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Biology subjects

Corman, V. M.

Publications and source records attributed to Corman, V. M..

18 recordsLinked to original sources

A global serosurvey of RNA virus-reactive antibodies in bats and rodents reveals the enzootic presence of flavi- and paramyxoviruses in African Pteropodidae

Bats and rodents have been identified as reservoir hosts of diverse RNA viruses that pose potential risks to humans. However, overall virus prevalence in wildlife and underlying factors determining the zoonotic potential of reservoir-borne viruses remain poorly characterized. Virus detection often relies on the identification of viral nucleotide sequences and may therefore be limited by variable virus concentration, tissue tropism, sample quality, and duration of infection. In this study, we applied a multiplex immunofluorescence assay to examine bat and rodent seroprevalence against 14 different human pathogenic RNA viruses spanning seven virus families (Coronaviridae, Flaviviridae, Hantaviridae, Paramyxoviridae, Phenuiviridae, Pneumoviridae, Togaviridae). We retrospectively analyzed 1,135 bat (16 species) and 454 rodent (15 species) blood or transudate specimens collected at 63 sites in seven countries. Tropical bats exhibited notably high rates of seropositivity against certain virus families (Flaviviridae: 42.8%; Paramyxoviridae: 60.4%; Togaviridae: 7.5%). Multivariable logistic regression models were created to evaluate the association of tropical bat characteristics with seropositivity. Preliminary findings indicate that large colony size, found among species such as Eidolon helvum and Rousettus aegyptiacus, is a risk factor for orthoflavi- and orthorubulavirus infection, consistent with the communal spread of bat-adapted viruses. Author SummaryMany animal populations carry viruses that have the potential to spill over to humans and cause severe disease. Despite surveillance efforts, it is logistically challenging to detect virus infections in wildlife, as viruses may have a short duration of infection or unknown routes of transmission. In this study, we examined blood and transudate samples from rodents and bats around the world for antibodies against 14 different viruses known to cause disease in humans. We analyzed the samples via a mosaic chip-based immunofluorescence test, which has the advantage of detecting antibodies against whole-virus antigen. This method allows for broad surveillance, as we would also expect to uncover evidence of past infection with bat- and rodent-adapted viruses that are related, but not identical, to known human pathogens. We detected antibodies against all seven virus families we examined, with especially high detection rates of antibodies in tropical bats. We used the results to construct multivariable logistic regression models of tropical bat seroprevalence to examine potential associations between tropical bat characteristics and previous infection by certain virus families. Bats with large colony sizes, such as Eidolon helvum and Rousettus aegyptiacus, were apparently at increased risk of infection with orthoflavi- and orthorubulaviruses compared to other tropical bat species.

microbiology↗

Q1020R in the spike proteins of MERS-CoV from Arabian camels and recent human cases confers resistance against soluble human DPP4

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a pre-pandemic coronavirus that is transmitted from camels, the natural reservoir, to humans and can cause severe disease. MERS cases have been documented in Arabia but not Africa, although the virus is circulating in both Arabian and African camels. Further, evidence has been provided that viruses in African camels might have a reduced capacity to cause disease. However, the underlying determinants are incompletely understood. Here, employing pseudotyped particles as model systems for MERS-CoV entry into cells, we compared cell entry of viruses from African and Arabian camels and its inhibition. We show that viruses found in Arabian camels and recent human cases are less susceptible to inhibition by human soluble DPP4 (sDPP4) than viruses from African camels, although both enter human cells efficiently and are comparably sensitive to inhibition by IFITM proteins and neutralizing antibodies. Furthermore, relative resistance to soluble DPP4 was linked to mutation Q1020R, present in the spike proteins of recent Arabian but not African viruses. These results support the concept that soluble DPP4 might constitute a natural barrier against human infection that is more efficiently overcome by viruses currently circulating in Arabian camels than those in African camels. IMPORTANCEMERS-CoV is an emerging virus that can cause severe lung disease, MERS, and is transmitted from camels to humans. Although MERS-CoV infects camels in both Africa and Arabia, MERS cases have only been documented in Arabia for reasons that remain incompletely understood. Here, we provide evidence that viruses recently circulating in Arabian camels and causing human infections are less susceptible to inhibition by human sDPP4 - a secreted version of the viral receptor that is present in various bodily fluids. Furthermore, we link sDPP4 resistance to mutation Q1020R in the spike protein of these viruses. These results suggest that viruses currently circulating in Arabian camels are better equipped to overcome a natural barrier to infection, sDPP4, than those circulating in African camels.

microbiology↗

A century-old museum sample reveals abandavirus with modern day presence in northernEuropean bats

Ancient genome sequences provide invaluable insights into the origin and evolution of viral pathogens, offering a broader temporal perspective that extends well beyond the limited timespan of clinical data, which typically covers at most a few decades. Whereas ancient viral DNA is relatively frequently recovered, ancient viral RNA genomes are scarce due to the fragile nature of RNA molecules. In this study, we explored the feasibility of detecting ancient viral RNA in ethanol-preserved bat samples from a museum collection. We not only detected viral genome fragments but also recovered the coding-complete genome of a bandavirus (species Bandavirus zwieselense, family Phenuiviridae, order Hareavirales, class Bunyaviricetes) from a Common pipistrelle (Pipistrellus pipistrellus) bat collected in northern Germany in 1919. To investigate the modern distribution of Bandavirus zwieselense, we screened bat organs collected in Germany and the Netherlands via RT-qPCR, identifying modern counterparts in nine Common Pipistrelle (P. pipistrellus) bats (collected between 2010 and 2018), and one Serotine bat (Eptesicus serotinus, collected in 1999). The resulting genomic data enabled us to map phylogenetic relationships within this previously uncharacterized virus species (Bandavirus zwieselense) and estimate the timeframe for the most recent common ancestor. Additionally, we performed functional analysis of the S segment encoded nonstructural (NSs) protein of Bandavirus zwieselense in human HEK-293T cells, demonstrating its ability to block interferon induction, a characteristic also observed in the related human-pathogenic Severe fever with thrombocytopenia syndrome virus (SFTSV, species Bandavirus dabieense). This study demonstrates the feasibility of recovering and characterizing viral genomes from ethanol-preserved ancient RNA material, underscoring the significant potential of museum collections to contribute to the understanding of RNA virus evolution.

microbiology↗

Rewired type I IFN signaling is linked to age-dependent differences in COVID-19

Advanced age is the most important risk factor for severe disease or death from COVID-19, but a thorough mechanistic understanding of the molecular and cellular underpinnings is lacking. Multi-omics analysis of samples from SARS-CoV-2 infected persons aged 1 to 84 years, revealed a rewiring of type I interferon (IFN) signaling with a gradual shift from signal transducer and activator of transcription 1 (STAT1) to STAT3 activation in monocytes, CD4+ T cells and B cells with increasing age. Diversion of interferon IFN signaling was associated with increased expression of inflammatory markers, enhanced release of inflammatory cytokines, and delayed contraction of infection-induced CD4+ T cells. A shift from IFN-responsive germinal center B (GCB) cells towards CD69high GCB and atypical B cells corresponded to the formation of IgA in children while complement fixing IgG was dominant in adults. Our data provide a mechanistic basis for inflammation-prone responses to infections and associated pathology during aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/619479v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@723896org.highwire.dtl.DTLVardef@e12b2aorg.highwire.dtl.DTLVardef@d8de22org.highwire.dtl.DTLVardef@1df96ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

MPXV Infects Human PBMCs in a Type I Interferon-Sensitive Manner

MPOX virus (MPXV), formerly known as monkeypox virus, led to a rapidly evolving pandemic starting May 2022, with over 90,000 cases reported beyond the African continent. This pandemic outbreak was driven by the MPXV variant Clade IIb. In addition, Clade I viruses circulating in the Democratic Republic of Congo (DRC) are drawing increased attention as cases constantly rise and Clade Ib, first identified in 2023, is now co-circulating with Clade Ia and seems to exhibit enhanced human-to-human transmissibility. While most infected individuals display a self-limiting disease with singular pox-like lesions, some endure systemic viral spread leading to whole-body rash with risks for necrosis, organ loss, and death. Intra-host dissemination and cellular tropism of MPXV are largely unexplored in humans. To establish a potential susceptibility of circulating immune cells to MPXV, we exposed human PBMCs from healthy donors ex vivo to a currently circulating MPXV clade IIb virus isolate in absence and presence of IFN-2a. qPCR of DNA extracted from cell lysates, but less from supernatants, revealed increasing MPXV DNA quantities that peaked at five to six days post-exposure, suggesting susceptibility of PBMCs to infection. IFN-2a pretreatment markedly reduced the quantity of MPXV DNA, suggesting that infection is sensitive to type I IFNs. Plaque assays from supernatants showed that infection gave rise to de novo production of infectious MPXV. In virus-inclusive scRNA-sequencing, monocytes, cycling NK cells and regulatory CD4+ T-cells scored positive for viral RNA, suggesting that these are the MPXV-susceptible cell types within the human PBMC population. Analysis of differentially expressed genes displayed a pronounced downregulation of expression pathways driving innate immunity in MPXV-infected cells, a well-established feature of poxviral infection. Pretreatment of PBMCs with current antivirals Cidofovir and Tecovirimat resulted in reduced amounts of viral antigen production and of released infectivity, suggesting suitability of the human PBMC infection model as a platform for evaluation of current and future antivirals and justifying trials to investigate Cidofovir and Tecovirimat as drugs reducing intra-patient viral spread. Together, our data suggest that human PBMCs are productively infected by MPXV which is accompanied by significant modulation of the cellular milieu. Our results have the potential to illuminate aspects of intra-host propagation of MPXV that may involve a lymphohematogenous route for replication and/or intra-host dissemination.

immunology↗

Ongoing evolution of Middle East Respiratory Syndrome Coronavirus, Kingdom of Saudi Arabia, 2023-2024

Middle East respiratory syndrome coronavirus (MERS-CoV) circulates in dromedary camels in the Arabian Peninsula and occasionally causes spillover infections in humans. Due to lack of sampling during the SARS-CoV-2 pandemic, current MERS-CoV diversity is poorly understood. Of 558 dromedary camel nasal swabs from Saudi Arabia, sampled November 2023 to January 2024, 39% were positive for MERS-CoV RNA by RT-PCR. We generated 42 MERS-CoV and seven human 229E-related CoV by high-throughput sequencing. For both viruses, the sequences fell into monophyletic clades apical to the most recent available genomes. The MERS-CoV sequences were most similar to those from lineage B5. The new MERS-CoVs sequences harbor unique genetic features, including novel amino acid polymorphisms in the Spike protein. The new variants require further phenotypic characterization to understand their impact. Ongoing MERS-CoV spillovers into humans pose significant public health concerns, emphasizing the need for continued surveillance and phenotypic studies.

evolutionary biology↗

Comparative Analysis of SARS-CoV-2 Antigenicity across Assays and in Human and Animal Model Sera

The antigenic evolution of SARS-CoV-2 requires ongoing monitoring to judge the immune escape of newly arising variants. A surveillance system necessitates an understanding of differences in neutralization titers measured in different assays and using human and animal sera. We compared 18 datasets generated using human, hamster, and mouse sera, and six different neutralization assays. Titer magnitude was lowest in human, intermediate in hamster, and highest in mouse sera. Fold change, immunodominance patterns and antigenic maps were similar among sera. Most assays yielded similar results, except for differences in fold change in cytopathic effect assays. Not enough data was available for conclusively judging mouse sera, but hamster sera were a consistent surrogate for human first-infection sera.

bioinformatics↗

Antigenic cartography using variant-specific hamster sera reveals substantial antigenic variation among Omicron subvariants

SARS-CoV-2 has developed substantial antigenic variability. As the majority of the population now has pre-existing immunity due to infection or vaccination, the use of experimentally generated animal immune sera can be valuable for measuring antigenic differences between virus variants. Here, we immunized Syrian hamsters by two successive infections with one of eight SARS-CoV-2 variants. Their sera were titrated against 14 SARS-CoV-2 variants and the resulting titers visualized using antigenic cartography. The antigenic map shows a condensed cluster containing all pre-Omicron variants (D614G, Alpha, Delta, Beta, Mu, and an engineered B.1+E484K variant), and a considerably more distributed positioning among a selected panel of Omicron subvariants (BA.1, BA.2, BA.4/5, the BA.5 descendants BF.7 and BQ.1.18; the BA.2.75 descendant BN.1.3.1; and the BA.2-derived recombinant XBB.2). Some Omicron subvariants were as antigenically distinct from each other as the wildtype is from the Omicron BA.1 variant. The results highlight the potential of using variant-specifically infected hamster sera for the continued antigenic characterisation of SARS-CoV-2.

immunology↗

Repurposing of the antibiotic nitroxoline for the treatment of mpox

The antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. Moreover, their use is affected by toxic side-effects (brincidofovir, cidofovir), limited availability (tecovirimat), and potentially by resistance formation. Hence, additional, readily available drugs are needed. Here, therapeutic concentrations of nitroxoline, a hydroxyquinoline antibiotic with a favourable safety profile in humans, inhibited the replication of 12 mpox virus isolates from the current outbreak in primary cultures of human keratinocytes and fibroblasts and a skin explant model by interference with host cell signalling. Tecovirimat, but not nitroxoline, treatment resulted in rapid resistance development. Nitroxoline remained effective against the tecovirimat-resistant strain and increased the anti-mpox virus activity of tecovirimat and brincidofovir. Moreover, nitroxoline inhibited bacterial and viral pathogens that are often co-transmitted with mpox. In conclusion, nitroxoline is a repurposing candidate for the treatment of mpox due to both antiviral and antimicrobial activity.

microbiology↗

Genetic variability, including gene duplication and deletion, in early sequences from the 2022 European monkeypox outbreak

Genome sequences from 47 monkeypox virus infections detected in a German university virology laboratory were analyzed in context of other sequences from the 2022 outbreak and earlier monkeypox genomes. Identical non-synonymous amino acid changes in six genes and the signature of APOBEC editing match other sequences from the European outbreak. Non-synonymous changes that were present in one to three sequences were found in 34 other genes. In sequences from two lesions of one patient, an 856 nucleotide translocation between genome termini resulted in the duplication of an initial 5 gene, and the disruption or complete deletion of four genes near the 3 genome end. Orthopoxvirus genome rearrangements of this nature are known to confer fitness advantages in the face of selection pressure. This change may therefore represent an early virus adaptation in the novel widespread and sustained human-to-human context of the current monkeypox outbreak.

bioinformatics↗

Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses

The furin cleavage site in SARS-CoV-2 is unique within the Severe acute respiratory syndrome-related coronavirus (SrC) species. We re-assessed diverse SrC from European horseshoe bats and reveal molecular determinants such as purine richness, RNA secondary structures and viral quasispecies potentially enabling furin cleavage. Furin cleavage thus likely emerged from the SrC bat reservoir via molecular mechanisms conserved across reservoir-bound RNA viruses, supporting a natural origin of SARS-CoV-2.

evolutionary biology↗

Post-entry, spike-dependent replication advantage of B.1.1.7 and B.1.617.2 over B.1 SARS-CoV-2 in an ACE2-deficient human lung cell line

Epidemiological data demonstrate that SARS-CoV-2 variants of concern (VOC) B.1.1.7 and B.1.617.2 are more transmissible and infections are associated with a higher mortality than non-VOC virus infections. Phenotypic properties underlying their enhanced spread in the human population remain unknown. B.1.1.7 virus isolates displayed inferior or equivalent spread in most cell lines and primary cells compared to an ancestral B.1 SARS-CoV-2, and were outcompeted by the latter. Lower infectivity and delayed entry kinetics of B.1.1.7 viruses were accompanied by inefficient proteolytic processing of spike. B.1.1.7 viruses failed to escape from neutralizing antibodies, but slightly dampened induction of innate immunity. The bronchial cell line NCI-H1299 supported 24- and 595-fold increased growth of B.1.1.7 and B.1.617.2 viruses, respectively, in the absence of detectable ACE2 expression and in a spike-determined fashion. Superior spread in NCI-H1299 cells suggests that VOCs employ a distinct set of cellular cofactors that may be unavailable in standard cell lines.

microbiology↗

SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies

SARS-CoV-2 Beta variant of concern (VOC) resists neutralization by major classes of antibodies from non-VOC COVID-19 patients and vaccinated individuals. Here, serum of Beta variant infected patients revealed reduced cross-neutralization of non-VOC virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of novel VOC-specific clonotypes and accommodation of VOC-defining amino acids into a major non-VOC antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with non-VOC-elicited antibodies, including a public VH1-58 clonotype targeting the RBD ridge independent of VOC mutations. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift with implications for design of next-generation vaccines and therapeutics. One sentence summarySARS-CoV-2 Beta variant elicits lineage-specific antibodies and antibodies with neutralizing breadth against wild-type virus and VOCs.

immunology↗

Enhanced fitness of SARS-CoV-2 variant of concern B.1.1.7, but not B.1.351, in animal models

Emerging variants of concern (VOCs) drive the SARS-CoV-2 pandemic. We assessed VOC B.1.1.7, now prevalent in several countries, and VOC B.1.351, representing the greatest threat to populations with immunity to the early SARS-CoV-2 progenitors. B.1.1.7 showed a clear fitness advantage over the progenitor variant (wt-S614G) in ferrets and two mouse models, where the substitutions in the spike glycoprotein were major drivers for fitness advantage. In the "superspreader" hamster model, B.1.1.7 and wt-S614G had comparable fitness, whereas B.1.351 was outcompeted. The VOCs had similar replication kinetics as compared to wt-S614G in human airway epithelial cultures. Our study highlights the importance of using multiple models for complete fitness characterization of VOCs and demonstrates adaptation of B.1.1.7 towards increased upper respiratory tract replication and enhanced transmission in vivo. Summary sentenceB.1.1.7 VOC outcompetes progenitor SARS-CoV-2 in upper respiratory tract replication competition in vivo.

microbiology↗

A SARS-CoV-2 neutralizing antibody protects from lung pathology in a COVID-19 hamster model

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC50 of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 [A] revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

immunology↗

At least seven distinct rotavirus genotype constellations in bats with evidence of reassortment and zoonotic transmissions

Bats host many viruses pathogenic to humans, and increasing evidence suggests that Rotavirus A (RVA) also belongs to this list. Rotaviruses cause diarrheal disease in many mammals and birds, and their segmented genomes allow them to reassort and increase their genetic diversity. Eighteen out of 2,142 bat fecal samples (0.8%) collected from Europe, Central America and Africa were PCR-positive for RVA and 11 of those were fully characterized using viral metagenomics. Upon contrasting their genomes with publicly available data, at least 7 distinct bat RVA genotype constellations (GCs) were identified, including evidence of reassortments and 6 novel genotypes. Some of these constellations are spread across the world, whereas others appear to be geographically restricted. Our analyses also suggest that several unusual human and equine RVA strains might be of bat RVA origin, based on their phylogenetic clustering, despite varying levels of nucleotide sequence identities between them. Although SA11 is one of the most widely used reference strains for RVA research and forms the backbone of a reverse genetics system, its origin remained enigmatic. Remarkably, the majority of the genotypes of SA11-like strains were shared with Gabonese bat RVAs, suggesting a potential common origin. Overall, our findings suggest an underexplored genetic diversity of RVAs in bats, which is likely only the tip of the iceberg. Increasing contact between humans and bat wildlife will further increase the zoonosis risk, which warrants closer attention to these viruses. ImportanceThe increased research on bat coronaviruses after SARS-CoV and MERS-CoVallowed the very rapid identification of SARS-CoV-2. This is an excellent example of the importance of knowing viruses harbored by wildlife in general and bats in particular, for global preparedness against emerging viral pathogens. The current effort to characterize bat rotavirus strains from 3 continents shed light on the vast genetic diversity of rotaviruses and also hinted at a bat origin for several atypical rotaviruses in humans and animals, implying that zoonoses of bat rotaviruses might occur more frequently than currently realized.

microbiology↗

Olfactory transmucosal SARS-CoV-2 invasion as port of Central Nervous System entry in COVID-19 patients

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease presenting with fever, cough, and often pneumonia. Moreover, thromboembolic events throughout the body including the central nervous system (CNS) have been described. Given first indication for viral RNA presence in the brain and cerebrospinal fluid and in light of neurological symptoms in a large majority of COVID-19 patients, SARS-CoV-2-penetrance of the CNS is likely. By precisely investigating and anatomically mapping oro- and pharyngeal regions and brains of 32 patients dying from COVID-19, we not only describe CNS infarction due to cerebral thromboembolism, but also demonstrate SARS-CoV-2 neurotropism. SARS-CoV-2 enters the nervous system via trespassing the neuro-mucosal interface in the olfactory mucosa by exploiting the close vicinity of olfactory mucosal and nervous tissue including delicate olfactory and sensitive nerve endings. Subsequently, SARS-CoV-2 follows defined neuroanatomical structures, penetrating defined neuroanatomical areas, including the primary respiratory and cardiovascular control center in the medulla oblongata.

neuroscience↗

Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an acute threat to public health and the world economy, especially because no approved specific drugs or vaccines are available. Pharmacological modulation of metabolism-dependent cellular pathways such as autophagy reduced propagation of highly pathogenic Middle East respiratory syndrome (MERS)-CoV. Here we show that SARS-CoV-2 infection limits autophagy by interfering with multiple metabolic pathways and that compound-driven interventions aimed at autophagy induction reduce SARS-CoV-2 propagation in vitro. In-depth analyses of autophagy signaling and metabolomics indicate that SARS-CoV-2 reduces glycolysis and protein translation by limiting activation of AMP-protein activated kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1). Infection also downregulates autophagy-inducing spermidine, and facilitates AKT1/SKP2-dependent degradation of autophagy-initiating Beclin-1 (BECN1). Targeting of these pathways by exogenous administration of spermidine, AKT inhibitor MK-2206, and the Beclin-1 stabilizing, antihelminthic drug niclosamide inhibited SARS-CoV-2 propagation by 85, 88, and >99%, respectively. In sum, SARS-CoV-2 infection causally diminishes autophagy. A clinically approved and well-tolerated autophagy-inducing compound shows potential for evaluation as a treatment against SARS-CoV-2.

microbiology↗