Biology subjects

Crotta, S.

Publications and source records attributed to Crotta, S..

7 recordsLinked to original sources

bioRxiv2026

Diverse lung challenges elicit a conserved monocyte-to-macrophage differentiation blueprint

Alveolar macrophages (AM) form a first line of defence to lung insults. These insults often lead to replacement of foetal-derived tissue-resident AMs (fAMs) by monocyte-derived AMs (mono-AMs) with different functionality, which impacts lung immunity long-term. However, whether these alterations are conserved or insult-specific is not well understood. Here, we show that respiratory syncytial virus (RSV) infection remodels the AM compartment long-term. We perform comparative analyses of fAMs and mono-AMs after RSV infection, influenza (IAV) infection and clodronate liposome administration to derive rules governing the functional and transcriptional changes in AM across insults. We identify a crucial tissue integration checkpoint of CD11b+ mono-AMs which involves acquisition of proliferative capacity and requires EGR2-mediated transcriptional rewiring. Mono-AMs elicited by RSV, influenza or clodronate liposomes have a hard-wired ontogeny-dependent stereotypical profile of transcription, metabolism and enhanced immunoreactivity despite a substantially different inflammatory environment during differentiation; accordingly, mono-AMs, whether elicited by infection or sterile depletion, protect from subsequent S. pneumoniae infection. By contrast, fAMs are more susceptible to subtle, context-dependent transcriptional alterations. Our findings highlight that long-term changes in the AM compartment show origin-dependent phenotypic divergence and that mono-AM integration follows a hard-wired trajectory fine-tuned by environmental factors.

immunology↗

bioRxiv2025

The ubiquitin E3 ligase Huwe1 facilitates viral and self RNA sensing by RIG-I-like receptors

RIG-I-like receptors (RLRs) are cytoplasmic RNA sensors that promote type I and type III interferon (IFN) production in response to RNA ligands of viral or endogenous origin. The RLR pathway is tightly regulated by dynamic post-translational modifications, including ubiquitination. Huwe1 is a HECT domain-containing giant ubiquitin E3 ligase that has not been implicated in the RLR or IFN pathway. Here, we investigated whether Huwe1 is required for type I IFN induction downstream of RLRs. We demonstrate that loss of Huwe1 severely attenuates the expression of IFN-{beta}, IFN-{lambda}1 and IFN-stimulated genes (ISGs) in ADAR1-deficient human cells and primary murine bone-marrow derived macrophages, in which unedited self RNAs that serve as RLR ligands accumulate. In addition, depletion of Huwe1 reduces the induction of type I and III IFNs upon transfection with synthetic viral RNA mimetics or infection with a picornavirus. Using proteomics, we identified several putative Huwe1 substrates, which include key components of the RLR pathway (MAVS, TRAFs). We demonstrate that these substrates interact with Huwe1 and that Huwe1 is essential for the activity of TRAF5 in type I IFN induction. Collectively, our results put Huwe1 on the map as an important ubiquitin E3 ligase in the RLR pathway and provide new insights into ubiquitin-dependent regulation of cell-intrinsic antiviral immune pathways.

immunology↗

bioRxiv2022

Impaired immune response drives age-dependent severity of COVID-19

SARS-CoV-2 is a highly contagious respiratory virus and the causative agent for COVID-19. The severity of disease varies from mildly symptomatic to lethal and shows an extraordinary correlation with increasing age, which represents the major risk factor for severe COVID-191. However, the precise pathomechanisms leading to aggravated disease in the elderly are currently unknown. Delayed and insufficient antiviral immune responses early after infection as well as dysregulated and overshooting immunopathological processes late during disease were suggested as possible mechanisms. Here we show that the age-dependent increase of COVID-19 severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) responses. To overcome the limitations of mechanistic studies in humans, we generated a mouse model for severe COVID-19 and compared the kinetics of the immune responses in adult and aged mice at different time points after infection. Aggravated disease in aged mice was characterized by a diminished IFN-{gamma} response and excessive virus replication. Accordingly, adult IFN-{gamma} receptor-deficient mice phenocopied the age-related disease severity and supplementation of IFN-{gamma} reversed the increased disease susceptibility of aged mice. Mimicking impaired type I IFN immunity in adult and aged mice, a second major risk factor for severe COVID-192-4, we found that therapeutic treatment with IFN-{lambda} in adult and a combinatorial treatment with IFN-{gamma} and IFN-{lambda} in aged Ifnar1-/-mice was highly efficient in protecting against severe disease. Our findings provide an explanation for the age-dependent disease severity of COVID-19 and clarify the nonredundant antiviral functions of type I, II and III IFNs during SARS-CoV-2 infection in an age-dependent manner. Based on our data, we suggest that highly vulnerable individuals combining both risk factors, advanced age and an impaired type I IFN immunity, may greatly benefit from immunotherapy combining IFN-{gamma} and IFN-{lambda}.

immunology↗

bioRxiv2022

Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model.

Understanding the host pathways that define susceptibility to SARS-CoV-2 infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in Syrian hamsters. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced the levels of infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.

microbiology↗

bioRxiv2021

Severity of SARS-CoV-2 infection as a function of the interferon landscape across the respiratory tract of COVID-19 patients.

The COVID-19 outbreak driven by SARS-CoV-2 has caused more than 2.5 million deaths globally, with the most severe cases characterized by over-exuberant production of immune-mediators, the nature of which is not fully understood. Interferons of the type I (IFN-I) or type III (IFN-III) families are potent antivirals, but their role in COVID-19 remains debated. Our analysis of gene and protein expression along the respiratory tract shows that IFNs, especially IFN-III, are over-represented in the lower airways of patients with severe COVID-19, while high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity; also, IFN expression varies with abundance of the cell types that produce them. Our data point to a dynamic process of inter- and intra-family production of IFNs in COVID-19, and suggest that IFNs play opposing roles at distinct anatomical sites.

immunology↗

bioRxiv2021

Rotavirus susceptibility of antibiotic-treated mice ascribed to diminished expression of interleukin-22

The commensal microbiota regulates susceptibility to enteric pathogens by fine-tuning mucosal innate immune responses, but how susceptibility to enteric viruses is shaped by the microbiota remains incompletely understood. Past reports have indicated that commensal bacteria may either promote or repress rotavirus replication in the small intestine of mice. We now report that rotavirus replicated more efficiently in the intestines of germ-free and antibiotic-treated mice compared to animals with an unmodified microbiota. Antibiotic treatment also facilitated rotavirus replication in type I and type III interferon (IFN) receptor-deficient mice, revealing IFN-independent proviral effects. Expression of interleukin-22 (IL-22) was strongly diminished in the intestine of antibiotic-treated mice. Treatment with exogenous IL-22 blocked rotavirus replication in microbiota-depleted wild-type and Stat1-/- mice, demonstrating that the antiviral effect of IL-22 in animals with altered microbiome is not dependent on IFN signaling. In antibiotic-treated animals, IL-22-induced a specific set of genes including Fut2, encoding fucosyl-transferase 2 that participates in the biosynthesis of fucosylated glycans which can mediate rotavirus binding. Interestingly, IL-22 also blocked rotavirus replication in antibiotic-treated Fut2-/- mice. Furthermore, IL-22 inhibited rotavirus replication in antibiotic-treated mice lacking key molecules of the necroptosis or pyroptosis pathways of programmed cell death. Taken together, our results demonstrate that IL-22 determines rotavirus susceptibility of antibiotic-treated mice, yet the IL-22-induced effector molecules conferring rotavirus resistance remain elusive.

immunology↗

bioRxiv2020

Type I and III interferons disrupt lung epithelial repair during recovery from viral infection

Excessive cytokine signalling frequently exacerbates lung tissue damage during respiratory viral infection. Type I and III interferons (IFN-/{beta} and IFN-{lambda}) are host-produced antiviral cytokines and currently considered as COVID-19 therapy. Prolonged IFN-/{beta} responses can lead to harmful proinflammatory effects, whereas IFN-{lambda} mainly signals in epithelia, inducing localised antiviral immunity. Here we show that IFN signalling interferes with lung repair during influenza recovery, with IFN-{lambda} driving these effects most potently. IFN-induced p53 directly reduces epithelial proliferation and differentiation, increasing disease severity and susceptibility to bacterial superinfections. Hence, excessive or prolonged IFN-production aggravates viral infection by impairing lung epithelial regeneration. Therefore, timing and duration are critical parameters of endogenous IFN action, and should be considered carefully for IFN therapeutic strategies against viral infections like influenza and COVID-19. One Sentence SummaryA novel IFN-mediated mechanism of immunopathology during respiratory virus infection by interference with lung tissue repair.

immunology↗