Severe fever with thrombocytopenia syndrome (SFTS) is an emerging disease in China, South Korea, and Japan caused by the tick-borne SFTS virus (SFTSV). Severe and fatal SFTS presents as a hemorrhagic fever characterized by high viral load, uncontrolled inflammatory response, dysregulated adaptive immunity, coagulation abnormalities, hemorrhage, and multiorgan failure with up to 33% case fatality rates (CFRs). Despite its public health significance in Asia, vaccines and specific therapeutics against SFTS are still unavailable. A better understanding of the pathogenesis of SFTS is crucial to improving medical countermeasures against this devastating disease. In this issue of the JCI, Suzuki and colleagues analyzed histopathological samples from 22 individuals who succumbed to SFTS, and identified antibody-producing B cell–lineage plasmablasts and macrophages as principal target cells for SFTSV infection in fatal SFTS. Their results suggest that SFTSV-infected post–germinal center B cells, plasmablasts, and macrophages affect systemic immunopathology and dysregulation, which likely leads to fatal outcomes.
Satoko Yamaoka, Carla Weisend, Hideki Ebihara
Liver disease as a result of chronic hepatitis C virus (HCV) infection is a global problem. While some HCV infections resolve spontaneously, viral persistence associates with compromised T cell immunity. In this issue of the JCI, Chen et al. and Coss et al. explored virus-specific CD4+ T cell response during HCV infection. Both studies evaluated the HCV-specific T cells of patients with different courses of infection. Chen et al. revealed that initial CD4+ T cell responses are similar during early infection and that T cell failure resulted from loss of the virus-specific T cells themselves. Coss et al. showed that HCV-specific CD4+ T cells temporarily recovered in some women following childbirth. These studies contribute to our understanding of CD4+ T cell functionality during different natural courses of infection, with the notable implication that restoring CD4+ T cell immunity might contribute to controlling HCV infection.
Benedikt Binder, Robert Thimme
KBTBD13 is a protein expressed in striated muscle whose precise function is unknown. Work by de Winter et al. in this issue of the JCI provides evidence that KBTBD13 localizes to the sarcomere and can directly bind actin. A mutation in KBTBD13 that is associated with nemaline myopathy alters the protein’s effects on actin, apparently increasing thin-filament stiffness and ultimately depressing contractile force and relaxation rate. We discuss here the implications of this new sarcomeric protein, some alternate explanations for the effects of KBTBD13R408C, and the advantages of using computational models to interpret functional data from muscle.
Stuart G. Campbell, Steven A. Niederer
Although iron deficiency continues to pose a problem for pregnant women and fetal development, an incomplete understanding of placental adaptation to limited iron availability has hindered efforts to identify optimal supplementation strategies. In this issue of the JCI, Sangkhae et al. used mouse models and human placentas to explore maternal, placental, and fetal responses to alterations in iron status during pregnancy. The authors identified molecular mechanisms that limit placental ability to upregulate iron transport in the setting of severe iron deficiency and explored a potential marker of placental maladaptation.
Nermi L. Parrow, Robert E. Fleming
XMEN (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia) is a complex primary immunological deficiency caused by mutations in MAGT1, a putative magnesium transporter. In this issue of the JCI, Ravell et al. greatly expand the clinical picture. The authors investigated patients’ mutations and symptoms and reported distinguishing immunophenotypes. They also showed that MAGT1 is required for N-glycosylation of key T cell and NK cell receptors that can account for some of the clinical features. Notably, transfection of the affected lymphocytes with MAGT1 mRNA restored both N-glycosylation and receptor function. Now we can add XMEN to the ever-growing family of congenital disorders of glycosylation (CDG).
Hudson H. Freeze
Excessive fecal bile acid (BA) loss causes symptoms in a large proportion of people diagnosed with irritable bowel syndrome with diarrhea, a common functional bowel disorder. This BA diarrhea (BAD) results from increased hepatic synthesis of BAs, with impaired negative feedback regulation by the ileal hormone fibroblast growth factor 19 (FGF19). In this issue of the JCI, Zhao et al. investigated BA metabolism, including fecal BAs, serum BAs, and FGF19, in patients and controls. They identified associations between fecal bacterial BA metabolism and specific microbiota, especially Clostridium scindens. These findings have been tested in a mouse model using microbiota transplants and antibiotic treatment. This group of organisms has potential as a biomarker for BAD and to be a target for therapy.
Julian R.F. Walters, Julian R. Marchesi
Albuminuria acts as a marker of progressive chronic kidney disease and as an indicator for initiation of hypertension treatment via modulation of the renin-angiotensin-aldosterone system with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors. However, the true significance of albuminuria has yet to be fully defined. Is it merely a marker of underlying pathophysiology, or does it play a causal role in the progression of kidney disease? The answer remains under debate. In this issue of the JCI, Bedin et al. used next-generation sequencing data to identify patients with chronic proteinuria who had biallelic variants in the cubilin gene (CUBN). Through investigation of these pathogenic mutations in CUBN, the authors have further illuminated the clinical implications of albuminuria.
Andrew Beenken, Jonathan M. Barasch, Ali G. Gharavi
Pancreatic ductal adenocarcinomas (PDACs) are classically immunologically cold tumors that have failed to demonstrate a significant response to immunotherapeutic strategies. This feature is attributed to both the immunosuppressive tumor microenvironment (TME) and limited immune cell access due to the surrounding stromal barrier, a histological hallmark of PDACs. In this issue of the JCI, Sharma et al. employ a broad glutamine antagonist, 6-diazo-5-oxo-l-norleucine (DON), to target a metabolic program that underlies both PDAC growth and hyaluronan production. Their findings describe an approach to converting the PDAC TME into a hot TME, thereby empowering immunotherapeutic strategies such as anti-PD1 therapy.
Won Jin Ho, Elizabeth M. Jaffee
Brown adipose tissue (BAT) contains mitochondria-enriched thermogenic fat cells (brown adipocytes) that play a crucial role in the regulation of energy metabolism and systemic glucose homeostasis. It was presumed that brown adipocytes are composed of a homogeneous cell population. In this issue of the JCI, however, Song and colleagues report a previously uncharacterized subpopulation of brown adipocytes that display distinct characteristics from the conventional brown adipocytes in their molecular signature, regulation, and fuel utilization. The present study provides novel insight into our understanding of cellular heterogeneity in adipose tissues.
Yasuo Oguri, Shingo Kajimura
Unconventional T cell subsets, including donor-unrestricted T cells (DURTs) and γδ T cells, are promising new players in the treatment and prevention of infectious diseases. In this issue of the JCI, Ogongo et al. used T cell receptor (TCR) sequencing to characterize unconventional T cell subsets in surgical lung resections and blood from Mycobacterium tuberculosis–infected (Mtb-infected) individuals with and without HIV coinfection. The study revealed highly localized expansions of γδ T cell clonotypes not previously associated with the immune response to Mtb and demonstrates the power of high-throughput analysis of the TCR repertoire directly from infected tissue. The findings contribute to our understanding of tuberculosis control and have implications for the development of both therapeutic and vaccination strategies.
Corinna A. Kulicke, Deborah A. Lewinsohn, David M. Lewinsohn
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