Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 55
Filter
1.
Virology ; 584: 9-23, 2023 07.
Article in English | MEDLINE | ID: covidwho-2317224

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) is a porcine enteropathogenic coronavirus causing severe watery diarrhea, vomiting, dehydration, and death in piglets. However, most commercial vaccines are developed based on the GI genotype strains, and have poor immune protection against the currently dominant GII genotype strains. Therefore, four novel replication-deficient human adenovirus 5-vectored vaccines expressing codon-optimized forms of the GIIa and GIIb strain spike and S1 glycoproteins were constructed, and their immunogenicity was evaluated in mice by intramuscular (IM) injection. All the recombinant adenoviruses generated robust immune responses, and the immunogenicity of recombinant adenoviruses against the GIIa strain was stronger than that of recombinant adenoviruses against the GIIb strain. Moreover, Ad-XT-tPA-Sopt-vaccinated mice elicited optimal immune effects. In contrast, mice immunized with Ad-XT-tPA-Sopt by oral gavage did not induce strong immune responses. Overall, IM administration of Ad-XT-tPA-Sopt is a promising strategy against PEDV, and this study provides useful information for developing viral vector-based vaccines.


Subject(s)
Adenoviruses, Human , Coronavirus Infections , Porcine epidemic diarrhea virus , Swine Diseases , Viral Vaccines , Animals , Swine , Mice , Humans , Antibodies, Viral , Porcine epidemic diarrhea virus/genetics , Vaccines, Synthetic/genetics , Viral Vaccines/genetics , Coronavirus Infections/prevention & control , Coronavirus Infections/veterinary , Genotype , Spike Glycoprotein, Coronavirus/genetics
2.
Front Oncol ; 13: 1105080, 2023.
Article in English | MEDLINE | ID: covidwho-2287666

ABSTRACT

Background: Signet-ring cell gastric carcinoma is a highly malignant tumor, with the characteristics of strong invasiveness, rapid progression, a high degree of malignancy, and generally poor prognosis. The most common site of metastases is the abdominal organs, especially the liver, while delayed cutaneous metastases are rare. Case presentation: We report a case of cutaneous metastases on the head, groin, and thigh, which recurred 7 years after signet-ring cell gastric carcinoma surgery. The patient was diagnosed with a 2.0×1.5×1.0cm tumor at the angle of stomach, and treated with Billroth II distal gastrectomy accompanied with D2 lymph node dissection. According the pathology, the stage was pT1N3M0. Then the patient received two cycles of oxaliplatin and tegafur chemotherapy, which was discontinued due to the inability to tolerate the side effects of chemotherapy. Seven years after the surgery, the patient initially presented with a fleshy mass on the head and beaded nodules in the groin; then, the mass gradually became larger, along with the thighs turning red, swollen, and crusty. Firstly, the patient was diagnosed with "lower extremity lymphangitis" and treated mostly with anti-inflammatory, promote lymphatic return, detumescence and elastic force cannula in vascular surgery department. However, the symptoms relieved insufficient. Finally, the skin biopsy indicates a signet-ring cell gastric carcinoma cutaneous metastasis. The whole-body PET-CT examination showed multiple nodules with increased metabolism. Then the patient was transferred to The Department of Oncology for further chemotherapy. Conclusion: Our case highlights that gastric tumor recurrence and metastasis should be highly suspected when skin lesions appear in patients with signet-ring cell gastric carcinoma. At the same time, multidisciplinary consultation and close cooperation between surgeons, oncologists, and dermatologists are of great significance to the diagnosis and treatment of this disease.

3.
Zhongguo Zhen Jiu ; 43(3): 255-60, 2023 Mar 12.
Article in Chinese | MEDLINE | ID: covidwho-2287436

ABSTRACT

OBJECTIVE: To observe the effect of Shugan Tiaoshen acupuncture (acupuncture for soothing the liver and regulating the mentality) combined with western medication on depression and sleep quality in the patients with depression-insomnia comorbidity due to COVID-19 quarantine, and investigate the potential mechanism from the perspective of cortical excitability. METHODS: Sixty patients with depression-insomnia comorbidity due to COVID-19 quarantine were randomly divided into an acupuncture group and a sham-acupuncture group, 30 cases in each one. The patients of both groups were treated with oral administration of sertraline hydrochloride tablets. In the acupuncture group, Shugan Tiaoshen acupuncture was supplemented. Body acupuncture was applied to Yintang (GV 24+), Baihui (GV 20), Hegu (LI 4), Zhaohai (KI 6), Qihai (CV 6), etc. The intradermal needling was used at Xin (CO15), Gan (CO12) and Shen (CO10). In the sham-acupuncture group, the sham-acupuncture was given at the same points as the acupuncture group. The compensatory treatment was provided at the end of follow-up for the patients in the sham-acupuncture group. In both groups, the treatment was given once every two days, 3 times a week, for consecutive 8 weeks. The self-rating depression scale (SDS) and insomnia severity index (ISI) scores were compared between the two groups before and after treatment and 1 month after the end of treatment (follow-up) separately. The cortical excitability indexes (resting motor threshold [rMT], motor evoked potential amplitude [MEP-A], cortical resting period [CSP]) and the level of serum 5-hydroxytryptamine (5-HT) were measured before and after treatment in the two groups. RESULTS: After treatment and in follow-up, SDS and ISI scores were decreased in both groups compared with those before treatment (P<0.05), and the scores in the acupuncture group were lower than those in the sham-acupuncture group (P<0.05), and the decrease range in the acupuncture group after treatment was larger than that in the sham-acupuncture group (P<0.05). After treatment, rMT was reduced (P<0.05), while MEP-A and CSP were increased (P<0.05) in the acupuncture group compared with that before treatment. The levels of serum 5-HT in both groups were increased compared with those before treatment (P<0.05). The rMT in the acupuncture group was lower than that in the sham-acupuncture group, while MEP-A and CSP, as well as the level of serum 5-HT were higher in the acupuncture group in comparison with the sham-acupuncture group (P<0.05). CONCLUSION: Shugan Tiaoshen acupuncture combined with western medication can relieve depression and improve sleep quality in the patients with depression-insomnia comorbidity due to COVID-19 quarantine, which is probably related to rectifying the imbalanced excitatory and inhibitory neuronal functions.


Subject(s)
Acupuncture Therapy , COVID-19 , Sleep Initiation and Maintenance Disorders , Humans , Depression , Quarantine , Serotonin , Comorbidity
4.
Cell ; 186(4): 850-863.e16, 2023 02 16.
Article in English | MEDLINE | ID: covidwho-2239711

ABSTRACT

It is unknown whether pangolins, the most trafficked mammals, play a role in the zoonotic transmission of bat coronaviruses. We report the circulation of a novel MERS-like coronavirus in Malayan pangolins, named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV). Among 86 animals, four tested positive by pan-CoV PCR, and seven tested seropositive (11 and 12.8%). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1). This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection, which is enhanced by a furin cleavage site that is absent in all known bat HKU4r-CoVs. The MjHKU4r-CoV-1 spike shows higher binding affinity for hDPP4, and MjHKU4r-CoV-1 has a wider host range than bat HKU4-CoV. MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice. Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.


Subject(s)
Coronavirus Infections , Coronavirus , Dipeptidyl Peptidase 4 , Pangolins , Animals , Humans , Mice , Chiroptera , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Endopeptidases/metabolism , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/metabolism , Peptide Hydrolases/metabolism , Receptors, Virus/metabolism , Virus Internalization , Coronavirus/physiology
5.
mBio ; 14(2): e0328522, 2023 04 25.
Article in English | MEDLINE | ID: covidwho-2246542

ABSTRACT

In the last 2 decades, pathogens originating in animals may have triggered three coronavirus pandemics, including the coronavirus disease 2019 pandemic. Thus, evaluation of the spillover risk of animal severe acute respiratory syndrome (SARS)-related coronavirus (SARSr-CoV) is important in the context of future disease preparedness. However, there is no analytical framework to assess the spillover risk of SARSr-CoVs, which cannot be determined by sequence analysis alone. Here, we established an integrity framework to evaluate the spillover risk of an animal SARSr-CoV by testing how viruses break through key human immune barriers, including viral cell tropism, replication dynamics, interferon signaling, inflammation, and adaptive immune barriers, using human ex vivo lung tissues, human airway and nasal organoids, and human lung cells. Using this framework, we showed that the two pre-emergent animal SARSr-CoVs, bat BtCoV-WIV1 and pangolin PCoV-GX, shared similar cell tropism but exhibited less replicative fitness in the human nasal cavity or airway than did SARS-CoV-2. Furthermore, these viruses triggered fewer proinflammatory responses and less cell death, yet showed interferon antagonist activity and the ability to partially escape adaptive immune barriers to SARS-CoV-2. Collectively, these animal viruses did not fully adapt to spread or cause severe diseases, thus causing successful zoonoses in humans. We believe that this experimental framework provides a path to identifying animal coronaviruses with the potential to cause future zoonoses. IMPORTANCE Evaluation of the zoonotic risk of animal SARSr-CoVs is important for future disease preparedness. However, there are misconceptions regarding the risk of animal viruses. For example, an animal SARSr-CoV could readily infect humans. Alternately, human receptor usage may result in spillover risk. Here, we established an analytical framework to assess the zoonotic risk of SARSr-CoV by testing a series of virus-host interaction profiles. Our data showed that the pre-emergent bat BtCoV-WIV1 and pangolin PCoV-GX were less adapted to humans than SARS-CoV-2 was, suggesting that it may be extremely rare for animal SARSr-CoVs to break all bottlenecks and cause successful zoonoses.


Subject(s)
COVID-19 , Chiroptera , Animals , Humans , Pangolins , SARS-CoV-2 , Zoonoses , Interferons , Phylogeny
6.
Int J Ophthalmol ; 16(1): 16-21, 2023.
Article in English | MEDLINE | ID: covidwho-2246482

ABSTRACT

AIM: To analyze the impact of the coronavirus disease-2019 (COVID-19) pandemic on the presentation and characteristics of patients hospitalized for ocular trauma in a tertiary hospital in China between 2019 and 2020. METHODS: A retrospective case study was designed to collect information on all cases of ocular trauma in a tertiary hospital from 2019 to 2020 and compare differences in inpatients' data (age, sex, admission vision acuity, type of diagnosis, hospital stays, mechanism of injury and location of injury). RESULTS: The total number of patients admitted to the Ophthalmology Department was 883 (mean 73.58±11.25 patients per month) in 2019 and 714 (59.50±17.92 patients per month) in 2020. The injury number of in work was also the most within the four types of location in this two year (42.36% in 2019, 43.84% in 2020). The mean hospital stays were 12.66d in 2019 and 10.81d in 2020. The highest incidence of ocular trauma was the middle-aged (41-65y) groups in 2019 and 2020. The most common cause of ocular trauma was sharp object in 2019 (47.34%) and 2020 (47.58%). The mechanical ocular trauma reaches 98.98% in 2019 and 99.72% in 2020. CONCLUSION: The number of patients with ocular trauma decreased in 2020, but middle-aged (41-65y) are still high incident groups. Mechanical ocular trauma remains the leading cause of hospitalization for ocular trauma patients and the proportion of patients injured at home increases. It is necessary to arouse social attention and the public's awareness of eye trauma protection should be strengthened during the pandemic.

7.
Cell Res ; 33(3): 201-214, 2023 03.
Article in English | MEDLINE | ID: covidwho-2185794

ABSTRACT

SARS-CoV-2 infection can trigger strong inflammatory responses and cause severe lung damage in COVID-19 patients with critical illness. However, the molecular mechanisms by which the infection induces excessive inflammatory responses are not fully understood. Here, we report that SARS-CoV-2 infection results in the formation of viral Z-RNA in the cytoplasm of infected cells and thereby activates the ZBP1-RIPK3 pathway. Pharmacological inhibition of RIPK3 by GSK872 or genetic deletion of MLKL reduced SARS-CoV-2-induced IL-1ß release. ZBP1 or RIPK3 deficiency leads to reduced production of both inflammatory cytokines and chemokines during SARS-CoV-2 infection both in vitro and in vivo. Furthermore, deletion of ZBP1 or RIPK3 alleviated SARS-CoV-2 infection-induced immune cell infiltration and lung damage in infected mouse models. These results suggest that the ZBP1-RIPK3 pathway plays a critical role in SARS-CoV-2-induced inflammatory responses and lung damage. Our study provides novel insights into how SARS-CoV-2 infection triggers inflammatory responses and lung pathology, and implicates the therapeutic potential of targeting ZBP1-RIPK3 axis in treating COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Mice , SARS-CoV-2/metabolism , COVID-19/pathology , RNA , Lung/pathology , Cytokines/metabolism , RNA-Binding Proteins/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
8.
Nat Commun ; 13(1): 7629, 2022 Dec 09.
Article in English | MEDLINE | ID: covidwho-2160211

ABSTRACT

The ongoing COVID-19 pandemic has demonstrated that viral diseases represent an enormous public health and economic threat to mankind and that individuals with compromised immune systems are at greater risk of complications and death from viral diseases. The development of broad-spectrum antivirals is an important part of pandemic preparedness. Here, we have engineer a series of designer cells which we term autonomous, intelligent, virus-inducible immune-like (ALICE) cells as sense-and-destroy antiviral system. After developing a destabilized STING-based sensor to detect viruses from seven different genera, we have used a synthetic signal transduction system to link viral detection to the expression of multiple antiviral effector molecules, including antiviral cytokines, a CRISPR-Cas9 module for viral degradation and the secretion of a neutralizing antibody. We perform a proof-of-concept study using multiple iterations of our ALICE system in vitro, followed by in vivo functionality testing in mice. We show that dual output ALICESaCas9+Ab system delivered by an AAV-vector inhibited viral infection in herpetic simplex keratitis (HSK) mouse model. Our work demonstrates that viral detection and antiviral countermeasures can be paired for intelligent sense-and-destroy applications as a flexible and innovative method against virus infection.


Subject(s)
COVID-19 , Virus Diseases , Viruses , Humans , Mice , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Virus Replication , Pandemics
10.
iScience ; 25(11): 105319, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2061302

ABSTRACT

SARS-CoV-2 infection induces imbalanced immune response such as hyperinflammation in patients with severe COVID-19. Here, we studied the immunometabolic regulatory mechanisms for the pathogenesis of COVID-19. We depicted the metabolic landscape of immune cells, especially macrophages, from bronchoalveolar lavage fluid of patients with COVID-19 at single-cell level. We found that most metabolic processes were upregulated in macrophages from lungs of patients with mild COVID-19 compared to cells from healthy controls, whereas macrophages from severe COVID-19 showed downregulation of most of the core metabolic pathways including glutamate metabolism, fatty acid oxidation, citrate cycle, and oxidative phosphorylation, and upregulation of a few pathways such as glycolysis. Rewiring cellular metabolism by amino acid supplementation, glycolysis inhibition, or PPARγ stimulation reduces inflammation in macrophages stimulated with SARS-CoV-2. Altogether, this study demonstrates that metabolic imbalance of bronchoalveolar macrophages may contribute to hyperinflammation in patients with severe COVID-19 and provides insights into treating COVID-19 by immunometabolic modulation.

11.
BMJ Open ; 12(8): e062664, 2022 08 29.
Article in English | MEDLINE | ID: covidwho-2020059

ABSTRACT

OBJECTIVES: The COVID-19 outbreak beginning in late 2019 has resulted in negative emotions among the public. However, many healthcare workers risked their lives by voluntarily travelling to the worst-hit area, Hubei Province, to support antipandemic work. This study explored the mental health changes in these healthcare workers and tried to discover the influencing factors. DESIGN: A longitudinal online survey was begun on 8 February 2020, using the snowball sampling method, and this first phase ended on 22 February 2020 (T1). The follow-up survey was conducted from 8 February to 22 February 2021 (T2). SETTING: Healthcare workers from outside of the Hubei area who went to the province to provide medical assistance. PARTICIPANTS: 963 healthcare workers who completed both surveys. MEASURES: Self-Rating Scale of Sleep (SRSS), Generalised Anxiety Scale (GAD-7) and 9-item Patient Health Questionnaire (PHQ-9). RESULTS: There were no significant differences in the SRSS scores or in the GAD-7 scores between T1 and T2 (t=0.994, 0.288; p>0.05). However, the PHQ-9 score at T2 was significantly higher than the score at T1 (t=-10.812, p<0.001). Through multiple linear regression analysis, we found that the following traits could predict higher GAD-7 and PHQ-9 scores at T2: male sex, single marital status, occupation of nurse, lower professional technical titles, healthcare workers having a history of psychosis, treating seriously ill patients, having relatively poor self-perceived health, caring for patients who died and having family members who had been infected with COVID-19. CONCLUSIONS: The results indicate that the depression levels of these special healthcare workers increased in the long term, and the initial demographics and experiences related to the pandemic played an important role in predicting their long-term poor mental health. In the future, more appropriate psychological decompression training should be provided for these special healthcare workers.


Subject(s)
COVID-19 , Anxiety/epidemiology , COVID-19/epidemiology , Depression/epidemiology , Disease Outbreaks , Health Personnel/psychology , Health Status , Humans , Male , Prospective Studies , SARS-CoV-2
12.
J Virol ; 96(17): e0006522, 2022 09 14.
Article in English | MEDLINE | ID: covidwho-2001768

ABSTRACT

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a recently emerging bat-borne coronavirus responsible for high mortality rates in piglets. In vitro studies have indicated that SADS-CoV has a wide tissue tropism in different hosts, including humans. However, whether this virus potentially threatens other animals remains unclear. Here, we report the experimental infection of wild-type BALB/c and C57BL/6J suckling mice with SADS-CoV. We found that mice less than 7 days old are susceptible to the virus, which caused notable multitissue infections and damage. The mortality rate was the highest in 2-day-old mice and decreased in older mice. Moreover, a preliminary neuroinflammatory response was observed in 7-day-old SADS-CoV-infected mice. Thus, our results indicate that SADS-CoV has potential pathogenicity in young hosts. IMPORTANCE SADS-CoV, which likely has originated from bat coronaviruses, is highly pathogenic to piglets and poses a threat to the swine industry. Little is known about its potential to disseminate to other animals. No efficient treatment is available, and the quarantine strategy is the only preventive measure. In this study, we demonstrated that SADS-CoV can efficiently replicate in suckling mice younger than 7 days. In contrast to infected piglets, in which intestinal tropism is shown, SADS-CoV caused infection and damage in all murine tissues evaluated in this study. In addition, neuroinflammatory responses were detected in some of the infected mice. Our work provides a preliminary cost-effective model for the screening of antiviral drugs against SADS-CoV infection.


Subject(s)
Alphacoronavirus , Coronavirus Infections , Diarrhea , Mice , Swine Diseases , Alphacoronavirus/pathogenicity , Animals , Chiroptera/virology , Coronavirus Infections/complications , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Diarrhea/complications , Diarrhea/veterinary , Diarrhea/virology , Humans , Mice/virology , Mice, Inbred BALB C , Mice, Inbred C57BL , Neuroinflammatory Diseases/complications , Neuroinflammatory Diseases/veterinary , Neuroinflammatory Diseases/virology , Swine/virology , Swine Diseases/virology
13.
Nat Commun ; 13(1): 4380, 2022 08 09.
Article in English | MEDLINE | ID: covidwho-1984384

ABSTRACT

Emerging diseases caused by coronaviruses of likely bat origin (e.g., SARS, MERS, SADS, COVID-19) have disrupted global health and economies for two decades. Evidence suggests that some bat SARS-related coronaviruses (SARSr-CoVs) could infect people directly, and that their spillover is more frequent than previously recognized. Each zoonotic spillover of a novel virus represents an opportunity for evolutionary adaptation and further spread; therefore, quantifying the extent of this spillover may help target prevention programs. We derive current range distributions for known bat SARSr-CoV hosts and quantify their overlap with human populations. We then use probabilistic risk assessment and data on human-bat contact, human viral seroprevalence, and antibody duration to estimate that a median of 66,280 people (95% CI: 65,351-67,131) are infected with SARSr-CoVs annually in Southeast Asia. These data on the geography and scale of spillover can be used to target surveillance and prevention programs for potential future bat-CoV emergence.


Subject(s)
COVID-19 , Chiroptera , Severe acute respiratory syndrome-related coronavirus , Animals , Asia, Southeastern/epidemiology , Evolution, Molecular , Humans , Phylogeny , Seroepidemiologic Studies
14.
Appl Acoust ; 197: 108940, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1956084

ABSTRACT

With the COVID-19 pandemic, the usage of personal protective equipment (PPE) has become 'the new normal'. Both surgical masks and N95 masks with a face shield are widely used in healthcare settings to reduce virus transmission, but the use of these masks has a negative impact on speech perception. Therefore, transparent masks are recommended to solve this dilemma. However, there is a lack of quantitative studies regarding the effect of PPE on speech perception. This study aims to compare the effect on speech perception of different types of PPE (surgical masks, N95 masks with face shield and transparent masks) in healthcare settings, for listeners with normal hearing in the audiovisual or auditory-only modality. The Bamford-Kowal-Bench (BKB)-like Mandarin speech stimuli were digitally recorded by a G.R.A.S KEMAR manikin without and with masks (surgical masks, N95 masks with face shield and transparent masks). Two variants of video display were created (with or without visual cues) and tagged to the corresponding audio recordings. The speech recording and video were presented to listeners simultaneously in each of four conditions: unattenuated speech with visual cues (no mask); surgical mask attenuated speech without visual cues; N95 mask with face shield attenuated speech without visual cues; and transparent mask attenuated speech with visual cues. The signal-to-noise ratio for 50 % correct scores (SNR50) threshold in noise was measured for each condition in the presence of four-talker babble. Twenty-four subjects completed the experiment. Acoustic spectra obtained from all types of masks were primarily attenuated at high frequencies, beyond 3 kHz, but to different extents. The mean SNR50 thresholds of the two auditory-only conditions (surgical mask and N95 mask with face shield) were higher than those of the audiovisual conditions (no mask and transparent mask). SNR50 thresholds in the surgical-mask conditions were significantly lower than those for the N95 masks with face shield. No significant difference was observed between the two audiovisual conditions. The results confirm that wearing a surgical mask or an N95 mask with face shield has a negative impact on speech perception. However, wearing a transparent mask improved speech perception to a similar level as unmasked condition for young normal-hearing listeners.

15.
Int J Biol Sci ; 18(12): 4648-4657, 2022.
Article in English | MEDLINE | ID: covidwho-1954693

ABSTRACT

Asymptomatic infection with SARS-CoV-2 is a major concern in the control of the COVID-19 pandemic. Many questions concerning asymptomatic infection remain to be answered, for example, what are the differences in infectivity and the immune response between asymptomatic and symptomatic infections? In this study, based on a cohort established by the Wuchang District Health Bureau of Wuhan in the early stage of the COVID-19 pandemic in Wuhan in 2019, we conducted a comprehensive analysis of the clinical, virological, immunological, and epidemiological data of asymptomatic infections. The major findings of this study included: 1) the asymptomatic cohort enrolled this study exhibited low-grade but recurrent activity of viral replication; 2) despite a lack of overt clinical symptoms, asymptomatic infections exhibited ongoing innate and adaptive immune responses; 3) however, the immune response from asymptomatic infections was not activated adequately, which may lead to delayed viral clearance. Given the fragile equilibrium between viral infection and host immunity, and the delayed viral clearance in asymptomatic individuals, close viral monitoring should be scheduled, and therapeutic intervention may be needed.


Subject(s)
COVID-19 , Asymptomatic Infections , Humans , Immunity , Immunity, Innate , Pandemics , SARS-CoV-2
16.
J Virol ; 96(9): e0003822, 2022 05 11.
Article in English | MEDLINE | ID: covidwho-1788914

ABSTRACT

Due to the limitation of human studies with respect to individual difference or the accessibility of fresh tissue samples, how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in pathological complications in lung, the main site of infection, is still incompletely understood. Therefore, physiologically relevant animal models under realistic SARS-CoV-2 infection conditions would be helpful to our understanding of dysregulated inflammation response in lung in the context of targeted therapeutics. Here, we characterized the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicates human symptoms, including severe lung pathology and lymphopenia. We showed a reduction of lymphocyte populations and an increase of neutrophils in lung and then demonstrated the key role of neutrophil-mediated lung immunopathology in both mice and humans. Under severe conditions, neutrophils recruited by a chemokine-driven positive feedback produced elevated "fatal signature" proinflammatory genes and pathways related to neutrophil activation or releasing of granular content. In addition, we identified a new Cd177high cluster that is undergoing respiratory burst and Stfahigh cluster cells that may dampen antigen presentation upon infection. We also revealed the devastating effect of overactivated neutrophil by showing the highly enriched neutrophil extracellular traps in lung and a dampened B-cell function in either lung or spleen that may be attributed to arginine consumption by neutrophil. The current study helped our understanding of SARS-CoV-2-induced pneumonia and warranted the concept of neutrophil-targeting therapeutics in COVID-19 treatment. IMPORTANCE We demonstrated the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicated human symptoms, including severe lung pathology and lymphopenia. Our comprehensive study revealed the key role of neutrophil-mediated lung immunopathology in SARS-CoV-2-induced severe pneumonia, which not only helped our understanding of COVID-19 but also warranted the concept of neutrophil targeting therapeutics in COVID-19 treatment.


Subject(s)
COVID-19 , Lung , Neutrophils , Animals , COVID-19/immunology , Disease Models, Animal , Humans , Lung/pathology , Lung/virology , Lymphopenia/virology , Mice , Neutrophils/immunology , SARS-CoV-2 , Spleen/pathology , Spleen/virology
17.
Signal Transduct Target Ther ; 7(1): 83, 2022 03 11.
Article in English | MEDLINE | ID: covidwho-1740428

ABSTRACT

SARS-CoV-2 induced marked lymphopenia in severe patients with COVID-19. However, whether lymphocytes are targets of viral infection is yet to be determined, although SARS-CoV-2 RNA or antigen has been identified in T cells from patients. Here, we confirmed that SARS-CoV-2 viral antigen could be detected in patient peripheral blood cells (PBCs) or postmortem lung T cells, and the infectious virus could also be detected from viral antigen-positive PBCs. We next prove that SARS-CoV-2 infects T lymphocytes, preferably activated CD4 + T cells in vitro. Upon infection, viral RNA, subgenomic RNA, viral protein or viral particle can be detected in the T cells. Furthermore, we show that the infection is spike-ACE2/TMPRSS2-independent through using ACE2 knockdown or receptor blocking experiments. Next, we demonstrate that viral antigen-positive T cells from patient undergone pronounced apoptosis. In vitro infection of T cells induced cell death that is likely in mitochondria ROS-HIF-1a-dependent pathways. Finally, we demonstrated that LFA-1, the protein exclusively expresses in multiple leukocytes, is more likely the entry molecule that mediated SARS-CoV-2 infection in T cells, compared to a list of other known receptors. Collectively, this work confirmed a SARS-CoV-2 infection of T cells, in a spike-ACE2-independent manner, which shed novel insights into the underlying mechanisms of SARS-CoV-2-induced lymphopenia in COVID-19 patients.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , SARS-CoV-2/metabolism , T-Lymphocytes/metabolism , Animals , Caco-2 Cells , Chlorocebus aethiops , Humans , Vero Cells
18.
Emerg Microbes Infect ; 11(1): 902-913, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1730557

ABSTRACT

The immune memory of over 400 million COVID-19 convalescents is not completely understood. In this integrated study, we recorded the post-acute sequelae symptoms and tested the immune memories, including circulating antibodies, memory B cell, and memory CD4 or CD8 T cell responses of a cohort of 65 COVID-19 patients over 1-year after infection. Our data show that 48% of them still have one or more sequelae symptoms and all of them maintain at least one of the immune components. The chances of having sequelae symptoms or having better immune memory are associated with peak disease severity. We did four-time points sampling per subject to precisely understand the kinetics of durability of SARS-CoV-2 circulating antibodies. We found that the RBD IgG levels likely reach a stable plateau at around 6 months, albeit it is waning at the first 6 months after infection. At 1-year after infection, more than 90% of the convalescents generated memory CD4 or CD8 T memory responses, preferably against the SARS-CoV-2 M peptide pool. The convalescents also have polyfunctional and central memory T cells that could provide rapid and efficient response to SARS-CoV-2 re-infection. Based on this information, we assessed the immune protection against the Omicron variant and concluded that convalescents should still induce effective T cell immunity against the Omicron. By studying the circulating antibodies and memory B or T cell responses to SARS-CoV-2 in an integrated manner, our study provides insight into the understanding of protective immunity against diseases caused by secondary SARS-CoV-2 infection.


Subject(s)
COVID-19 , Antibodies, Viral , Humans , Immunity, Cellular , Longitudinal Studies , SARS-CoV-2
19.
Nat Rev Microbiol ; 20(5): 315, 2022 May.
Article in English | MEDLINE | ID: covidwho-1705646
20.
Virol Sin ; 37(2): 187-197, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1648554

ABSTRACT

The nationwide COVID-19 epidemic ended in 2020, a few months after its outbreak in Wuhan, China at the end of 2019. Most COVID-19 cases occurred in Hubei Province, with a few local outbreaks in other provinces of China. A few studies have reported the early SARS-CoV-2 epidemics in several large cities or provinces of China. However, information regarding the early epidemics in small and medium-sized cities, where there are still traditionally large families and community culture is more strongly maintained and thus, transmission profiles may differ, is limited. In this study, we characterized 60 newly sequenced SARS-CoV-2 genomes from Anyang as a representative of small and medium-sized Chinese cities, compared them with more than 400 reference genomes from the early outbreak, and studied the SARS-CoV-2 transmission profiles. Genomic epidemiology revealed multiple SARS-CoV-2 introductions in Anyang and a large-scale expansion of the epidemic because of the large family size. Moreover, our study revealed two transmission patterns in a single outbreak, which were attributed to different social activities. We observed the complete dynamic process of single-nucleotide polymorphism development during community transmission and found that intrahost variant analysis was an effective approach to studying cluster infections. In summary, our study provided new SARS-CoV-2 transmission profiles representative of small and medium-sized Chinese cities as well as information on the evolution of SARS-CoV-2 strains during the early COVID-19 epidemic in China.


Subject(s)
COVID-19 , Epidemics , COVID-19/epidemiology , China/epidemiology , Cities/epidemiology , Culture Media , Humans , SARS-CoV-2/genetics
SELECTION OF CITATIONS
SEARCH DETAIL