedaquiline, delamanid, and pretomanid. Unfortunately, they cannot represent the definitive solution to the clinical management of drug-resistant tuberculosis forms, particularly in intermediate economy settings where the prevalence of drug-resistance is high (China, India, and Former Soviet Union countries among others). Last but not least, new evidence on the burden of posttuberculosis lung disease calls for effective prevention, treatment, and rehabilitation of this form of disease. New research and development activities are urgently needed. Public health policies are required to preserve the new and old therapeutic options.
Host-directed therapies (HDTs) to increase host control of Mycobacterium tuberculosis and limit the pathology caused by tuberculosis (TB) have advanced from the laboratory to the clinic. Several of these HDTs are repurposed drugs, which provide significant advantages over lengthy and costly traditional drug discovery approaches. This review covers the preclinical, retrospective clinical, and randomized controlled trial (RCT) evidence supporting the rapid repurposing of drugs for use as TB HDTs. We explore classes of potential HDTs by preclinical mechanism of action to identify cases where the concept of the therapy is sound, but the current availability of therapeutic agent is lacking. Apart from the drugs that have progressed through to RCTs, we highlight drugs with strong preclinical and retrospective portfolios that may form the next wave of trial candidates. Overall, HDTs are poised to contribute to a reduction in the global burden of TB and posttreatment lung disease.
Biological risks are increasingly shaped by globally distributed scientific capability, accelerating technological change and a rapidly evolving information environment. This review examines how these dynamics challenge traditional biosafety and biosecurity governance. It analyzes the internationalization of high-risk life science capacity, the expanding scope of pathogen research, and the implications of digitalization, artificial intelligence (AI)-enabled design tools and cloud laboratories. It then traces the historical foundations of biosafety and biosecurity, highlights the fragmentation across health, environmental and security instruments, and assesses how divergent national systems shape global vulnerability. The article further explores cross-border scientific collaboration, movement of materials and data, and the complexities of ambiguous outbreaks, investigation mechanisms and information integrity. It concludes by identifying strategic gaps and outlining priorities for a more adaptive, interoperable and equitable governance architecture capable of operating in a world where biological capability is widely dispersed and biological risks increasingly dematerialized.
Mycobacterium tuberculosis (Mtb) induces necrotic cell death of infected macrophages, which contributes to tissue necrosis and the progressive loss of lung function during tuberculosis. Mtb can induce multiple forms of programmed necrosis, including necroptosis, pyroptosis and ferroptosis. Concurrently, Mtb also inhibits apoptosis to prevent a host-beneficial cell death response. This paper will first provide an overview of the programmed cell death pathways relevant to Mtb infection. It will then discuss how Mtb activates and manipulates these pathways under different conditions, including a comparison of the findings across mouse, human, and zebrafish-derived macrophages.
