Immunoparalysis and Adverse Outcomes from Critical Illness

Frazier, W. Joshua; Hall, Mark W.

doi:10.1016/j.pcl.2008.02.009

Cited by 134 publications

(127 citation statements)

References 100 publications

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…Proper cytokine expression is necessary for disease recovery, defending against virus infection, and recruiting inflammatory cells to the sites of infection through a delicate balance between pro-and anti-inflammatory mediators (37). However, to clear highly pathogenic viruses, proinflammatory cytokines are massively and persistently activated and recruited, causing the host immunologic balance to break down and cascade into an uncontrolled cytokine storm.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the Internal Genes of Influenza A (H7N9) Virus Contributing to High Pathogenicity in Mice

Xie

Zhang

et al. 2015

J Virol

View full text Add to dashboard Cite

The recently identified H7N9 influenza A virus has caused severe economic losses and worldwide public concern. Genetic analysis indicates that its six internal genes all originated from H9N2 viruses. However, the H7N9 virus is more highly pathogenic in humans than H9N2, which suggests that the internal genes of H7N9 have mutated. To analyze which H7N9 virus internal genes contribute to its high pathogenicity, a series of reassortants was generated by reverse genetics, with each virus containing a single internal gene of the typical A/Anhui/1/2013 (H7N9) (AH-H7N9) virus in the genetic background of the A/chicken/Shandong/ lx1023/2007 (H9N2) virus. The replication ability, polymerase activity, and pathogenicity of these viruses were then evaluated in vitro and in vivo. These recombinants displayed high genetic compatibility, and the H7N9-derived PB2, M, and NP genes were identified as the virulence genes for the reassortants in mice. Further investigation confirmed that the PB2 K627 residue is critical for the high pathogenicity of the H7N9 virus and the reassortant containing the H7N9-derived PB2 segment (H9N2-AH/ PB2). Notably, the H7N9-derived PB2 gene displayed greater compatibility with the H9N2 genome than that of H7N9, endowing the H9N2-AH/PB2 reassortant with greater viability and virulence than the parental H7N9 virus. In addition, the H7N9 virus, with the exception of the H9N2 reassortants, could effectively replicate in human A549 cells. Our results indicate that PB2, M, and NP are the key virulence genes, together with the surface hemagglutinin (HA) and neuraminidase (NA) proteins, contributing to the high infectivity of the H7N9 virus in humans. IMPORTANCETo date, the novel H7N9 influenza A virus has caused 437 human infections, with approximately 30% mortality. Previous work has primarily focused on the two viral surface proteins, HA and NA, but the contribution of the six internal genes to the high pathogenicity of H7N9 has not been systematically studied. Here, the H9N2 virus was used as a genetic backbone to evaluate the virulence genes of H7N9 virus in vitro and in vivo. Our data indicate that the PB2, M, and NP genes play important roles in viral infection in mice and, together with HA and NA, contribute to the high infectivity of the H7N9 virus in humans. A vian influenza virus (AIV) is an enveloped, single-stranded negative-sense RNA virus that belongs to the influenza A genus of the Orthomyxoviridae family. The AIV genome is comprised of eight gene segments: hemagglutinin (HA), neuraminidase (NA), basic polymerase 2 (PB2), basic polymerase 1 (PB1), acidic polymerase (PA), nucleoprotein (NP), matrix (M), and nonstructural protein (NS). Based on the antigenic properties of the HA (H1 to H16) and NA (N1 to N9) surface glycoproteins, as well as two recently discovered bat-derived H17N10 and H18N11 influenza-like genomes (1), AIV can be further divided into subtypes.AIV is generally considered species specific and rarely crosses the species barrier to infect mammals and humans (2). However...

show abstract

Section: Discussionmentioning

confidence: 99%

Assessment of the Internal Genes of Influenza A (H7N9) Virus Contributing to High Pathogenicity in Mice

Xie

Zhang

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…These factors are believed to be associated with an imbalance of inflammation and immune reactions, which may be responsible for determining severity and prognosis in several life-threatening conditions (16,17). However, to our knowledge, no reports have examined the correlation between macrolide combination effects and immune checkpoint systems in S. pneumoniae pneumonia.…”

Section: Cd86 and Major Histocompatibility Complex Class II [Mhc-ii])mentioning

confidence: 99%

Efficacy of β-Lactam-plus-Macrolide Combination Therapy in a Mouse Model of Lethal Pneumococcal Pneumonia

Yoshioka

Kajiwara

Ishii

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

b Community-acquired pneumonia is a common disease with considerable morbidity and mortality, for which Streptococcus pneumoniae is accepted as a leading cause. Although ␤-lactam-plus-macrolide combination therapy for this disease is recommended in several guidelines, the clinical efficacy of this strategy against pneumococcal pneumonia remains controversial. In this study, we examined the effects of ␤-lactam-plus-macrolide combination therapy on lethal mouse pneumococcal pneumonia and explored the mechanisms of action in vitro and in vivo. We investigated survival, lung bacterial burden, and cellular host responses in bronchoalveolar lavage fluids obtained from mice infected with pneumonia and treated with ceftriaxone, azithromycin, or both in combination. Although in vitro synergy was not observed, significant survival benefits were demonstrated with combination treatment. Lung neutrophil influx was significantly lower in the ceftriaxone-plus-azithromycin-treated group than in the ceftriaxone-treated group, whereas no differences in the lung bacterial burden were observed on day 3 between the ceftriaxone-plus-azithromycin-treated group and the ceftriaxone-treated group. Notably, the analysis of cell surface markers in the ceftriaxone-plus-azithromycin combination group exhibited upregulation of presumed immune checkpoint ligand CD86 and major histocompatibility complex class II in neutrophils and CD11b-positive CD11c-positive (CD11b ؉ CD11c ؉ ) macrophages and dendritic cells, as well as downregulation of immune checkpoint receptors cytotoxic-T lymphocyte-associated antigen 4 and programmed death 1 in T helper and T regulatory cells. Our data demonstrate that the survival benefits of ceftriaxoneplus-azithromycin therapy occur through modulation of immune checkpoints in mouse pneumococcal pneumonia. In addition, immune checkpoint molecules may be a novel target class for future macrolide research.

show abstract

“…Monocytes express human leukocyte antigen-DR (HLA-DR) molecules, which are responsible for antigen presentation to T cells, thereby presenting antigens to adaptive immune system cells. Cytokines released from monocytes mediate responses to other cells and activate complement and coagulation cascades (4).…”

mentioning

confidence: 99%

“…This downregulation, the compensatory anti-inflammatory response syndrome (CARS), either acts as a protective mechanism or, if prolonged or extensive, becomes harmful in adults. Decrease in HLA-DR expression is indicative for CARS (4). Persistent low (<60%) HLA-DR expression on monocytes is termed immunodepression or, if monocyte HLA-DR expression is <30%, immunoparalysis (4,5).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Low monocyte HLA-DR expression as an indicator of immunodepression in very low birth weight infants

et al. 2012

View full text Add to dashboard Cite

Immunoparalysis and Adverse Outcomes from Critical Illness

Cited by 134 publications

References 100 publications

Assessment of the Internal Genes of Influenza A (H7N9) Virus Contributing to High Pathogenicity in Mice

Assessment of the Internal Genes of Influenza A (H7N9) Virus Contributing to High Pathogenicity in Mice

Efficacy of β-Lactam-plus-Macrolide Combination Therapy in a Mouse Model of Lethal Pneumococcal Pneumonia

Low monocyte HLA-DR expression as an indicator of immunodepression in very low birth weight infants

Contact Info

Product

Resources

About