Spatiotemporal analysis of lung immune dynamics in lethal Coccidioides posadasii infection

mBio, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 29, 2024

ABSTRACT Coccidioidomycosis, or Valley fever, is a lung disease caused by inhalation of Coccidioides fungi, prevalent in the Southwestern United States, Mexico, and parts Central South America. Annually, States reports 10,000–20,000 cases, although those numbers are expected to increase as climate change expands fungal geographic range. While 60% infections asymptomatic, 40% symptomatic often misdiagnosed due similarities with bronchitis pneumonia. A small subset infection progress severe illness, necessitating better understanding immune responses during lethal infection. Using single-cell RNA sequencing spatial transcriptomics, we characterized We identified monocyte-derived Spp1 -expressing macrophages potential mediators tissue remodeling fibrosis, marked high expression profibrotic proinflammatory transcripts. These showed elevated TGF-β IL-6 signaling, pathways involved fibrosis pathogenesis. Additionally, observed significant neutrophil infiltration defective lymphocyte responses, indicating adaptive immunity dysregulation lethal, acute findings enhance our suggest new therapeutic targets. IMPORTANCE commonly known which With potentially expanding range this fungus, crucial. Our study used advanced techniques analyze infection, identifying specific cells that may contribute damage fibrosis. provide insights into mechanisms targets for intervention, could improve outcomes patients suffering from fever.

Language: Английский

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SARS-CoV2 infection in whole lung primarily targets macrophages that display subset-specific responses

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: Aug. 15, 2024

Abstract Deciphering the initial steps of SARS-CoV-2 infection, that influence COVID-19 outcomes, is challenging because animal models do not always reproduce human biological processes and in vitro systems recapitulate histoarchitecture cellular composition respiratory tissues. To address this, we developed an innovative ex vivo model whole lung infection with SARS-CoV-2, leveraging a transplantation technique. Through single-cell RNA-seq, identified alveolar monocyte-derived macrophages (AMs MoMacs) were targets virus. Exposure isolated AMs, MoMacs, classical monocytes non-classical (ncMos) to variants revealed while all subsets responded, MoMacs produced higher levels inflammatory cytokines than ncMos contributed least. A Wuhan lineage appeared be more potent D614G virus, dose-dependent manner. Amidst ambiguity literature regarding cell target, our study reveals AMs are dominant primary entry points for suggests their responses may conduct subsequent injury, depending on abundance, viral strain dose. Interfering virus interaction should considered prophylactic strategies.

Language: Английский

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Spatiotemporal Analysis of Lung Immune Dynamics in Lethal Coccidioides posadasii Infection

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 22, 2024

Abstract Coccidioidomycosis, or Valley Fever, is a lung disease caused by inhalation of Coccidioides fungi, prevalent in the Southwestern U.S., Mexico, and parts Central South America. 350,000 cases are reported annually although that number expected to increase as climate change expands fungal geographic range. While 60% infections asymptomatic, symptomatic 40% often misdiagnosed due similarities with bronchitis pneumonia. A small subset infection progress severe illness, necessitating better understanding immune responses during lethal infection. Using single-cell RNA sequencing spatial transcriptomics, we characterized We identified monocyte-derived Spp1 -expressing macrophages potential mediators tissue remodeling fibrosis, marked high expression profibrotic proinflammatory transcripts. These showed elevated TGF-β IL-6 signaling, pathways involved fibrosis pathogenesis. Additionally, observed significant neutrophil infiltration defective lymphocyte responses, indicating adaptive immunity dysregulation lethal, acute findings enhance our suggest new therapeutic targets. Importance: commonly known which With potentially expanding range this fungus, crucial. Our study used advanced techniques analyze infection, identifying specific cells may contribute damage fibrosis. provide insights into mechanisms targets for intervention, could improve outcomes patients suffering from Fever.

Language: Английский

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Post-Acute Sequelae and Mitochondrial Aberration in SARS-CoV-2 Infection

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 9050 - 9050

Published: Aug. 21, 2024

This review investigates links between post-acute sequelae of SARS-CoV-2 infection (PASC), post-infection viral persistence, mitochondrial involvement and aberrant innate immune response cellular metabolism during infection. Advancement proteomic metabolomic studies now allows deeper investigation alterations to metabolism, autophagic processes dysfunction caused by infection, while computational biology machine learning have advanced methodologies predicting virus–host gene protein interactions. Particular focus is given the interaction genes proteins with function that system. Finally, authors hypothesise persistence may be a in sequestration genetic material. While further work necessary understand mechanisms definitively, number point resolution questions regarding pathogenesis PASC.

Language: Английский

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Tumour-derived Extracellular Vesicle and Particle Reprogramming of Interstitial Macrophages in the Lung Pre-Metastatic Niche Enhances Vascular Permeability and Metastatic Potential

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 30, 2024

Extracellular vesicles and particles (EVPs) are pivotal mediators of pre-metastatic niche formation cancer progression, including induction vascular permeability, which facilitates tumor cell extravasation metastasis. However, the mechanisms through EVPs exert this effect remain poorly understood. Here, we elucidate a novel mechanism by enhance endothelial extravasation, lung metastasis to different degrees, depending on type. Strikingly, leakiness is observed within 48h following implantation as early one hour intravenous injection tumour-derived in naïve mice. Surprisingly, rather than acting directly cells, first activate interstitial macrophages (IMs) leading activation JAK/STAT signaling IL-6 secretion IMs subsequently promote permeability. Depletion significantly reduces EVP-dependent metastatic potential. Tumour that strongly induce express high levels ITGα5, ITGα5 ablation impairs IM activation, cytokine secretion, permeability Importantly, expression elevated from non-involved tumor-adjacent tissue compared distal patients, highlight clinical relevance our discovery. Our findings identify key role for an initiating step type-specific EVP-driven metastasis, offering promising targets therapeutic intervention.

Language: Английский

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SARS-CoV2 infection in whole lung primarily targets macrophages that display subset-specific responses

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 14, 2024

Deciphering the initial steps of SARS-CoV-2 infection, that influence COVID-19 outcomes, is challenging because animal models do not always reproduce human biological processes and in vitro systems recapitulate histoarchitecture cellular composition respiratory tissues. To address this, we developed an innovative ex vivo model whole lung infection with SARS-CoV-2, leveraging a transplantation technique. Through single-cell RNA-seq, identified alveolar monocyte-derived macrophages (AMs MoMacs) were targets virus. Exposure isolated AMs, MoMacs, classical monocytes non-classical (ncMos) to variants revealed while all subsets responded, MoMacs produced higher levels inflammatory cytokines than ncMos contributed least. A Wuhan lineage appeared be more potent D614G virus, in dose-dependent manner. Amidst ambiguity literature regarding cell target, our study reveals AMs are dominant primary entry points for suggests their responses may conduct subsequent injury, depending on abundance, viral strain dose. Interfering virus interaction should considered prophylactic strategies.

Language: Английский

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B cells modulate lung antiviral inflammatory responses via the neurotransmitter acetylcholine

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 25, 2024

The rapid onset of innate immune defenses is critical for early control viral replication in an infected host, yet it can also lead to irreversible tissue damage, especially the respiratory tract. Intricate regulatory mechanisms must exist that modulate inflammation, while controlling infection. Here, B cells expressing choline acetyl transferase (ChAT), enzyme required production metabolite and neurotransmitter acetylcholine (ACh) are identified as such regulators immediate response influenza A virus. Lung ChAT + shown interact with a7 nicotinic Ach receptor-expressing lung interstitial macrophages mice within 24h infection their TNFa, shifting balance towards reduced inflammation at cost enhanced replication. Thus, innate-stimulated key participants immediate-early cascade controls damage after

Language: Английский

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IL-1β-driven NF-κB transcription of ACE2 as a Mechanism of Macrophage Infection by SARS-CoV-2

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 26, 2024

ABSTRACT Coronavirus disease 2019 (COVID-19), caused by infection with the enveloped RNA betacoronavirus, SARS-CoV-2, led to a global pandemic involving over 7 million deaths. Macrophage inflammatory responses impact COVID-19 severity; however, it is unclear whether macrophages are infected SARS-CoV-2. We sought identify mechanisms regulating macrophage expression of ACE2, primary receptor for and determine if susceptible productive infection. developed humanized ACE2 ( hACE2 ) mouse whereby cDNA was cloned into locus under control native promoter. validated susceptibility mice SARS-CoV-2 relative wild-type an established K18-hACE2 model acute fulminating disease. Intranasal exposure pulmonary consolidations cellular infiltrate, edema, hemorrhage, consistent pneumonia, yet unlike model, survived maintained stable weight. Infected also exhibited unique plasma chemokine, cytokine, growth factor signature mice. demonstrated evidence viral replication in infiltrating lung macrophages, vitro revealed transcriptional profile indicative altered ribosomal processing machinery as well activated antiviral defense. IL-1β-driven NF-κB transcription important mechanism dynamic upregulation, promoting Experimental models that make use will allow mechanistic insight factors can either promote host resilience or increase worsening severity

Language: Английский

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Interactions of SARS-CoV-2 with Human Target Cells—A Metabolic View

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 9977 - 9977

Published: Sept. 16, 2024

Viruses are obligate intracellular parasites, and they exploit the cellular pathways resources of their respective host cells to survive successfully multiply. The strategies viruses concerning how take advantage metabolic capabilities for own replication can vary considerably. most common alterations triggered by affect central carbon metabolism infected cells, in particular glycolysis, pentose phosphate pathway, tricarboxylic acid cycle. upregulation these processes is aimed increase supply nucleotides, amino acids, lipids since products crucial efficient viral proliferation. In detail, however, this manipulation may multiple sites regulatory mechanisms host-cell metabolism, depending not only on specific but also type cells. review, we report situations reprogramming different human tissues, organs that favorable acute persistent SARS-CoV-2 infection. This knowledge be fundamental development host-directed therapies.

Language: Английский

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