Apoptosis and Pro-inflammatory Cytokine Response of Mast Cells Induced by Influenza A Viruses

Liu, Bo; Meng, Di; Wei, Tangting; Zhang, Siyi; Hu, Yanxin; Wang, Ming

doi:10.1371/journal.pone.0100109

Cited by 40 publications

(51 citation statements)

References 46 publications

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“…Notably, the delay of cell death-related pathways may contribute to improved survival of distinct populations of immune cells, which in turn can alter pathogenesis in the host. The specific induction of mast cell apoptosis early following LUJV infection may partly explain the milder pathology, as mast cells have been associated with inflammatory pathology in response to virus infection (36)(37)(38)(39)(40)(41)(42)(43)(44), including vascular leakage associated with dengue hemorrhagic fever (45). The early selective depletion of mast cells may account for immune responses associated with controlled antiviral responses rather than uncontrolled inflammation and consequent mild disease during LUJV infection.…”

Section: Discussionmentioning

confidence: 99%

Delayed Inflammatory and Cell Death Responses Are Associated with Reduced Pathogenicity in Lujo Virus-Infected Cynomolgus Macaques

Rasmussen

Tchitchek

Safronetz

et al. 2015

J Virol

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To identify host factors associated with arenavirus virulence, we used a cynomolgus macaque model to evaluate the pathogenesis of Lujo virus (LUJV), a recently emerged arenavirus that caused an outbreak of severe viral hemorrhagic fever in southern Africa. In contrast to human cases, LUJV caused mild, nonlethal illness in macaques. We then compared this to contrasting clinical outcomes during arenavirus infection, specifically to samples obtained from macaques infected with three highly pathogenic lines of Lassa virus (LASV), the causative agent of Lassa fever (LF). We assessed gene expression in peripheral blood mononuclear cells (PBMC) and determined genes that significantly changed expression relative to that in uninfected animals over the course of infection. We detected a 72-h delay in the induction of host responses to infection during LUJV infection compared to that of the animals infected with LASV. This included genes associated with inflammatory and antiviral responses and was particularly apparent among groups of genes promoting cell death. We also observed early differential expression of a subset of genes specific to LUJV infection that accounts for the delayed inflammatory response. Cell type enrichment analysis suggested that host response induction delay and an LUJV-specific profile are due to a different proportion of natural killer cells responding in LUJV infection than that in the LASV-infected animals. Together, these data indicate that delayed proinflammatory and proapoptotic host responses to arenavirus infection could ameliorate disease severity. This conclusion provides insight into the cellular and molecular mechanisms of arenaviral hemorrhagic fever and suggests potential strategies for therapeutic development. IMPORTANCEOld World arenaviruses are significant human pathogens that often are associated with high mortality. However, mechanisms underlying disease severity and virulence in arenavirus hemorrhagic fever are largely unknown, particularly regarding host responses that contribute to pathogenicity. This study describes a comparison between Lujo and Lassa virus infection in cynomolgus macaques. Lujo virus-infected macaques developed only mild illness, while Lassa virus-infected macaques developed severe illness consistent with Lassa fever. We determined that mild disease is associated with a delay in host expression of genes linked to virulence, such as those causing inflammation and cell death, and with distinct cell types that may mediate this delay. This is the first study to associate the timing and directionality of gene expression with arenaviral pathogenicity and disease outcome and evokes new potential approaches for developing effective therapeutics for treating these deadly emerging pathogens. Since their discovery in the early 20th century, arenaviruses have been consistently associated with outbreaks of severe illness, including viral hemorrhagic fever (VHF) and encephalitis. Arenaviruses are bisegmented, ambisense, single-stranded, negative-sense RNA viruses t...

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Section: Discussionmentioning

confidence: 99%

Delayed Inflammatory and Cell Death Responses Are Associated with Reduced Pathogenicity in Lujo Virus-Infected Cynomolgus Macaques

Rasmussen

Tchitchek

Safronetz

et al. 2015

J Virol

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“…The extrinsic and intrinsic pathways are two well-studied mechanisms that contribute to the execution of apoptosis (Figure 1; [10,11,12,13,14,15]). The binding between death ligands, including Fas ligand (Fas L), tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), and TNF-α, and corresponding death receptors result in the assembly of death-inducing signaling complexes which initiate the extrinsic pathway by activating caspase-8 [23].…”

Section: Overview Of Apoptosismentioning

confidence: 99%

“…The intrinsic pathway is activated in the presence of numerous intracellular stimuli, including DNA damage, endoplasmic reticular stress, oxidative stress, and breakage of mitochondrial membranes [12,13]. Activation of multiple death receptors or the withdrawal of cytokines induces extrinsic pathway-mediated apoptosis [14,15]. Both the intrinsic and extrinsic pathways lead to the release of cytochrome C and other apoptosis-inducing factors, which subsequently activate downstream caspases [16].…”

Section: Introductionmentioning

confidence: 99%

Differential Impacts of Alternative Splicing Networks on Apoptosis

Lin

Tsao

Lin

2016

IJMS

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Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The biological functions of several apoptotic factors are manipulated through alternative splicing mechanisms which expand gene diversity by generating discrete variants from one messenger RNA precursor. It is widely observed that alternatively-spliced variants encoded from apoptosis-related genes exhibit differential effects on apoptotic regulation. Alternative splicing events are meticulously regulated by the interplay between trans-splicing factors and cis-responsive elements surrounding the regulated exons. The major focus of this review is to highlight recent studies that illustrate the influences of alternative splicing networks on apoptotic regulation which participates in diverse cellular processes and diseases.

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“…The virus infects human mast cells lines and primary cultured mast cells and starts to replicate, but there is no release of infectious particles, perhaps because the cells may lack the machinery to assemble the virus or because of active antiviral mechanisms (Marcet et al, 2013). These observations may reflect the characteristics of the cells or viral strains used, since the murine mastocytosis cell line P815 can support productive replication of influenza A virus, which leads to cytokine production and finally apoptosis of this line (Liu et al, 2014). Interestingly, H5N1 influenza activates mast cells in vitro and in vivo (Hu et al, 2012); H5N1 infection increases the number of mast cells in the airway mucosa and the mast cells appear degranulated.…”

Section: Infectionsmentioning

confidence: 99%