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1.
mSphere ; : e0021122, 2022 Jul 12.
Article in English | MEDLINE | ID: covidwho-1938010

ABSTRACT

The innate interferon (IFN) response constitutes the first line of host defense against viral infections. It has been shown that IFN-I/III treatment could effectively contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro. However, how SARS-CoV-2 survives through the innate antiviral mechanism remains to be explored. Our study uncovered that human angiotensin-converting enzyme 2 (ACE2), identified as a primary receptor for SARS-CoV-2 entry, can disturb the IFN-I signaling pathway during SARS-CoV-2 infection in human lung cells. We identified that ACE2 was significantly upregulated by SARS-CoV-2 and Sendai virus (SeV) infection, and exogenous expression of ACE2 suppressed IFN-I production in a dose-dependent manner. Mechanistically, ACE2 disrupted poly (I:C)-mediated inhibition of SARS-CoV2 replication by antagonizing IFN-I production by blocking IRF3 phosphorylation and nuclear translocation. Moreover, ACE2 quenched the IFN-mediated antiviral immune response by degrading endogenous STAT2 protein, inhibiting STAT2 phosphorylation and nuclear translocation. Interestingly, IFN-inducible short ACE2 (dACE2 or MIRb-ACE2) can also be induced by virus infection and inhibits the IFN signaling. Thus, our findings provide mechanistic insight into the distinctive role of ACE2 in promoting SARS-CoV-2 infection and enlighten us that the development of interventional strategies might be further optimized to interrupt ACE2-mediated suppression of IFN-I and its signaling pathway. IMPORTANCE Efficient antiviral immune responses against SARS-CoV-2 infection play a key role in controlling the coronavirus diseases 2019 (COVID-19) caused by this virus. Although SARS-CoV-2 has developed strategies to counteract the IFN-I signaling through the virus-derived proteins, our knowledge of how SARS-CoV-2 survives through the innate antiviral mechanism remains poor. We herein discovered the distinctive role of ACE2 as a restraining factor of the IFN-I signaling in facilitating SARS-CoV-2 infection in human lung cells. Both full-length ACE2 and truncated dACE2 can antagonize IFN-mediated antiviral response. These findings are key to understanding the counteraction between SARS-CoV-2 pathogenicity and the host antiviral defenses.

2.
J Virol ; 96(4): e0157821, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1759290

ABSTRACT

The ongoing SARS-CoV-2 pandemic poses a severe global threat to public health, as do influenza viruses and other coronaviruses. Here, we present chimpanzee adenovirus 68 (AdC68)-based vaccines designed to universally target coronaviruses and influenza. Our design is centered on an immunogen generated by fusing the SARS-CoV-2 receptor-binding domain (RBD) to the conserved stalk of H7N9 hemagglutinin (HA). Remarkably, the constructed vaccine effectively induced both SARS-CoV-2-targeting antibodies and anti-influenza antibodies in mice, consequently affording protection from lethal SARS-CoV-2 and H7N9 challenges as well as effective H3N2 control. We propose our AdC68-vectored coronavirus-influenza vaccine as a universal approach toward curbing respiratory virus-causing pandemics. IMPORTANCE The COVID-19 pandemic exemplifies the severe public health threats of respiratory virus infection and influenza A viruses. The currently envisioned strategy for the prevention of respiratory virus-causing diseases requires the comprehensive administration of vaccines tailored for individual viruses. Here, we present an alternative strategy by designing chimpanzee adenovirus 68-based vaccines which target both the SARS-CoV-2 receptor-binding-domain and the conserved stalk of influenza hemagglutinin. When tested in mice, this strategy attained potent neutralizing antibodies against wild-type SARS-CoV-2 and its emerging variants, enabling an effective protection against lethal SARS-CoV-2 challenge. Notably, it also provided complete protection from lethal H7N9 challenge and efficient control of H3N2-induced morbidity. Our study opens a new avenue to universally curb respiratory virus infection by vaccination.


Subject(s)
COVID-19/prevention & control , Influenza A Virus, H7N9 Subtype/immunology , Influenza Vaccines , Orthomyxoviridae Infections/prevention & control , SARS-CoV-2/immunology , Animals , COVID-19/epidemiology , COVID-19/genetics , COVID-19/immunology , /immunology , Female , HEK293 Cells , Humans , Influenza A Virus, H7N9 Subtype/genetics , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Influenza Vaccines/pharmacology , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Mice, Transgenic , Orthomyxoviridae Infections/epidemiology , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/immunology , Pandemics , SARS-CoV-2/genetics
3.
Emerg Microbes Infect ; 10(1): 1555-1573, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1324547

ABSTRACT

To curb the pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), multiple platforms have been employed toward a safe and highly effective vaccine. Here, we develop a novel cell-based vaccine candidate, namely K562-S, by utilizing human cell K562 as a cellular carrier to display Spike (S) protein of SARS-CoV-2 on the membrane. Analogous to the traditional inactivated vaccine, K562-S cells can be propagated to a large scale by culturing and completely lose their viability after exposure to X-ray irradiation or formalin. We in turn demonstrated high immunogenicity of formalin-inactivated K562-S vaccine in both mouse and non-human primates and its protective efficacy in mice. In mice, immunization with inactivated K562-S vaccines can elicit potent neutralizing antibody (nAb) responses persisting longer than 5 months. We consequently showed in a hACE2 mouse model of SARS-CoV-2 infection that a two-shot vaccination with adjuvanted K562-S rendered greater than 3 log reduction in viral lung load and concomitant ameliorated lung pathology. Of importance, the administration of the same regimen in non-human primates was able to induce a neutralizing antibody titer averaging three-fold higher relative to human convalescent serum. These results together support the promise of K562-based, S-protein-expressing vaccines as a novel vaccination approach against SARS-CoV-2. Importantly, with a powerful capacity to carry external genes for cell-based vectors, this platform could rapidly generate two- and multiple-valent vaccines by incorporating SARS-CoV-2 mutants, SARS-CoV, or MERS-CoV.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , Animals, Genetically Modified , COVID-19 Vaccines/administration & dosage , Female , HEK293 Cells , Humans , K562 Cells , Macaca mulatta , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Primates , Specific Pathogen-Free Organisms , Spike Glycoprotein, Coronavirus/administration & dosage , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/immunology
4.
J Infect Dis ; 223(4): 568-580, 2021 02 24.
Article in English | MEDLINE | ID: covidwho-1101847

ABSTRACT

BACKGROUND: The immune protective mechanisms during severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection remain to be deciphered for the development of an effective intervention approach. METHODS: We examined early responses of interleukin 37 (IL-37), a powerful anti-inflammatory cytokine, in 254 SARS-CoV-2-infected patients before any clinical intervention and determined its correlation with clinical prognosis. RESULTS: Our results demonstrated that SARS-CoV-2 infection causes elevation of plasma IL-37. Higher early IL-37 responses were correlated with earlier viral RNA negative conversion, chest computed tomographic improvement, and cough relief, consequently resulted in earlier hospital discharge. Further assays showed that higher IL-37 was associated with lower interleukin 6 and interleukin 8 (IL-8) and higher interferon α responses and facilitated biochemical homeostasis. Low IL-37 responses predicted severe clinical prognosis in combination with IL-8 and C-reactive protein. In addition, we observed that IL-37 administration was able to attenuate lung inflammation and alleviate respiratory tissue damage in human angiotensin-converting enzyme 2-transgenic mice infected with SARS-CoV-2. CONCLUSIONS: Overall, we found that IL-37 plays a protective role by antagonizing inflammatory responses while retaining type I interferon, thereby maintaining the functionalities of vital organs. IL-37, IL-8, and C-reactive protein might be formulated as a precise prediction model for screening severe clinical cases and have good value in clinical practice.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/virology , Interleukin-1/blood , Adult , Animals , C-Reactive Protein/metabolism , COVID-19/blood , Female , Humans , Inflammation/immunology , Inflammation/virology , Interleukin-8/blood , Male , Mice , Mice, Transgenic , Middle Aged
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