Biology subjects

Amer, A.

Publications and source records attributed to Amer, A..

6 recordsLinked to original sources

bioRxiv2026

Gelsolin protects mitochondria and regulates inflammation during Legionella pneumophila infection

Legionella pneumophila (L. pneumophila) is the causative agent of Legionnaires' disease, a severe bacterial pneumonia. Difficulty in diagnosing Legionnaires' disease leads to an underreporting of cases and delayed treatment. Rapid-acting, broad-spectrum therapies are needed to treat pathology while avoiding antibiotic resistance. We showed that gelsolin knockout (gsn-/-) mice succumb more quickly to severe L. pneumophila infection despite no difference in bacterial loads in the lung compared to wild type mice. There is an increase in CXCL1/KC production from macrophages from gsn-/- mice, which is accompanied by increased neutrophils and apoptosis in their lungs. Neutrophils lacking gelsolin produce fewer neutrophil extracellular traps, and their mitochondrial capacity is diminished in response to L. pneumophila. Gelsolin is required for maintaining mitochondrial network morphology and respiration in L. pneumophila infected macrophages. When given recombinant gelsolin protein, gsn-/- mice survive significantly longer during severe L. pneumophila infection, with reduced lung pathology, and the inflammatory signature of their macrophages was reduced in vitro. Together, gelsolin protects mice during severe L. pneumophila infection, dampens inflammation, promotes mitochondrial health, and maintains neutrophil function.

immunology↗

bioRxiv2025

Caspase-11 Mediated Hyperinflammation Impairs CD8⁺ T Cell Immunity and Viral Clearance in Severe SARS-CoV-2 Infection

Severe SARS-CoV-2 infection is characterized by lung hyperinflammation, impaired interferon responses, and defective T-cell activation, yet the molecular drivers of these immune dysregulations remain incompletely understood. Caspase-11 (CASP11), a key mediator of the non-canonical inflammasome, has been shown to mediate an innate hyperinflammatory response and cytokine release in a non-severe, non-lethal SARS-CoV-2 infection model. However, the role played by CASP11 in severe SARS-CoV-2 disease and how it impacts adaptive immunity is not identified. Here, we newly discover that CASP11 exacerbates severe SARS-CoV-2 pathogenesis by amplifying early innate immune responses while concurrently impairing antiviral CD8 T-cell immunity. Using global knockouts, reciprocal bone marrow chimeras, and phagocyte-monocyte system (PMS) cell-specific CASP11 deletion models, we show that CASP11 deletion in monocyte-derived cells reduces lung inflammation, enhances type I and II interferon signaling, and promotes robust virus-specific effector CD8 T-cell response. This was associated with enhanced viral clearance and improved survival, even under lethal infection conditions. Importantly, CASP11 KO mice also exhibited faster resolution of post-viral inflammation, suggesting a role in long-term immune remodeling. These findings position CASP11 as a promising immunomodulatory target for acute and delayed manifestations of severe SARS-CoV-2.

microbiology↗

bioRxiv2025

Activity Protects Spinal Premotor Interneurons from Microglial Phagocytosis and Transneuronal Degeneration After Corticospinal Injury

Spinal premotor circuits play a fundamental role in motor control. The corticospinal tract (CST) provides control signals to premotor circuits in the spinal cord, guiding voluntary skilled movements. Unilateral selective lesion of the CST in the medullary pyramidal tract (PTX) produces transneuronal degeneration, whereby Choline Acetyltransferase-positive (ChAT) premotor interneurons contralesionally undergo non-apoptotic degeneration by microglial phagocytosis. Evidence shows that transneuronal degeneration has an activity dependence: MCX inactivation produces transneuronal degeneration and spinal DC neuromodulation after PTX ameliorates it. This study expands our understanding of transneuronal degeneration mechanisms by examining the activity-dependence of degeneration vulnerability and the implications for motor recovery in a mouse model of a complete CST lesion model (bilateral PTX). We address four key unanswered questions: Are Chx10 (VGlut2) interneurons, the largest spinal interneuron class to receive direct synaptic connections from the CST vulnerable to transneuronal degeneration after CST loss; using DREADD neuromodulation, what are effective sources of presynaptic activation for protecting spinal premotor interneurons after CST loss; how are ameliorating transneuronal interneuron degeneration and reducing microglial activation associated; and does effective rescue of interneuron degeneration rescue grip strength after injury? Transneuronal degeneration is a pervasive pathophysiological change injury; CST lesion produces significant Chx10 interneuron loss. Multiple sources of neuronal DREADD activation--motor cortex, reticular formation, and spinal interneurons--are effective in ameliorating transneuronal degeneration. Interneuron rescue is strongly associated with ameliorating inflammation, showing potential causality between interneuron degeneration and inflammation after CST lesion. Finally, rescuing spinal interneurons was associated with restoring function. Our findings demonstrate the interplay between neuronal activity, microglia actions mediating transneuronal degeneration, and motor recovery following CNS injury.

neuroscience↗

bioRxiv2023

The Septin Cytoskeleton is Required for Plasma Membrane Repair

Mammalian cells are frequently exposed to mechanical and biochemical stressors resulting in plasma membrane injuries. Repair mechanisms reseal the plasma membrane to restore homeostasis and prevent cell death. In the present work, a silencing RNA screen was performed to uncover plasma membrane repair mechanisms of cells exposed to a pore-forming toxin (listeriolysin O). This screen identified molecules previously known to repair the injured plasma membrane such as annexin A2 (ANXA2) as well as novel plasma membrane repair candidate proteins. Of the novel candidates, we focused on septin 7 (SEPT7) because the septins are an important family of conserved eukaryotic cytoskeletal proteins. Using diverse experimental approaches, we established for the first time that SEPT7 plays a general role in plasma membrane repair of cells perforated by pore-forming toxins and mechanical wounding. Remarkably, upon cell injury, the septin cytoskeleton is extensively redistributed in a Ca2+-dependent fashion, a hallmark of plasma membrane repair machineries. The septins reorganize into subplasmalemmal domains arranged as knob and loop (or ring) structures containing F-actin, myosin II, and annexin A2 (ANXA2) and protrude from the cell surface. Importantly, the formation of these domains correlates with the plasma membrane repair efficiency. Super-resolution microscopy shows that septins and actin are arranged in intertwined filaments associated with ANXA2. Silencing SEPT7 expression prevented the formation of the F-actin/myosin II/ANXA2 domains, however, silencing expression of ANXA2 had no observable effect on their formation. These results highlight the key structural role of the septins in remodeling the plasma membrane and in the recruitment of the repair molecule ANXA2. Collectively, our data support a novel model in which the septin cytoskeleton acts as a scaffold to promote the formation of plasma membrane repair domains containing contractile F-actin and annexin A2.

cell biology↗

bioRxiv2023

Physiological phenotypes differ among color morphs in introduced populations of the common wall lizard, Podarcis muralis

Many species exhibit color polymorphisms which have distinct physiological and behavioral characteristics. However, the consistency of morph trait covariation patterns across species, time, and ecological contexts remains unclear. This trait covariation is especially relevant in the context of invasion biology and urban adaptation. Specifically, physiological and behavioral traits pertaining to energy maintenance are crucial to fitness, given their immediate ties to individual reproduction, growth, and population establishment. We investigated the physiological and behavioral traits of Podarcis muralis, a versatile color polymorphic species that thrives in urban environments (including invasive populations in Ohio, USA). We measured five physiological and behavioral traits (circulating corticosterone and triglycerides, hematocrit, body condition, and field body temperature) which compose an integrated multivariate phenotype. We then tested variation among stable color polymorphisms in the context of establishment in an urban environment. We found that the traits describing physiological status and strategy shifted across the active season in a morph-dependent manner-the white and yellow morphs exhibited clearly different multivariate physiological phenotypes, characterized primarily by differences in circulating corticosterone. This suggests that morphs have different strategies in physiological regulation, the flexibility of which is crucial to urban adaptation. The white-yellow morph exhibited an intermediate phenotype, suggesting an intermediary energy maintenance strategy. Orange morphs also exhibited distinct phenotypes, but the low prevalence of this morph in our study populations precludes clear interpretation. Our work provides insight into how differences among stable polymorphisms exist across axes of the phenotype and how this variation may aid in establishment within novel environments. O_QDEpigraph: "If you are only moved by color relationships, you are missing the point." - Mark Rothko, Latvian-American abstract painter C_QD

zoology↗

bioRxiv2021

Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and thrombosis

SARS-CoV-2 is a worldwide health concern, and new treatment strategies are needed 1. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that human caspase-4 (CASP4), and its mouse homologue, caspase-11 (CASP11), are upregulated in SARS-CoV-2 infections, and that CASP4 expression correlates with severity of SARS-CoV-2 infection in humans. SARS-CoV-2-infected Casp11-/- mice were protected from severe weight loss and lung pathology, including blood vessel damage, compared to wild-type (WT) and gasdermin-D knock out (Gsdmd-/-) mice. GSDMD is a downstream effector of CASP11 and CASP1. Notably, viral titers were similar in the three genotypes. Global transcriptomics of SARS-CoV-2-infected WT, Casp11-/- and Gsdmd-/- lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp11-/- mice. We confirmed that protein levels of inflammatory mediators IL-1{beta}, IL6, and CXCL1, and neutrophil functions, were reduced in Casp11-/- lungs. Additionally, Casp11-/- lungs accumulated less von Willebrand factor, a marker for endothelial damage, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity. Overall, our results demonstrate that CASP4/11, promotes detrimental SARS-CoV-2-associated inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.

immunology↗