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Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M pro ) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M pro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M pro -induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19. A novel study led by scientists in Lübeck, Germany, shows that SARS-CoV-2-infected brain endothelial cells undergo cell death due to the cleavage of NEMO by the viral protease M pro , potentially causing cerebral COVID-19 and ‘long COVID’ symptoms.

Key Points Tuberculous meningitis (TBM) causes death and disability, with especially high rates of poor outcomes in children and individuals with an HIV-1 co-infection Important risk factors for poor outcome are delayed diagnosis, delayed treatment, advanced disease, and antitubercular drug resistance Intracerebral and spinal pathology in TBM is mediated by a dysregulated inflammatory response that contributes to meningitis, tuberculoma formation, arteritis, obstruction of cerebrospinal fluid (CSF) flow, and vascular complications including stroke Diagnosis of TBM is insensitive and laborious; clinical scoring algorithms are imperfect and few rigorous evaluations of diagnostics have been performed Multidrug antitubercular antibiotic therapy is the mainstay of treatment; however, CSF penetration is probably a major limitation of these therapies, and evidence supporting dosage and treatment combinations is weak The supportive management of TBM complications, which include hyponatraemia, hydrocephalus, hypoxic brain damage and infarction, is poorly understood and researched, but is vital to outcome Tuberculous menigitis (TBM) presents a major health burden around the world, especially in individuals with concomitant HIV infection, in whom mortality is nearly 50%. Here, members of the TBM International Research Consortium summarize our current understanding of TBM pathogenesis, diagnosis and management, and discuss key avenues for future research. Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens for TBM are based on those used to treat pulmonary tuberculosis, which probably results in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood–brain barrier penetrance. The role of adjunctive anti-inflammatory, host-directed therapies — including corticosteroids, aspirin and thalidomide — has not been extensively explored. To address this deficit, two expert meetings were held in 2009 and 2015 to share findings and define research priorities. This Review summarizes historical and current research into TBM and identifies important gaps in our knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential modulation; vascular and hypoxia-mediated tissue injury; the role of intensified antibiotic treatment; and the importance of rapid and accurate diagnostics and supportive care in TBM.

Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) is an agnostic method for broad-based diagnosis of central nervous system (CNS) infections. Here we analyzed the 7-year performance of clinical CSF mNGS testing of 4,828 samples from June 2016 to April 2023 performed by the University of California, San Francisco (UCSF) clinical microbiology laboratory. Overall, mNGS testing detected 797 organisms from 697 (14.4%) of 4,828 samples, consisting of 363 (45.5%) DNA viruses, 211 (26.4%) RNA viruses, 132 (16.6%) bacteria, 68 (8.5%) fungi and 23 (2.9%) parasites. We also extracted clinical and laboratory metadata from a subset of the samples ( n  = 1,164) from 1,053 UCSF patients. Among the 220 infectious diagnoses in this subset, 48 (21.8%) were identified by mNGS alone. The sensitivity, specificity and accuracy of mNGS testing for CNS infections were 63.1%, 99.6% and 92.9%, respectively. mNGS testing exhibited higher sensitivity (63.1%) than indirect serologic testing (28.8%) and direct detection testing from both CSF (45.9%) and non-CSF (15.0%) samples ( P  < 0.001 for all three comparisons). When only considering diagnoses made by CSF direct detection testing, the sensitivity of mNGS testing increased to 86%. These results justify the routine use of diagnostic mNGS testing for hospitalized patients with suspected CNS infection. Next-generation metagenomic testing increases the accuracy and sensitivity of the etiology of central nervous system infections in hospitalized patients.

Classically, the CNS is described as displaying immune privilege, as it shows attenuated responses to challenge by alloantigen. However, the CNS does show local inflammation in response to infection. Although pathogen access to the brain parenchyma and retina is generally restricted by physiological and immunological barriers, certain pathogens may breach these barriers. In the CNS, such pathogens may either cause devastating inflammation or benefit from immune privilege in the CNS, where they are largely protected from the peripheral immune system. Thus, some pathogens can persist as latent infections and later be reactivated. We review the consequences of immune privilege in the context of CNS infections and ask whether immune privilege may provide protection for certain pathogens and promote their latency.

Japanese encephalitis is a mosquito-borne disease that occurs in Asia and is caused by Japanese encephalitis virus (JEV), a member of the genus Flavivirus. Although many flaviviruses can cause encephalitis, JEV causes particularly severe neurological manifestations. The virus causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition. Despite substantial advances in our understanding of Japanese encephalitis from in vitro studies and animal models, studies of pathogenesis and treatment in humans are lagging behind. Few mechanistic studies have been conducted in humans, and only four clinical trials of therapies for Japanese encephalitis have taken place in the past 10 years despite an estimated incidence of 69,000 cases per year. Previous trials for Japanese encephalitis might have been too small to detect important benefits of potential treatments. Many potential treatment targets exist for Japanese encephalitis, and pathogenesis and virological studies have uncovered mechanisms by which these drugs could work. In this Review, we summarize the epidemiology, clinical features, prevention and treatment of Japanese encephalitis and focus on potential new therapeutic strategies, based on repurposing existing compounds that are already suitable for human use and could be trialled without delay. We use our newly improved understanding of Japanese encephalitis pathogenesis to posit potential treatments and outline some of the many challenges that remain in tackling the disease in humans.

Key Points In most clinical centres in Africa, despite access to antiretroviral therapies, cases of HIV-associated cryptococcal meningitis (CM) are not decreasing owing to challenges with retention and adherence to HIV care CM in HIV-negative individuals is relatively rare, but carries a mortality at least as high as in HIV-associated disease; therefore, CM must be considered in all cases of lymphocytic meningitis — even in the apparently immunocompetent A point-of-care, lateral flow 'dipstick' test to detect cryptococcal antigen in the blood or cerebrospinal fluid (CSF) is a significant advance: it is highly specific, sensitive, and easy to use Amphotericin B (in conventional or liposomal formulation) combined with flucytosine remains the induction therapy of choice, and is associated with a survival advantage over amphotericin B alone Measurement of CSF opening pressure and appropriate management of raised CSF pressure can reduce mortality Any future attempts at adjunctive immunotherapies will need to be closely guided by the specific immune status of the host at the time of any intervention Cryptococcal meningitis is a major cause of morbidity and mortality in immunocompromized individuals, and, even in apparently immunocompetent individuals, carries a high risk of mortality. Treatment in immunocompromized patients is challenging because these patients are at risk of immune reconstitution inflammatory syndrome (IRIS). This Review summarizes the diagnosis and treatment of cryptococcal disease in various disease. HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions.

Key Points Despite entering the era of combination antiretroviral therapy (CART), HIV-associated neurocognitive disorder (HAND) remains prevalent; however, less severe forms of HAND now predominate, and the most severe form, HIV-associated dementia, is rare In individuals treated with CART, the risk of HAND increases with age and in the presence of cardiovascular disease risk factors Latent HIV can persist in the brain even when systemic virological control is achieved with CART, thereby hampering efforts to eradicate HIV Animal models of CNS HIV infection — such as macaques infected with simian immunodeficiency virus — develop severe HAND, viral encephalitis and neuronal apoptosis, and are central to understanding the immunopathogenesis of HIV-induced CNS damage A growing body of work indicates that mild HAND can be modelled in immunocompetent mice infected with chimeric HIV (a model known as EcoHIV), and in chronically HIV-infected immunodeficient mice reconstituted with human immune systems To date, clinical trials of HAND therapies have been unsuccessful, but further trials for the treatment of HAND are forthcoming, including a trial of intranasal insulin Despite highly effective combination antiretroviral therapies, the prevalence of HIV-associated neurocognitive disorder (HAND) has not reduced. To date, clinical trials of HAND therapies have been unsuccessful, calling for better understanding of HAND pathogenesis to develop more-effective treatment strategies. In this Review, Justin McArthur and colleagues discuss recent proceedings in understanding the immunopathogenesis of HAND, drawing from human studies and animal models. In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies — treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism — are needed to reverse or improve HAND-related neurological dysfunction.

Key Points There is a growing appreciation that the gut microbiota plays a key role in maintaining homeostasis and that a disruption in its composition contributes to various disease states, including CNS disorders. The concept of a microbiota–gut–brain axis, although debated, is emerging to capture the importance that the microbiota has on regulating bidirectional gut–brain communication pathways. It is clear that stress, including stress in early life, can alter microbiota composition and this can have marked consequences on physiology in adulthood. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain. Although not as conceptually or empirically developed, the gut microbiota has also been implicated in obesity, autism and multiple sclerosis. Mechanisms as to how the microbiota are affecting gut–brain signalling are only now being unravelled. These mechanisms may include alterations in microbial composition, immune activation, vagus nerve signalling, alterations in tryptophan metabolism, production of specific microbial neuroactive metabolites and bacterial cell wall sugars. Harnessing such mechanisms may pave the way for microbial-based therapeutics for various CNS disorders. Gut microbiota are increasingly being recognized as influencing many aspects of human health. In this Review, Cryan and Dinan discuss rapidly emerging evidence that the gut microbiota also influence brain and behaviour and may have a role in anxiety, mood, cognition and pain. Recent years have witnessed the rise of the gut microbiota as a major topic of research interest in biology. Studies are revealing how variations and changes in the composition of the gut microbiota influence normal physiology and contribute to diseases ranging from inflammation to obesity. Accumulating data now indicate that the gut microbiota also communicates with the CNS — possibly through neural, endocrine and immune pathways — and thereby influences brain function and behaviour. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain. Thus, the emerging concept of a microbiota–gut–brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.

Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 + T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45RO + GZMB + Ki67 + ) CD4 cells. We also identified Epstein–Barr virus-specific T cell receptors and EBV + lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 + and CD8 + T cells as culprits of checkpoint inhibitor-associated immune encephalitis. Deep molecular profiling of a single case of severe anti-PD-1-induced neurotoxicity shows oligoclonal cytotoxic memory CD4 + T cells are enriched in inflamed brain tissue.

The idea that infectious agents in the brain have a role in the pathogenesis of Alzheimer disease (AD) was proposed nearly 30 years ago. However, this theory failed to gain substantial traction and was largely disregarded by the AD research community for many years. Several recent discoveries have reignited interest in the infectious theory of AD, culminating in a debate on the topic at the Alzheimer’s Association International Conference (AAIC) in July 2019. In this Viewpoint article, experts who participated in the AAIC debate weigh up the evidence for and against the infectious theory of AD and suggest avenues for future research and drug development.In 2019, the Alzheimer’s Association International Conference featured a debate on the role of infections in AD pathogenesis. Here, participants from that debate discuss the evidence regarding the infectious theory of AD and suggest avenues for future investigation.