Biology subjects

Zhong, N.

Publications and source records attributed to Zhong, N..

At least 19 recordsLinked to original sources

bioRxiv2026

Information regimes in population-graph neuroimaging: cohort context and implementation-dependent evaluation sensitivity

Population-graph models aggregate a query subject with an unlabeled cohort, so their reported performance can depend on the evaluation regime rather than on predictive information alone. Evaluation context has two separable axes: the visibility of the cohort during training, and the context available at inference. We study the training-time axis under a protocol fixed before analysis, on an ABIDE-I cohort of 871 subjects (20 acquisition sites). Two population-graph implementations are compared: a learned/adaptive graph (EV-GCN) and a static weighted graph (Parisot-GCN). Within each implementation the cohort, connectivity features, outer splits and training and selection rules are held fixed, and only the information available to the graph varies. The primary estimand is the implementation-by-training-context interaction: the difference between the P0-to-P1 AUC changes of the two implementations ({Delta}{Delta}AUC). Across three preselected outer splits (666, 1024, 2024) the direction is consistent and positive, with observed interaction range 0.06285-0.13090; uncertainty is assessed separately within each split by paired subject and site-cluster bootstrap resampling and is reported per split. Splits are replication units: they are not pooled and no cross-split average is reported, so the result is not a claim of invariance to arbitrary splits. These findings tie reported population-graph performance to the evaluation information regime and motivate explicit reporting of cohort visibility. The contribution is methodological: a two-axis taxonomy of information regimes, preselected cross-split evidence that the sensitivity of reported performance to cohort context depends on the implementation, and a reusable reporting checklist.

neuroscience↗

bioRxiv2026

Tracing high transductive cohort AUC to same-site supervision in a site-aware population GNN for multisite fMRI

Population-graph models can use cohort-level context, complicating interpretation of strong multisite neuroimaging performance. We investigated which information pathways accounted for high transductive cohort discrimination in a site-aware heterogeneous population graph neural network for autism classification. Using a frozen ABIDE-I cohort (871 participants, 20 sites) and evaluation protocol, we applied controlled graph, feature, supervision, and architecture interventions to a clean-room re-implementation across C-PAC and NIAK preprocessing pipelines. Cohort out-of-fold AUC was approximately 0.94. A site-only graph retained similarly high discrimination (0.948 versus 0.941 for the full model), with no statistically significant difference detected. Removing same-site supervision under a site-wise intervention reduced AUC to 0.480, whereas a supervision-budget control retaining same-site supervision achieved 0.921. Among the alternative heads evaluated, the high cohort AUC was observed only with the sex-heterogeneous dual-channel head; a canonical topology-only Parisot-GCN did not reproduce it. A demographic classifier using site, sex, and their interaction achieved a best pooled AUC of 0.51. Under leave-one-site-out evaluation, AUC was 0.522 for C-PAC and 0.532 for NIAK, with confidence intervals including 0.5 and no clear evidence of unseen-site discrimination; an imaging-only reference achieved 0.653 and 0.588. Because leave-one-site-out evaluation jointly changes supervision availability, target-site topology, and training-domain composition, the decrease cannot be attributed to a single factor. These findings distinguish cohort-visible transductive performance from unseen-site generalization and motivate explicit site-only, no-graph, and site-held-out controls.

neuroscience↗

bioRxiv2026

Beyond Respiration: Heme A Synthase (CtaA) Orchestrates Hydrogen Sulfide Production and Virulence via Metabolic Reprogramming in Staphylococcus aureus

Endogenous hydrogen sulfide (H2S) serves as a pivotal gasotransmitter conferring antimicrobial resistance and shielding bacteria from oxidative stress. While cystathionine {gamma}-lyase (CSE)-dependent H2S production is critical for Staphylococcus aureus survival, the upstream regulatory nodes linking metabolic status to H2S-mediated redox defense remain elusive. Here, we identify heme A synthase (CtaA) as a master regulator that couples respiratory metabolism with H2S biosynthesis, specifically under glucose-depleted conditions mimicking host niches such as abscesses and phagosomes. Using a Himar1 transposon screen followed by a high efficiency detection method, we demonstrate that CtaA deficiency precipitates a catastrophic collapse in H2S levels (<10% of wild-type), leading to severe virulence and antimicrobial resistance changes. Specifically, the {Delta}ctaA mutant exhibits attenuated hemolytic activity and significantly reduced virulence in a Galleria mellonella model, despite displaying paradoxical resistance to specific antimicrobials. Mechanistically, CtaA deletion triggers a maladaptive metabolic reprogramming characterized by the downregulation of the L-cysteine transporter TcyP and dysregulation of arginine metabolism, which collectively impair the bacteriums capacity to produce endogenous H2S to defense oxidative stress. Notably, this redox vulnerability is linked to altered endogenous nitric oxide (NO) dynamics, suggesting a disrupted H2S-NO crosstalk essential for stress adaptation. Our findings elucidate a novel metabolic-redox axis where CtaA governs H2S homeostasis to counteract host-imposed oxidative stress. Targeting the CtaA-H2S axis represents a promising therapeutic strategy to sensitize S. aureus to host immune clearance by dismantling its critical redox shield.

microbiology↗

bioRxiv2026

Enhanced Target Binding by Leritrelvir Restores Dimerization of Mpro Mutants and Mitigates Drug Resistance

The SARS-CoV-2 main protease (Mpro) has been a major target of antiviral drug development, leading to the development of inhibitors such as nirmatrelvir, the antiviral component of the COVID-19 drug Paxlovid. However, resistance-associated mutations that reduce the efficacy of current Mpro inhibitors, particularly nirmatrelvir, have emerged. Here, we evaluated the inhibitory activity of leritrelvir (RAY1216), an Mpro inhibitor approved in China for COVID-19 monotherapy, against a panel of Mpro variants carrying mutations at 12 resistance-associated residues distributed across four catalytic subsites. Using integrated biochemical, biophysical, structural, and cellular analyses, we demonstrate that leritrelvir retains stronger inhibitory activity against most tested resistant mutants compared with nirmatrelvir. Most of the tested mutations promote Mpro dimer dissociation, with E166V showing a particularly pronounced effect and markedly compromising nirmatrelvir binding. In contrast, thermal shift and size-exclusion chromatography assays demonstrate that leritrelvir binding restores dimerization of these Mpro mutants. Sixteen high-resolution crystal structures reveal that leritrelvir binding re-instates key dimer-interface interactions disrupted by resistance mutations. Mini-replicon assays further confirm leritrelvir to possess enhanced cellular antiviral efficacy compared with nirmatrelvir. Our findings indicate that tighter leritrelvir binding enables more effective inhibition of dissociation-prone Mpro mutants than nirmatrelvir, supporting its use as a more resilient antiviral agent for SARS-CoV-2 treatment.

molecular biology↗

bioRxiv2025

Single-cell Genomic Copy Number Evolution Reveals Frequent Loss of the Y chromosome in Esophageal Adenocarcinoma

The incidence of esophageal adenocarcinoma (EAC), an aggressive cancer, is rising in Western countries, and incidence is higher in men. To better understand the roles of DNA copy number evolution, tumor heterogeneity, and tumor microenvironment in EAC and its origins, we evaluated EAC, Barretts Esophagus (BE), and normal adjacent tissue using our previously developed ultra-sensitive, single-nucleus DNA copy number analysis (12,186 nuclei, 20 specimens) and single-nucleus RNA-sequencing (snRNA-seq; 87,027 nuclei, 32 specimens). Loss of Y (LOY) chromosome was rare in BE but markedly enriched in EAC. In genome unstable cells, complete LOY chromosome often coincided with X-chromosome duplication. We did not detect X-chromosome inactivation via XIST expression in cells with LOY, suggesting increased expression of X-chromosome genes and potential effects on tumor immune evasion. When considering patients clinical features, we identified distinct differences in tumor microenvironment by sex, age, and obesity status, particularly massively reduced immune cell composition in obese patients. Finally, our cell line models recapitulate LOY, and we identify the first candidate anti-LOY agent. Our findings highlight how LOY affects tumor subpopulations and shapes the tumor microenvironment during EAC progression.

cancer biology↗

bioRxiv2025

The stress response factor SigH mediates intrinsic resistance to multiple antibiotics in Mycobacterium abscessus

Mycobacterium abscessus (Mab) causes pulmonary diseases with limited treatment options due to its high level of intrinsic resistance to available drugs. Mab possesses complex and poorly understood drug resistance mechanisms. Identifying new drug targets and gaining a deeper understanding of drug resistance mechanisms are essential for discovering novel therapeutic alternatives. Here, we investigated the role of a putative sigma factor SigH in intrinsic multi-drug resistance in Mab. Mab SigH shares an 84% peptide sequence identity with Mycobacterium tuberculosis (Mtb) SigH, a well-known stress response protein and global transcriptional regulator. We constructed a sigH gene deletion strain of Mab ({Delta}sigH) and complemented strains by expressing either Mab sigH (CPMabsigH) or Mtb sigH (CPMtbsigH) in {Delta}sigH. The {Delta}sigH strain exhibited hypersensitivity to a broad range of antibiotics, including levofloxacin, moxifloxacin, tigecycline, tetracycline, amikacin, vancomycin, and rifabutin and all complemented strains restored the drug resistance phenotype. Additionally, {Delta}sigH showed increased sensitivity to oxidative and heat stress compared to the wild-type Mab and complemented strains. Transcriptomic analysis revealed that deletion of sigH disrupted the balance of gene expression, primarily elevating the expression of genes encoding YrbE and MCE family proteins and downregulating genes expressing ABC-type transporters, sigma and anti-sigma factors and other genes associated with antimicrobial resistance. Collectively, our findings indicate that SigH is a key regulator of global gene expression in response to environmental stresses, including antimicrobial treatment, and is crucial for the intrinsic drug resistance of Mab. SigH represents a promising target for the development of novel therapeutic strategies against Mab infections.

molecular biology↗

bioRxiv2024

High-throughput Screening of Compounds against Autoluminescent Nonreplicating Mycobacterium tuberculosis under Diverse Conditions

The screening of new anti-mycobacterial chemicals is primarily focused on inhibiting the active growing bacteria. However, a major challenge in tuberculosis control is the ability of Mycobacterium tuberculosis to enter a nonreplicating state for extended periods, rendering it resistant to many clinical drugs and complicating eradication efforts. Existing low-oxygen-recovery assays designed for screening compounds targeting nonreplicating M. tuberculosis have limitations, including the colony-forming unit counting for non-luminous M. tuberculosis and the instability of the free plasmid carrying luxAB genes in luminescent M. tuberculosis, along with exogenous substrate requirements for light producing. Moreover, these assays fail to accurately replicate the growth conditions of nonreplicating M. tuberculosis in vitro, thus resulting in less convincing results. To address these challenges, we have developed an autoluminescence-based, cholesterol-enriched culture evaluation model to assess 17 anti-tuberculosis drugs of different classes against nonreplicating M. tuberculosis. Our findings indicate that the relative light unit, measured in real-time, serves as a reliable surrogate marker for colony-forming unit, which typically becomes available one month later. This suggests the utility of our model for the rapid determination of drug susceptibility dynamically. The autoluminescent M. tuberculosis, harbouring luxCDABE gene cluster within its genome, can emit blue-green light stably and autonomously without requiring an external substrate supplement. The minimal inhibitory concentrations of all the drugs tested under anaerobic conditions are significantly different from that detected in aerobic environment. Our model allows for rapid, precise, and efficient assessment of drug activity under anaerobic conditions, thereby enabling a more comprehensive evaluation of anti-mycobacterial efficacy. Overall, our model represents a significant advancement in anti-tuberculosis drug discovery and pharmaceutical development.

microbiology↗

bioRxiv2024

Establishment of an Inhalation Administration Noninvasive Murine Model for Rapidly Testing Drug Activity against Mycobacterium tuberculosis

The efficacy of many compounds against Mycobacterium tuberculosis is often limited when administered via conventional oral or injection routes due to suboptimal pharmacokinetic characteristics. Inhalation delivery methods have been investigated to achieve high local therapeutic doses in the lungs. However, previous models, typically employing wild-type M. tuberculosis strains, were intricate, time-consuming, labor-intensive, and with poor repeatability. In this study, we developed an autoluminescence-based inhalation administration model to evaluate drug activity by quantifying relative light units (RLUs) emitted from live mice infected with autoluminescent M. tuberculosis. This novel approach has several improvements: it eliminates the need for anesthesia in mice during administration and simplifies the instrument manipulation; it is cost-effective by utilizing mice instead of larger animals; it shortens time from several months to 16 or 17 days for obtaining result; it is non-invasive by measuring the live RLUs of mice; up to six mice can be administrated daily and simultaneously, even 2-3 times/day; results are relatively objective and repeatable minimizing human factors. Proof-of-concept experiments demonstrated that inhalable rifampicin, isoniazid, and ethambutol showed anti-M. tuberculosis activity at concentrations as low as 0.5, 0.5, and 0.625 mg/mL, respectively, as evidenced by comparing the live RLUs of mice. Furthermore, consistency between RLUs and colony-forming units of the lungs reaffirms the reliability of RLUs as an indicator of drug efficacy, highlighting the potential of this approach for accurately assessing anti-M. tuberculosis activity in vivo. This autoluminescence-based and non-invasive inhalation model offers a substantial reduction in the time, effort, and cost required for evaluating the efficacy of screening new drugs and repurposing old drugs in vivo via inhalation administration.

microbiology↗

bioRxiv2024

Ilamycins are dual inhibitors of ClpX and ClpC1 involved in proteostasis in Mycobacteria

The mycobacterial caseinolytic protease (Clp) system has been recognized as a promising therapeutic target. In this study, we identified two novel ilamycin analogs, ilamycin E (ILE) and ilamycin F (ILF), both targeting the ClpC1 component of the ClpC1P1P2 proteasome. ILE potently disrupts ClpC1P1P2-mediated proteolysis, leading to delayed bactericidal activity, while ILF also binds ClpC1, albeit with lower affinity. Notably, we discovered a unique mutation in clpX and a novel insertion in clpC1, both conferring resistance to ILE and ILF in mycobacterium, validated by gene editing. Furthermore, ILE can also inhibit the proteolytic activity of ClpXP1P2 in a manner dependent on the substrates tag sequence and adaptor. This first demonstration of clpX- and clpC1-mediated ilamycin resistance underscores the potential of ilamycins to target multiple components of the Clp protease system, offering a novel dual-target strategy for combating mycobacterial infections.

microbiology↗

bioRxiv2024

A Novel Mouse Model for LAMA2-Related Muscular Dystrophy: Analysis of Molecular Pathogenesis and Clinical Phenotype

Our understanding of the molecular pathogenesis of LAMA2-related muscular dystrophy (LAMA2-MD) requires improving. Here, we report the phenotype, neuropathology and transcriptomics data (scRNA-seq and bulk RNA-seq) of a new Lama2 knockout mouse (dyH/dyH) which was created based on the human LAMA2-MD mutation hotspot region using CRISPR-Cas9. The dyH/dyH mice presented severe phenotype with muscular dystrophy. Mouse brain scRNA-seq showed that Lama2 gene was expressed predominantly and specifically in vascular and leptomeningeal fibroblasts and vascular smooth muscle cells, and weakly in astrocytes in wild-type mouse. Laminin 2 expression on the cortical surface was observed with immunofluorescence. In dyH/dyH, Lama2 expression was decreased in those cell types, which might be associated with the disruption of gliovascular basal lamina assembly. Additionally, transcriptomic investigation of muscles showed 2020 differentially expressed genes, mainly associated with the impaired muscle cytoskeleton and development. In summary, this study provided potentially useful information for understanding the molecular pathogenesis of LAMA2-MD.

neuroscience↗

bioRxiv2023

Inhibition mechanism and antiviral activity of an α-ketoamide based SARS-CoV-2 main protease inhibitor

SARS-CoV-2 has demonstrated extraordinary ability to evade antibody immunity by antigenic drift. Small molecule drugs may provide effective therapy while being part of a solution to circumvent SARS-CoV-2 immune escape. In this study we report an -ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease (Mpro), RAY1216. Enzyme inhibition kinetic analysis established that RAY1216 is a slow-tight inhibitor with a Ki of 8.6 nM; RAY1216 has a drug-target residence time of 104 min compared to 9 min of PF-07321332 (nirmatrelvir), the antiviral component in Paxlovid, suggesting that RAY1216 is approximately 12 times slower to dissociate from the protease-inhibitor complex compared to PF-07321332. Crystal structure of SARS-CoV-2 Mpro:RAY1216 complex demonstrates that RAY1216 is covalently attached to the catalytic Cys145 through the -ketoamide warhead; more extensive interactions are identified between bound RAY1216 and Mpro active site compared to PF-07321332, consistent with a more stable acyl-enzyme inhibition complex for RAY1216. In cell culture and human ACE2 transgenic mouse models, RAY1216 demonstrates comparable antiviral activities towards different SARS-CoV-2 virus variants compared to PF-07321332. Improvement in pharmacokinetics has been observed for RAY1216 over PF-07321332 in various animal models, which may allow RAY1216 to be used without ritonavir. RAY1216 is currently undergoing phase III clinical trials (https://clinicaltrials.gov/ct2/show/NCT05620160) to test real-world therapeutic efficacy against COVID-19.

biochemistry↗

bioRxiv2022

An engineered xCas12i with high activity, high specificity and broad PAM range

The type-V CRISPR effector Cas12i, with its smaller size, short crRNA guiding, and self-processing features, is a potentially versatile genome editing tool. By screening Cas12i proteins from a metagenomic database, we identified a natural variant with high activity in mammalian cells, named as xCas12i. We further engineered the PAM-interacting, REC, and RuvC domains for enhanced cleavage activity and specificity. This variant, named as high-fidelity Cas12Max, exhibited robust genome editing activity and minimal off-target activity with a broad 5-TN recognition profile. With the fusion of deaminase TadA8e and further optimization of xCas12i, the base editor dCas12i-Tad8e also showed the high editing efficiency. This study provides highly efficient and specific tools for gene therapy.

bioengineering↗

bioRxiv2022

Spatiotemporal landscape of SARS-CoV-2 pulmonary infection reveals Slamf9+Spp1+ macrophages promoting viral clearance and inflammation resolution

While SARS-CoV-2 pathogenesis has been intensively investigated, the host mechanisms of viral clearance and inflammation resolution are still elusive because of the ethical limitation of human studies based on COVID-19 convalescents. Here we infected Syrian hamsters by authentic SARS-CoV-2 and built an ideal model to simulate the natural recovery process of SARS-CoV-2 infection from severe pneumonia1,2. We developed and applied a spatial transcriptomic sequencing technique with subcellular resolution and tissue-scale extensibility, i.e., Stereo-seq3, together with single-cell RNA sequencing (scRNA-seq), to the entire lung lobes of 45 hamsters and obtained an elaborate map of the pulmonary spatiotemporal changes from acute infection, severe pneumonia to the late viral clearance and inflammation resolution. While SARS-CoV-2 infection caused massive damages to the hamster lungs, including naive T cell infection and deaths related to lymphopenia, we identified a group of monocyte-derived proliferating Slamf9+Spp1+ macrophages, which were SARS-CoV-2 infection-inducible and cell death-resistant, recruiting neutrophils to clear viruses together. After viral clearance, the Slamf9+Spp1+ macrophages differentiated into Trem2+ and Fbp1+ macrophages, both responsible for inflammation resolution and replenishment of alveolar macrophages. The existence of this specific macrophage subpopulation and its descendants were validated by RNAscope in hamsters, immunofluorescence in hACE2 mice, and public human autopsy scRNA-seq data of COVID-19 patients. The spatiotemporal landscape of SARS-CoV-2 infection in hamster lungs and the identification of Slamf9+Spp1+ macrophages that is pivotal to viral clearance and inflammation resolution are important to better understand the critical molecular and cellular players of COVID-19 host defense and also develop potential interventions of COVID-19 immunopathology.

immunology↗

bioRxiv2022

Aucubin promoted neuron functional recovery by suppressing inflammation and neuronal apoptosis in a spinal cord injury model

Spinal cord injury (SCI) can cause severe motor impairment. Post-SCI treatment has focused primarily on secondary injury, with neuroinflammation and neuronal apoptosis as the primary therapeutic targets. Aucubin (Au), a Chinese herbal medicine, exerts anti-inflammatory and neuroprotective effects. The therapeutic effects of Au in SCI have not been reported. We showed that Au can promote functional recovery after SCI. Recovery may occur through the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-{kappa}B) pathway to promote M2/M1 polarization in microglia and inhibit mitochondrial dysfunction to reduce neuronal apoptosis. These biochemical changes result in reduced secondary injury and facilitate axon regeneration. Therefore, Au may be a promising post-SCI therapeutic medication.

cell biology↗

bioRxiv2021

Develop an efficient and specific AAV-based labeling system for Muller glia in mice

Cell degeneration in the retina leads to several ocular diseases and vision loss. Considerable research efforts focus on reprogramming Muller glia (MG) into functional cells to rescue vision as a promising therapeutic strategy, although whether MG can convert into functional bipolar cells, retinal ganglia cells (RGCs), rods or cones in mammals remains controversial. The broad applicability of tracking MG differentiation thus presents a need for improved labeling efficiency and specificity. Here, we compared AAV-based labeling strategies with conventional lineage-tracking by crossing transgenic mouse lines. We found that reporter expression was weak and not MG-specific in mGFAP-Cre transgenic mice. Different AAV serotypes showed a range of efficiency and specificity in labeling MG, leading us to optimize a human GFAP-Cre reporter system packaged in the AAV9 serotype with the WPRE (WPRE, woodchuck hepatitis virus post-transcriptional regulatory element) removed. The hGFAP-Cre- {Delta}WPRE reporter could label 20-73.8% MGs, with non-specific RGC labeling rates ranging from 0-0.08% at doses of 1 x 108 to 1010 vector genomes (vg) per eye, an approximate 40-fold reduction compared with the AAV9-hGFAP-Cre-WPRE labeling system. Furthermore, we validated the availability of the label system to trace MG reprogramming and also detected false-positive results reported previously. The AAV9-hGFAP-Cre-{Delta}WPRE system thus represents a highly efficient and specific labeling system for MG, providing a valuable tool for tracking cell fate in vivo.

neuroscience↗

bioRxiv2021

A recombinant selective drug-resistant M. bovis BCG enhances the bactericidal activity of a second-line tuberculosis regimen

Drug-resistant tuberculosis (DR-TB) results from infection by Mycobacterium tuberculosis strains resistant to at least rifampin or isoniazid. To improve the treatment outcome in DR-TB, therapeutic vaccines are considered an ideal choice as they can enhance pathogen clearance and minimize disease sequelae. To date, there is no therapeutic vaccine reported to be effective when combined with a chemotherapy regimen against DR-TB. The only available TB vaccine, the M. bovis BCG (BCG) is susceptible to several anti-TB drugs hence not a perfect option for therapeutic vaccination. Herein, we developed a recombinant BCG (RdrBCG) overexpressing Ag85B and Rv2628 with resistance to selected anti-TB drugs. When administered three times adjunct to a second-line anti-TB regimen in a classical murine model of DR-TB, the RdrBCG lowered lung M. tuberculosis colony-forming units by 1 log10. Furthermore, vaccination with the RdrBCG adjunct to TB chemotherapy minimized lung tissue pathology in mice. Most importantly, the RdrBCG maintained the exogenously inserted genes and showed almost the same virulence as its parent BCG Tice strain in severe combined immune-deficient mice. All these suggested that the RdrBCG was stable, safe and effective. Hence, the "recombinant" plus "drug-resistant" BCG strategy could be a useful concept for developing therapeutic vaccines against DR-TB.

microbiology↗

bioRxiv2021

Incidence and Characteristics of Co-infection and Secondary Infection in Patients with COVID-19

ObjectiveThe etiology and epidemiology of co-infection and secondary infection in COVID-19 patients remain unknown. The study aims to investigate the occurrence and characteristics of co-infection and secondary infection in COVID-19 patients, mainly focusing on Streptococcus pneumoniae co-infections. MethodsThis study was a prospective, observational cohort study of the inpatients diagnosed with COVID-19 in two designated hospitals in south China enrolled between Jan 11 and Feb 22, 2020. The urine specimen was collected on admission and applied for pneumococcal urinary antigen tests (PUATs). Demographic, clinical and microbiological data of patients were recorded simultaneously. ResultA total of 146 patients with a confirm diagnosis of COVID-19 at the median age of 50.0 years (IQR 36.0-61.0) were enrolled, in which, 16 (11.0%) were classified as severe cases and 130 (89.0%) as non-severe cases. Of the enrolled patients, only 3 (2.1%) were considered to present the co-infection, in which 1 was co-infected with S.pneumoniae, 1 with B. Ovatus infection and the other one with Influenza A virus infection. Secondary infection occurred in 16 patients, with S. maltophilia as the most commonly isolated pathogen (43.8%), followed by P. aeruginosa (25.0%), E. aerogenes (25.0%), C. parapsilosis (25.0%) and A. fumigates (18.8%). ConclusionPatients with confirmed COVID-19 were rarely co-infected with Streptococcus pneumoniae or other pathogens, indicating that the application of antibiotics against CAP on admission may not be necessary in the treatment of COVID-19 cases.

microbiology↗

bioRxiv2020

Population Bottlenecks and Intra-host Evolution during Human-to-Human Transmission of SARS-CoV-2Population Bottlenecks and Intra-host Evolution during Human-to-Human Transmission of SARS-CoV-2

The emergence of the novel human coronavirus, SARS-CoV-2, causes a global COVID-19 (coronavirus disease 2019) pandemic. Here, we have characterized and compared viral populations of SARS-CoV-2 among COVID-19 patients within and across households. Our work showed an active viral replication activity in the human respiratory tract and the co-existence of genetically distinct viruses within the same host. The inter-host comparison among viral populations further revealed a narrow transmission bottleneck between patients from the same households, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions. Author summaryIn this study, we compared SARS-CoV-2 populations of 13 Chinese COVID-19 patients. Those viral populations contained a considerable proportion of viral sub-genomic messenger RNAs (sgmRNA), reflecting an active viral replication activity in the respiratory tract tissues. The comparison of 66 identified intra-host variants further showed a low viral genetic distance between intra-household patients and a narrow transmission bottleneck size. Despite the co-existence of genetically distinct viruses within the same host, most intra-host minor variants were not shared between transmission pairs, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions. Furthermore, the narrow bottleneck and active viral activity in the respiratory tract show that the passage of a small number of virions can cause infection. Our data have therefore delivered a key genomic resource for the SARS-CoV-2 transmission research and enhanced our understanding of the evolutionary dynamics of SARS-CoV-2.

genetics↗