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Middle East respiratory syndrome coronavirus
shows poor replication but significant induction of antiviral responses
in human monocyte-derived macrophages and dendritic cells.
J Gen Virol. 2016 Feb;97(2):344-355. doi: 10.1099/jgv.0.000351. Epub 2015 Nov 24.
PMID: 26602089
Free PMC article.
n this study we assessed the ability of Middle East respiratory syndrome
coronavirus (MERS-CoV) to replicate and induce innate immunity in human
monocyte-derived macrophages and dendritic cells (MDDCs), and compared
it with severe acute respiratory syndrome coronavirus (SARS-CoV).
Assessments of viral protein and RNA levels in infected cells showed
that both viruses were impaired in their ability to replicate in these
cells. Some induction of IFN-λ1, CXCL10 and MxA mRNAs in both
macrophages and MDDCs was seen in response to MERS-CoV infection, but
almost no such induction was observed in response to SARS-CoV infection.
ELISA and Western blot assays showed clear production of CXCL10 and MxA
in MERS-CoV-infected macrophages and MDDCs. Our data suggest that
SARS-CoV and MERS-CoV replicate poorly in human macrophages and MDDCs,
but MERS-CoV is nonetheless capable of inducing a readily detectable
host innate immune response. Our results highlight a clear difference
between the viruses in activating host innate immune responses in
macrophages and MDDCs, which may contribute to the pathogenesis of
infection.
2.
IFN-lambda preferably inhibits PEDV infection of porcine intestinal epithelial cells compared with IFN-alpha.
Antiviral Res. 2017 Apr;140:76-82. doi: 10.1016/j.antiviral.2017.01.012. Epub 2017 Jan 19.
PMID: 28109912
Free PMC article.
In contrast to type I interferons that target various types of cells and
organs, interferon lambda (IFN-L) primarily acts on mucosal epithelial
cells and exhibits robust antiviral activity within the mucosal surface.
Porcine epidemic diarrhea virus (PEDV), which causes high morbidity and
mortality in piglets, is an enteropathogenic coronavirus with economic
importance. Here, we demonstrated that both recombinant porcine IFN-L1
(rpIFN-L1) and rpIFN-L3 have powerful antiviral activity against PEDV
infection of both Vero E6 cells and the intestinal porcine epithelial
cell line J2 (IPEC-J2). Both forms of rpIFN-L inhibited two genotypes of
PEDV (strain CV777 of genotype 1 and strain LNCT2
of genotype 2). rpIFN-L1 primarily controlled viral infection in the
early stage and had less antiviral activity in IPEC-J2 than in rpIFN-L3
cells infected with PEDV. In addition, rpIFN-L1 exhibited greater
antiviral activity against PEDV infection of IPEC-J2 cells than that of
porcine IFN-alpha. Consistent with this finding, rpIFN-L1 triggered
higher levels of certain antiviral IFN-stimulated genes (ISGs) (ISG15,
OASL, and MxA) in IPEC-J2 cells than porcine IFN-alpha. Although IPEC-J2
cells responded to both IFN-alpha and lambda, transcriptional profiling
of ISGs (specifically ISG15, OASL, MxA, and IFITMs) differed when
induced by either IFN-alpha or rpIFN-L. Therefore, our data provide the
experimental evidence that porcine IFN-L suppresses PEDV infection of
IPEC-J2 cells, which may offer a promising therapeutic for combating PED
in piglets.
3.
Blood MxA protein as a marker for respiratory virus infections in young children.
J Clin Virol. 2015 Jan;62:8-13. doi: 10.1016/j.jcv.2014.11.018. Epub 2014 Nov 18.
PMID: 25542463
Free PMC article.
BACKGROUND: Type I interferon induced MxA response can differentiate viral from bacterial infections, but MxA
responses in rhinovirus or asymptomatic virus infections are not known.
4.
Background:
Type I interferon induced MxA response can differentiate viral
from bacterial infections, but MxA responses in rhinovirus or
asymptomatic virus infections are not known.
Objective: To study MxA protein levels in healthy state and during respiratory virus infection of young children in an observational prospective cohort.
Study design: Blood samples and nasal swabs were collected from 153 and 77 children with and without symptoms of respiratory infections, respectively. Blood MxA protein levels were measured by an enzyme immunoassay and PCR methods were used for the detection of respiratory viruses in nasal swabs.
Results: Respiratory viruses were detected in 81% of symptomatic children. They had higher blood MxA protein levels (median [interquartile range]) than asymptomatic virus-negative children (695 [345-1370] μg/L vs. 110 [55-170] μg/L; p < 0.001). Within asymptomatic children, no significant difference was observed in MxA responses between virus-positive and virus-negative groups. A cut-off level of 175 μg/L had 92% sensitivity and 77% specificity for a symptomatic respiratory virus infection. Rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, coronavirus, and human metapneumovirus infections were associated with elevated MxA responses. Asymptomatic virus-negative children vaccinated with a live virus vaccine had elevated MxA protein levels (240 [120-540] μg/L), but significantly lower than children with an acute respiratory infection, who had not received vaccinations (740 [350-1425] μg/L; p<0 .001="" p=""> Conclusion: Blood MxA protein levels are increased in young children with symptomatic respiratory virus infections, including rhinovirus infections. MxA is an informative general marker for the most common acute virus infections.
Keywords:
Interferon; MxA protein; Respiratory virus infection; Rhinovirus; Rotavirus vaccine; STEPS study.Objective: To study MxA protein levels in healthy state and during respiratory virus infection of young children in an observational prospective cohort.
Study design: Blood samples and nasal swabs were collected from 153 and 77 children with and without symptoms of respiratory infections, respectively. Blood MxA protein levels were measured by an enzyme immunoassay and PCR methods were used for the detection of respiratory viruses in nasal swabs.
Results: Respiratory viruses were detected in 81% of symptomatic children. They had higher blood MxA protein levels (median [interquartile range]) than asymptomatic virus-negative children (695 [345-1370] μg/L vs. 110 [55-170] μg/L; p < 0.001). Within asymptomatic children, no significant difference was observed in MxA responses between virus-positive and virus-negative groups. A cut-off level of 175 μg/L had 92% sensitivity and 77% specificity for a symptomatic respiratory virus infection. Rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, coronavirus, and human metapneumovirus infections were associated with elevated MxA responses. Asymptomatic virus-negative children vaccinated with a live virus vaccine had elevated MxA protein levels (240 [120-540] μg/L), but significantly lower than children with an acute respiratory infection, who had not received vaccinations (740 [350-1425] μg/L; p<0 .001="" p=""> Conclusion: Blood MxA protein levels are increased in young children with symptomatic respiratory virus infections, including rhinovirus infections. MxA is an informative general marker for the most common acute virus infections.
4.
Human β-defensin 2 plays a regulatory role in innate
antiviral immunity and is capable of potentiating the induction of
antigen-specific immunity.
5.
Virol J. 2018 Aug 8;15(1):124. doi: 10.1186/s12985-018-1035-2.
PMID: 30089512
Free PMC article.
Background:
Antimicrobial peptides (AMPs) are primarily known for their innate
immune defense against invading microorganisms, including viruses. In
addition, recent research has suggested their modulatory activity in
immune induction. Given that most subunit vaccines require an adjuvant
to achieve effective immune induction through the activation of innate
immunity, AMPs are plausible candidate molecules for stimulating not
only innate immune but also adaptive immune responses.
Results: In this study, we investigated the ability of human β-defensin (HBD) 2 to promote antiviral immunity in vitro and in vivo using a receptor-binding domain (RBD) of Middle East respiratory syndrome-coronavirus (MERS-CoV) spike protein (S RBD) as a model antigen (Ag). When HBD 2-conjugated S RBD was used to treat THP-1 human monocytic cells, the expression levels of antiviral (IFN-β, IFN-γ, MxA, PKR, and RNaseL) and primary immune-inducing (NOD2, TNF-α, IL-1β, and IL-6) molecules were enhanced compared to those expressed after treatment with S RBD only. The expression of chemokines capable of recruiting leukocytes, including monocytes/macrophages, natural killer cells, granulocytes, T cells, and dendritic cells, was also increased following HBD 2-conjugated S RBD treatment. More important, immunization of mice with HBD 2-conjugated S RBD enhanced the immunogenicity of the S RBD and elicited a higher S RBD-specific neutralizing antibody response than S RBD alone.
Conclusions: We conclude that HBD 2 activates the primary antiviral innate immune response and may also mediate the induction of an effective adaptive immune response against a conjugated Ag.
Keywords:
Adjuvant; Antibody; Antigen; Human β-defensin; MERS-CoV.Results: In this study, we investigated the ability of human β-defensin (HBD) 2 to promote antiviral immunity in vitro and in vivo using a receptor-binding domain (RBD) of Middle East respiratory syndrome-coronavirus (MERS-CoV) spike protein (S RBD) as a model antigen (Ag). When HBD 2-conjugated S RBD was used to treat THP-1 human monocytic cells, the expression levels of antiviral (IFN-β, IFN-γ, MxA, PKR, and RNaseL) and primary immune-inducing (NOD2, TNF-α, IL-1β, and IL-6) molecules were enhanced compared to those expressed after treatment with S RBD only. The expression of chemokines capable of recruiting leukocytes, including monocytes/macrophages, natural killer cells, granulocytes, T cells, and dendritic cells, was also increased following HBD 2-conjugated S RBD treatment. More important, immunization of mice with HBD 2-conjugated S RBD enhanced the immunogenicity of the S RBD and elicited a higher S RBD-specific neutralizing antibody response than S RBD alone.
Conclusions: We conclude that HBD 2 activates the primary antiviral innate immune response and may also mediate the induction of an effective adaptive immune response against a conjugated Ag.
5.
The antiviral effect of interferon-beta against SARS-coronavirus is not mediated by MxA protein.
J Clin Virol. 2004 Jul;30(3):211-3. doi: 10.1016/j.jcv.2003.11.013.
PMID: 15135736
Free PMC article.
Severe acute respiratory syndrome (SARS) is caused by a novel
coronavirus termed SARS-CoV. No antiviral treatment has been established
so far. Interferons are cytokines which induce the synthesis of several
antivirally active proteins in the cell. In this study, we demonstrated
that multiplication of SARS-CoV in cell culture can be strongly
inhibited by pretreatment with interferon-beta. Interferon-alpha and
interferon-gamma, by contrast, were less effective. The human MxA
protein is one of the most prominent proteins induced by
interferon-beta. Nevertheless, no interference with SARS-CoV replication
was observed in Vero cells stably expressing MxA. Therefore, other
interferon-induced proteins must be responsible for the strong
inhibitory effect of interferon-beta against SARS-CoV.
6.
Significance of the myxovirus resistance A (MxA) gene -123C>a single-nucleotide polymorphism in suppressed interferon beta induction of severe acute respiratory syndrome coronavirus infection.
J Infect Dis. 2010 Jun 15;201(12):1899-908. doi: 10.1086/652799.
PMID: 20462354
Free PMC article.
Myxovirus resistance A (MxA) is an antiviral protein induced by
interferon alpha and beta (IFN-alpha, IFN-beta) that can inhibit viral
replication. The minor alleles of the -88G>T and -123C>A MxA
promoter single-nucleotide polymorphisms (SNPs) are associated with
increased promoter activity and altered response to IFN-alpha and
IFN-beta treatment. Here, we demonstrate that the -123A minor allele
provided stronger binding affinity to nuclear proteins extracted from
IFN-beta-untreated cells than did the wild-type allele, whereas the -88T
allele showed preferential binding after IFN-beta stimulation.
Endogenous IFN-alpha and IFN-beta induction can be suppressed in severe
acute respiratory syndrome (SARS) coronavirus infection. In support of
our in vitro findings, a large case-control genetic-association study
for SARS coronavirus infection confirmed that the -123A minor-allele
carriers were significantly associated with lower risk of SARS
coronavirus infection, whereas the -88T minor-allele carriers were
insignificant after adjustment for confounding effects. This suggests
that -123C>A plays a more important role in modulating basal MxA
expression, thus contributing more significantly to innate immune
response against viral infections that suppress endogenous IFN-alpha and
IFN-beta induction such as SARS coronavirus.
7.
Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons.
Antivir Ther. 2004 Dec;9(6):1003-11.
PMID: 15651759
There is currently an urgent need to identify effective antiviral agents
that will prevent and treat severe acute respiratory syndrome
coronavirus (SARS-CoV) infection. In this study, we have investigated
and compared the antiviral effect of different interferons (IFNs) on
SARS-CoV replication in the epithelial kidney monkey Vero cell line. The
results showed that SARS-CoV grown in Vero cells is moderately
sensitive to IFN-beta and only weakly sensitive to IFN-alpha and
IFN-gamma, in comparison to other IFN-sensitive viruses, such as those
for encephalomyocarditis, vesicular stomatitis and Newcastle disease.
Simultaneous incubation of Vero cells with IFN-beta and IFN-gamma
indicated that they may act synergistically against SARS-CoV
replication. The IFN-induced MxA protein was detected in the IFN-treated
Vero cells. The data, however, suggest that the antiviral activity of
IFN against SARS-CoV virus is independent of MxA expression.
8.
Multi-tiered screening and diagnosis strategy for
COVID-19: a model for sustainable testing capacity in response to
pandemic.
Ann Med. 2020 May 14:1-8. doi: 10.1080/07853890.2020.1763449. Online ahead of print.
PMID: 32370561
Coronavirus disease 2019 (COVID-19), caused by novel enveloped single
stranded RNA coronavirus (SARS-CoV-2), is responsible for an ongoing
global pandemic. While other countries deployed widespread testing as an
early mitigation strategy, the U.S. experienced delays in development
and deployment of organism identification assays. As such, there is
uncertainty surrounding disease burden and community spread, severely
hampering containment efforts. COVID-19 illuminates the need for a
tiered diagnostic approach to rapidly identify clinically significant
infections and reduce disease spread. Without the ability to efficiently
screen patients, hospitals are overwhelmed, potentially delaying
treatment for other emergencies. A multi-tiered, diagnostic strategy
incorporating a rapid host immune response assay as a screening test,
molecular confirmatory testing and rapid IgM/IgG testing to assess
benefit from quarantine/further testing and provide information on
population exposure/herd immunity would efficiently evaluate potential
COVID-19 patients. Triaging patients within minutes with a fingerstick
rather than hours/days after an invasive swab is critical to pandemic
response as reliance on the existing strategy is limited by assay
accuracy, time to results, and testing capacity. Early screening and
triage is achievable from the outset of a pandemic with point-of-care
host immune response testing which will improve response time to
clinical and public health actions.Key messages Delayed testing
deployment has led to uncertainty surrounding overall disease burden and
community spread, severely hampering public health containment and
healthcare system preparation efforts.A multi-tiered testing strategy
incorporating rapid, host immune point-of-care tests can be used now and
for future pandemic planning by effectively identifying patients at
risk of disease thereby facilitating quarantine earlier in the
progression of the outbreak during the weeks and months it can take for
pathogen specific confirmatory tests to be developed, validated and
manufactured in sufficient quantities.The ability to triage patients at
the point of care and support the guidance of medical and therapeutic
decisions, for viral isolation or confirmatory testing or for
appropriate treatment of COVID-19 and/or bacterial infections, is a
critical component to our national pandemic response and there is an
urgent need to implement the proposed strategy to combat the current
outbreak.
9.
Association of SARS susceptibility with single nucleic acid polymorphisms of OAS1 and MxA genes: a case-control study.
BMC Infect Dis. 2006 Jul 6;6:106. doi: 10.1186/1471-2334-6-106.
PMID: 16824203
Free PMC article. Background:
Host genetic factors may play a role in susceptibility and
resistance to SARS associated coronavirus (SARS-CoV) infection. The
study was carried out to investigate the association between the genetic
polymorphisms of 2',5'-oligoadenylate synthetase 1 (OAS1) gene as well
as myxovirus resistance 1 (MxA) gene and susceptibility to SARS in
Chinese Han population.
Methods:
A hospital-based case-control study was conducted. A collective of
66 SARS cases and 64 close contact uninfected controls were enrolled in
this study. End point real time polymerase chain reaction (PCR) and
PCR-based Restriction Fragment Length Polymorphism (RFLP) analysis were
used to detect the single nucleic polymorphisms (SNPs) in OAS1 and MxA
genes. Information on other factors associated with SARS infection was
collected using a pre-tested questionnaire. Univariate and multivariate
logistic analyses were conducted.
Results: One polymorphism in the 3'-untranslated region (3'-UTR) of the OAS1 gene was associated with SARS infection. Compared to AA genotype, AG and GG genotypes were found associated with a protective effect on SARS infection with ORs (95% CI) of 0.42 (0.20-0.89) and 0.30 (0.09-0.97), respectively. Also, a GT genotype at position 88 in the MxA gene promoter was associated with increased susceptibility to SARS infection compared to a GG genotype (OR = 3.06, 95% CI: 1.25-7.50). The associations of AG genotype in OAS1 and GT genotype in MxA remained significant in multivariate analyses after adjusting for SARS protective measures (OR = 0.38, 95% CI: 0.14-0.98 and OR = 3.22, 95% CI: 1.13-9.18, respectively).
Conclusion: SNPs in the OAS1 3'-UTR and MxA promoter region appear associated with host susceptibility to SARS in Chinese Han population.
10.
Results: One polymorphism in the 3'-untranslated region (3'-UTR) of the OAS1 gene was associated with SARS infection. Compared to AA genotype, AG and GG genotypes were found associated with a protective effect on SARS infection with ORs (95% CI) of 0.42 (0.20-0.89) and 0.30 (0.09-0.97), respectively. Also, a GT genotype at position 88 in the MxA gene promoter was associated with increased susceptibility to SARS infection compared to a GG genotype (OR = 3.06, 95% CI: 1.25-7.50). The associations of AG genotype in OAS1 and GT genotype in MxA remained significant in multivariate analyses after adjusting for SARS protective measures (OR = 0.38, 95% CI: 0.14-0.98 and OR = 3.22, 95% CI: 1.13-9.18, respectively).
Conclusion: SNPs in the OAS1 3'-UTR and MxA promoter region appear associated with host susceptibility to SARS in Chinese Han population.
10.
Severe acute respiratory syndrome coronavirus fails to activate cytokine-mediated innate immune responses in cultured human monocyte-derived dendritic cells.
J Virol. 2005 Nov;79(21):13800-5. doi: 10.1128/JVI.79.21.13800-13805.2005.
PMID: 16227300
Free PMC article.
Activation of host innate immune responses was studied in severe acute
respiratory syndrome coronavirus (SCV)-infected human A549 lung
epithelial cells, macrophages, and dendritic cells (DCs). In all cell
types, SCV-specific subgenomic mRNAs were seen, whereas no expression of
SCV proteins was found. No induction of cytokine genes (alpha
interferon [IFN-alpha], IFN-beta, interleukin-28A/B [IL-28A/B], IL-29,
tumor necrosis factor alpha, CCL5, or CXCL10) or IFN-alpha/beta-induced
MxA gene was seen in SCV-infected A549 cells, macrophages, or DCs. SCV
also failed to induce DC maturation (CD86 expression) or enhance major
histocompatibility complex class II expression. Our data strongly
suggest that SCV fails to activate host cell cytokine gene expression in
human macrophages and DCs.
Inhibition of cytokine gene expression and induction of
chemokine genes in non-lymphatic cells infected with SARS coronavirus.
Virol J. 2006 Mar 29;3:17. doi: 10.1186/1743-422X-3-17.
PMID: 16571117
Free PMC article.
Background:
SARS coronavirus (SARS-CoV) is the etiologic agent of the severe
acute respiratory syndrome. SARS-CoV mainly infects tissues of
non-lymphatic origin, and the cytokine profile of those cells can
determine the course of disease. Here, we investigated the cytokine
response of two human non-lymphatic cell lines, Caco-2 and HEK 293,
which are fully permissive for SARS-CoV.
Results: A comparison with established cytokine-inducing viruses revealed that SARS-CoV only weakly triggered a cytokine response. In particular, SARS-CoV did not activate significant transcription of the interferons IFN-alpha, IFN-beta, IFN-lambda1, IFN-lambda2/3, as well as of the interferon-induced antiviral genes ISG56 and MxA, the chemokine RANTES and the interleukine IL-6. Interestingly, however, SARS-CoV strongly induced the chemokines IP-10 and IL-8 in the colon carcinoma cell line Caco-2, but not in the embryonic kidney cell line 293.
Conclusion: Our data indicate that SARS-CoV suppresses the antiviral cytokine system of non-immune cells to a large extent, thus buying time for dissemination in the host. However, synthesis of IP-10 and IL-8, which are established markers for acute-stage SARS, escapes the virus-induced silencing at least in some cell types. Therefore, the progressive infiltration of immune cells into the infected lungs observed in SARS patients could be due to the production of these chemokines by the infected tissue cells.
Results: A comparison with established cytokine-inducing viruses revealed that SARS-CoV only weakly triggered a cytokine response. In particular, SARS-CoV did not activate significant transcription of the interferons IFN-alpha, IFN-beta, IFN-lambda1, IFN-lambda2/3, as well as of the interferon-induced antiviral genes ISG56 and MxA, the chemokine RANTES and the interleukine IL-6. Interestingly, however, SARS-CoV strongly induced the chemokines IP-10 and IL-8 in the colon carcinoma cell line Caco-2, but not in the embryonic kidney cell line 293.
Conclusion: Our data indicate that SARS-CoV suppresses the antiviral cytokine system of non-immune cells to a large extent, thus buying time for dissemination in the host. However, synthesis of IP-10 and IL-8, which are established markers for acute-stage SARS, escapes the virus-induced silencing at least in some cell types. Therefore, the progressive infiltration of immune cells into the infected lungs observed in SARS patients could be due to the production of these chemokines by the infected tissue cells.
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