PLoS One. 2014 Mar 10;9(3):e90855. doi: 10.1371/journal.pone.0090855. eCollection 2014.
Direct Infection of Dendritic Cells during Chronic Viral Infection Suppresses Antiviral T Cell Proliferation and Induces IL-10 Expression in CD4 T Cells.
Baca Jones C,
Filippi C,
Sachithanantham S,
Rodriguez-Calvo T,
Ehrhardt K,
von Herrath M.
Author information
Abstract
Elevated levels of systemic IL-10 have been associated with several chronic viral infections, including HCV, EBV, HCMV and LCMV. In the chronic LCMV infection model, both elevated IL-10 and enhanced infection of dendritic cells (DCs) are important for viral persistence.
This report highlights the relationship between enhanced viral tropism for DCs and the induction of IL-10 in CD4 T cells, which we identify as the most frequent IL-10-expressing cell type in chronic LCMV infection.
Here we report that infected CD8αneg DCs express elevated IL-10, induce IL-10 expression in LCMV specific CD4 T cells, and suppress LCMV-specific T cell proliferation. DCs exposed in vivo to persistent LCMV retain the capacity to stimulate CD4 T cell proliferation but induce IL-10 production by both polyclonal and LCMV-specific CD4 T cells.
Our study delineates the unique effects of direct infection versus viral exposure on DCs. Collectively these data point to enhanced infection of DCs as a key trigger of the IL-10 induction cascade resulting in maintenance of elevated IL-10 expression in CD4 T cells and inhibition of LCMV-specific CD4 and CD8 T cell proliferation.
Introduction
The host-pathogen relationship in chronic viral infections requires the establishment of equilibrium between the host immune response and viral replication. While this balance of competing interests aids in protecting the host from the immunopathologic consequences of continuous inflammation, such a truce can also result in the prolonged persistence of the virus within its host. Studies over the last decade have identified several characteristics common to multiple persistent viral infections including elevated levels of systemic IL-10 and T cell exhaustion
[1]–
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Also
PLoS One. 2013; 8(4): e62850.
Published online Apr 24, 2013. doi:
10.1371/journal.pone.0062850
PMCID: PMC3634751
Epstein Barr Virus and Helicobacter pylori Co-Infection Are Positively Associated with Severe Gastritis in Pediatric Patients
María G. Cárdenas-Mondragón,
Ricardo Carreón-Talavera,
Margarita Camorlinga-Ponce,
Alejandro Gomez-Delgado,
Javier Torres, and
Ezequiel M. Fuentes-Pananá*
Yoshio Yamaoka, Editor
Abstract
Background
H. pylori infection is acquired during childhood and causes a chronic inflammatory response in the gastric mucosa, which is considered the main risk factor to acquire gastric cancer (GC) later in life.
More recently, infection by Epstein-Barr virus (EBV) have also been associated with GC. The role of EBV in early inflammatory responses and its relationship with H. pylori infection remains poorly studied.
Here, we assessed whether EBV infection in children correlated with the stage of gastritis and whether co-infection with H. pylori affected the severity of inflammation.
Methodology/Principal Findings
333 pediatric patients with chronic abdominal pain were studied. From them, gastric biopsies were taken and inflammation graded according to the Sydney system; peripheral blood was drawn and antibodies against EBV (IgG and IgM anti-VCA) and H. pylori (IgG anti-whole bacteria and anti-CagA) were measured in sera. We found that children infected only by EBV presented mild mononuclear (MN) and none polymorphonuclear (PMN) cell infiltration, while those infected by H. pylori presented moderate MN and mild PMN.
In contrast, patients co-infected with both pathogens were significantly associated with severe gastritis. Importantly, co-infection of H. pylori CagA+/EBV+ had a stronger association with severe MN (PR 3.0) and PMN (PR 7.2) cells than cases with single H. pylori CagA+ infection.
Conclusions/Significance
Co-infection with EBV and H. pylori in pediatric patients is associated with severe gastritis. Even single infections with H. pylori CagA+ strains are associated with mild to moderate infiltration arguing for a cooperative effect of H. pylori and EBV in the gastric mucosa and re
vealing a critical role for EBV previously un-appreciated.
This study points out the need to study both pathogens to understand the mechanism behind severe damage of the gastric mucosa, which could identified children with increased risk to present more serious lesions later in life.
Introduction
Persistent infections often lead to chronic inflammation, a well documented cancer risk factor. Gastric cancer (GC) generally starts with an inflammatory process mainly associated with infection by Helicobacter pylori (H. pylori)
[1].
GC is the fourth most common type of cancer and the second cause of death by cancer world-wide, affecting particularly Asian and Latin American countries
[2]. More recently, GC has also been associated with Epstein-Barr virus (EBV) but the role of the viral infection in early inflammatory gastric responses remains poorly studied.
H. pylori infects over 50% of the world population, with a higher prevalence in developing countries. Infection is usually acquired early in life; in Mexico, about 50% of children are infected by the age of 10
[3].
Inflammation after infection in children is usually associated with a low level of polymorphonuclear (PMN) and mononuclear (MN) cells infiltrating the gastric mucosa
[4]. It has been suggested than the earlier the infection, the greater the risk to present GC later in life, conceivable because of a long lasting (decades) chronic inflammatory reaction to the infection
[5].
Only a fraction of H. pylori infected individuals develop gastroduodenal disease: <15% peptic ulcer, <3% GC and <1% MALT lymphoma
[6].
The outcome of H. pylori infection depends also on environmental, host and bacterial factors.
Among the most important bacterial virulence factors is the pathogenicity island (CagPAI), which encodes a type IV secretion system (T4SS) that translocates the effector protein CagA into epithelial cells
[7]. CagA activates multiple signaling pathways triggering cellular phenotypes associated with oncogenic transformation
[7]. Moreover, transgenic mice expressing CagA develop adenocarcinomas of the digestive tract. Based on these data, CagA has been recognized as the first known bacterial oncoprotein
[8],
[9].
EBV infection has been consistently associated with several types of lymphoma, nasopharyngeal carcinoma (NPC)
[10],
[11] and more recently to GC
[12],
[13],
[14].
EBV infection also occurs early in childhood and usually persists in B cells, with most infected individuals carrying the virus asymptomatically in a latent stage in these cells.
It is not clear when EBV infects the gastric mucosa and whether infection induces an inflammatory reaction, as observed with H. pylori.
EBV reactivation from infected B cells has been proposed to facilitate infection of the epithelial basolateral face
[15]. In that scenario, the titer of anti-EBV antibodies against structural proteins has been proposed to correlate with the level of viral reactivation and as a prognostic marker in NPC
[10],
[16],
[17].
To our knowledge, no studies have previously addressed whether EBV infection in children is associated with inflammation in the gastric mucosa or whether there exists a cooperative effect between EBV and H. pylori correlating with the severity of the inflammatory reaction.
In this study, we analyzed antibodies against EBV and H. pylori in sera of pediatric patients with chronic abdominal pain.
Our results strongly suggest that single infection by either EBV or H. pylori is associated with a mild to moderate inflammatory response in the gastric mucosa; however, co-infection with both pathogens is significantly associated with severe gastritis.
Even infection with H. pylori cagA+ strains is not associated with severe inflammatory responses in the absence of EBV.
These data argue for a previously unknown critical role of EBV infection in the induction of an inflammatory response in the gastric mucosa of children.
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