Neutrophils (also called polymorphonuclear leukocytes, PMNs) are the most abundant white blood cells in humans and play a central role in innate host defense. Another distinguishing feature of PMNs ...is their short lifespan. Specifically, these cells survive for less than 24 hours in the bloodstream and are inherently pre-programed to die by constitutive apoptosis. Recent data indicate that this process is regulated by intracellular signaling and changes in gene expression that define an “apoptosis differentiation program.” Infection typically accelerates neutrophil turnover, and as such, phagocytosis induced cell death (PICD) and subsequent clearance of the corpses by macrophages are essential for control of infection and resolution of the inflammatory response. Herein we reprise recent advances in our understanding of the molecular mechanisms of neutrophil apoptosis with a focus on regulatory factors and pathway intermediates that are specific to this cell type. In addition, we summarize mechanisms whereby perturbation of PMN death contributes directly to the pathogenesis of many infectious and inflammatory disease states.
Over the past decades, significant strides have been made in understanding the pathobiology, prognosis, and treatment options for mantle cell lymphoma (MCL). The heterogeneity observed in MCL's ...biology, genomics, and clinical manifestations, including indolent and aggressive forms, is intricately linked to factors such as the mutational status of the variable region of the immunoglobulin heavy chain gene, epigenetic profiling, and Sox11 expression. Several intriguing subtypes of MCL, such as Cyclin D1-negative MCL, in situ mantle cell neoplasm, CCND1/IGH FISH-negative MCL, and the impact of karyotypic complexity on prognosis, have been explored. Notably, recent immunochemotherapy regimens have yielded long-lasting remissions in select patients. The therapeutic landscape for MCL is continuously evolving, with a shift towards nonchemotherapeutic agents like ibrutinib, acalabrutinib, and venetoclax. The introduction of BTK inhibitors has brought about a transformative change in MCL treatment. Nevertheless, the challenge of resistance to BTK inhibitors persists, prompting ongoing efforts to discover strategies for overcoming this resistance. These strategies encompass non-covalent BTK inhibitors, immunomodulatory agents, BCL2 inhibitors, and CAR-T cell therapy, either as standalone treatments or in combination regimens. Furthermore, developing novel drugs holds promise for further improving the survival of patients with relapsed or refractory MCL. In this comprehensive review, we methodically encapsulate MCL's clinical and pathological attributes and the factors influencing prognosis. We also undertake an in-depth examination of stratified treatment alternatives. We investigate conceivable resistance mechanisms in MCL from a genetic standpoint and offer precise insights into various therapeutic approaches for relapsed or refractory MCL.
Francisella tularensis is a facultative intracellular bacterium that infects many cell types, including neutrophils. We demonstrated previously that F. tularensis inhibits NADPH oxidase assembly and ...activity and then escapes the phagosome to the cytosol, but effects on other aspects of neutrophil function are unknown. Neutrophils are short-lived cells that undergo constitutive apoptosis, and phagocytosis typically accelerates this process. We now demonstrate that F. tularensis significantly inhibited neutrophil apoptosis as indicated by morphologic analysis as well as annexin V and TUNEL staining. Thus, ∼80% of infected neutrophils remained viable at 48 h compared with ∼50% of control cells, and ∼40% of neutrophils that ingested opsonized zymosan. In keeping with this finding, processing and activation of procaspases-8, -9, and -3 were markedly diminished and delayed. F. tularensis also significantly impaired apoptosis triggered by Fas crosslinking. Of note, these effects were dose dependent and could be conferred by either intracellular or extracellular live bacteria, but not by formalin-killed organisms or isolated LPS and capsule, and were not affected by disruption of wbtA2 or FTT1236/FTL0708-genes required for LPS O-antigen and capsule biosynthesis. In summary, we demonstrate that F. tularensis profoundly impairs constitutive neutrophil apoptosis via effects on the intrinsic and extrinsic pathways, and thereby define a new aspect of innate immune evasion by this organism. As defects in neutrophil turnover prevent resolution of inflammation, our findings also suggest a mechanism that may in part account for the neutrophil accumulation, granuloma formation, and severe tissue damage that characterizes lethal pneumonic tularemia.
Francisella tularensis infects several cell types including neutrophils, and aberrant neutrophil accumulation contributes to tissue destruction during tularaemia. We demonstrated previously that ...F. tularensis strains Schu S4 and live vaccine strain markedly delay human neutrophil apoptosis and thereby prolong cell lifespan, but the bacterial factors that mediate this aspect of virulence are undefined. Herein, we demonstrate that bacterial conditioned medium (CM) can delay apoptosis in the absence of direct infection. Biochemical analyses show that CM contained F. tularensis surface factors as well as outer membrane components. Our previous studies excluded roles for lipopolysaccharide and capsule in apoptosis inhibition, and current studies of 14C acetate‐labelled bacteria argue against a role for other bacterial lipids in this process. At the same time, studies of isogenic mutants indicate that TolC and virulence factors whose expression requires FevR or MglA were also dispensable, demonstrating that apoptosis inhibition does not require Type I or Type VI secretion. Instead, we identified bacterial lipoproteins (BLPs) as active factors in CM. Additional studies of isolated BLPs demonstrated dose‐dependent neutrophil apoptosis inhibition via a TLR2‐dependent mechanism that is significantly influenced by a common polymorphism, rs5743618, in human TLR1. These data provide fundamental new insight into pathogen manipulation of neutrophil lifespan and BLP function.
Tularemia is a disease characterized by profound neutrophil accumulation and tissue destruction. The causative organism, Francisella tularensis, is a facultative intracellular bacterium that ...replicates in neutrophil cytosol, inhibits caspase activation and profoundly prolongs cell lifespan. Here, we identify unique features of this infection and provide fundamental insight into the mechanisms of apoptosis inhibition. Mitochondria are critical regulators of neutrophil apoptosis. We demonstrate that F. tularensis significantly inhibits Bax translocation and Bid processing during 24-48 h of infection, and in this manner sustains mitochondrial integrity. Downstream of mitochondria, X-linked inhibitor of apoptosis protein (XIAP) and proliferating cell nuclear antigen (PCNA) inhibit caspase-9 and caspase-3 by direct binding. Notably, we find that PCNA disappeared rapidly and selectively from infected cells, thereby demonstrating that it is not essential for neutrophil survival, whereas upregulation of calpastatin correlated with diminished calpain activity and reduced XIAP degradation. In addition, R-roscovitine is a cyclin-dependent kinase inhibitor developed for the treatment of cancer; it also induces neutrophil apoptosis and can promote the resolution of several infectious and inflammatory disorders. We confirm the ability of R-roscovitine to induce neutrophil apoptosis, but also demonstrate that its efficacy is significantly impaired by F. tularensis. Collectively, our findings advance the understanding of neutrophil apoptosis and its capacity to be manipulated by pathogenic bacteria.
Pathogenic mycobacteria, which cause multiple diseases including tuberculosis, secrete factors essential for disease via the ESX-1 protein export system and are partially protected from host defenses ...by their lipid-rich cell envelopes. These pathogenic features of mycobacterial biology are believed to act independently of each other. Key ESX-1 components include three ATPases, and EccA1 (Mycobacterium marinum MMAR_5443; M. tuberculosis Rv3868) is the least characterized. Here we show that M. marinum EccA1's ATPase activity is required for ESX-1-mediated protein secretion, and surprisingly for the optimal synthesis of mycolic acids, integral cell-envelope lipids. Increased mycolic acid synthesis defects, observed when an EccA1-ATPase mutant is expressed in an eccA1-null strain, correlate with decreased in vivo virulence and intracellular growth. These data suggest that two mycobacterial virulence hallmarks, ESX-1-dependent protein secretion and mycolic acid synthesis, are critically linked via EccA1.
► ESX-1 protein export and full mycolate production require EccA1 ATPase function ► EccA1 and lipid synthases important for virulence copurify from the cytosol ► ATPase mutant EccA1 expression sensitizes cells to mycolic acid synthesis stress ► Mycolate synthesis defects may support decreased in vivo virulence and growth
The third flight of the
High-Resolution Coronal Imager
(Hi-C 2.1) occurred on May 29, 2018; the Sounding Rocket was launched from White Sands Missile Range in New Mexico. The instrument has been ...modified from its original configuration (Hi-C 1) to observe the solar corona in a passband that peaks near 172 Å, and uses a new, custom-built low-noise camera. The instrument targeted Active Region 12712, and captured 78 images at a cadence of 4.4 s (18:56:22 – 19:01:57 UT; 5 min and 35 s observing time). The image spatial resolution varies due to quasi-periodic motion blur from the rocket; sharp images contain resolved features of at least 0.47 arcsec. There are coordinated observations from multiple ground- and space-based telescopes providing an unprecedented opportunity to observe the mass and energy coupling between the chromosphere and the corona. Details of the instrument and the data set are presented in this paper.
The outcomes of survivors of critical illness due to coronavirus disease (COVID-19) compared with non-COVID-19 are yet to be established.
We aimed to investigate new disability at 6 months in ...mechanically ventilated patients admitted to Australian ICUs with COVID-19 compared with non-COVID-19.
We included critically ill patients with COVID-19 and non-COVID-19 from two prospective observational studies. Patients were eligible if they were adult (age ⩾ 8 yr) and received ⩾24 hours of mechanical ventilation. In addition, patients with COVID-19 were eligible with a positive laboratory PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Demographic, intervention, and hospital outcome data were obtained from electronic medical records. Survivors were contacted by telephone for functional outcomes with trained outcome assessors using the World Health Organization Disability Assessment Schedule 2.0. Between March 6, 2020, and April 21, 2021, 120 critically ill patients with COVID-19, and between August 2017 and January 2019, 199 critically ill patients without COVID-19, fulfilled the inclusion criteria. Patients with COVID-19 were older (median interquartile range, 62 55-71 vs. 58 44-69 yr;
= 0.019) with a lower Acute Physiology and Chronic Health Evaluation II score (17 13-20 vs. 19 15-23;
= 0.011). Although duration of ventilation was longer in patients with COVID-19 than in those without COVID-19 (12 5-19 vs. 4.8 2.3-8.8 d;
< 0.001), 180-day mortality was similar between the groups (39/120 32.5% vs. 70/199 35.2%;
= 0.715). The incidence of death or new disability at 180 days was similar (58/93 62.4% vs. 99/150 66/0%;
= 0.583).
At 6 months, there was no difference in new disability for patients requiring mechanical ventilation for acute respiratory failure due to COVID-19 compared with non-COVID-19. Clinical trial registered with www.clinicaltrials.gov (NCT04401254).
The third flight of the High-Resolution Coronal Imager (Hi-C 2.1) occurred on May 29, 2018, the Sounding Rocket was launched from White Sands Missile Range in New Mexico. The instrument has been ...modified from its original configuration (Hi-C 1) to observe the solar corona in a passband that peaks near 172 Angstrom and uses a new, custom-built low-noise camera. The instrument targeted Active Region 12712, and captured 78 images at a cadence of 4.4 sec (18:56:22 - 19:01:57 UT; 5 min and 35 sec observing time). The image spatial resolution varies due to quasi-periodic motion blur from the rocket; sharp images contain resolved features of at least 0.47 arcsec. There are coordinated observations from multiple ground- and space-based telescopes providing an unprecedented opportunity to observe the mass and energy coupling between the chromosphere and the corona. Details of the instrument and the data set are presented in this paper.
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