Age-Dependent Effects of Type I and Type III IFNs in the Pathogenesis of Bordetella pertussis Infection and Disease

Abstract

Type I and III IFNs play diverse roles in bacterial infections, being protective for some but deleterious for others. Using RNA-sequencing transcriptomics we investigated lung gene expression responses to Bordetella pertussis infection in adult mice, revealing that type I and III IFN pathways may play an important role in promoting inflammatory responses. In B. pertussisinfected mice, lung type I/III IFN responses correlated with increased proinflammatory cytokine expression and with lung inflammatory pathology. In mutant mice with increased type I IFN receptor (IFNAR) signaling, B. pertussis infection exacerbated lung inflammatory pathology, whereas knockout mice with defects in type I IFN signaling had lower levels of lung inflammation than wild-type mice. Curiously, B. pertussis-infected IFNAR1 knockout mice had wild-type levels of lung inflammatory pathology. However, in response to infection these mice had increased levels of type III IFN expression, neutralization of which reduced lung inflammation. In support of this finding, B. pertussis-infected mice with a knockout mutation in the type III IFN receptor (IFNLR1) and double IFNAR1/IFNLR1 knockout mutant mice had reduced lung inflammatory pathology compared with that in wild-type mice, indicating that type III IFN exacerbates lung inflammation. In marked contrast, infant mice did not upregulate type I or III IFNs in response to B. pertussis infection and were protected from lethal infection by increased type I IFN signaling. These results indicate age-dependent effects of type I/III IFN signaling during B. pertussis infection and suggest that these pathways represent targets for therapeutic intervention in pertussis. Pertussis, also referred to as whooping cough, is a highly contagious respiratory disease caused by infection with the bacterial pathogen Bordetella pertussis. There has been a recent resurgence in pertussis, with 48,277 reported cases in the United States in 2012, the most since 1955 (1). In older children and adults, symptoms build up to periods of severe paroxysmal coughing, often for several weeks after onset, but other complications are relatively rare (2, 3). However, for infants, pertussis can be a fatal disease because of

Distinct molecular phenotypes involving several human diseases are induced by IFN-λ3 and IFN-λ4 in monocyte-derived macrophages

“…5 ). It is known that IFN-λ gene polymorphisms are associated with CMV infections in humans [ 33 ] and recent reports suggest type III IFNs are important for inflammatory responses in Bordetella pertussis infection in mice [ 34 ]. Other than the disease-related pathways, several other critical pathways involved in physiology and pathology like cytokine-cytokine receptor interaction, transcriptional misregulation in cancer, viral protein interaction with cytokine and cytokine receptor, NF-kB signaling pathway, Toll-like receptor (TLR) signaling pathway and others were significantly affected in one or two of the three comparison sets (Fig.…”

Mechanisms regulating transitory suppressive activity of neutrophils in newborns: PMNs-MDSCs in newborns

“…It is resistant to ubiquitination and degradation because it lacks critical Ser526 phosphorylation of which enables the recruitment of β‐TrCP E3 ligase 23,24 . Naïve Ifnar1 SA mice did not exhibit an overt phenotype, however, they maintained IFNAR1 expression even when challenged with inflammation, 25 viral, 26 or bacterial 27 infection. PMNs‐MDSCs from 7‐day‐old SA mice expressed markedly higher amount of IFNAR1 than wild‐type (WT) counterpart (Figure 2(B)).…”

“…21,22 PMNs-MDSCs from 7-day-old mice had markedly lower expression of IFNAR1 than PMNs from 14-day-and 6-week-old mice (Figure 2 It is resistant to ubiquitination and degradation because it lacks critical Ser526 phosphorylation of which enables the recruitment of β-TrCP E3 ligase. 23,24 Naïve Ifnar1 SA mice did not exhibit an overt phenotype, however, they maintained IFNAR1 expression even when challenged with inflammation, 25 viral, 26 or bacterial 27 NEC, the most common gastrointestinal emergency in preterm infants, is a cause for severe neonatal morbidities. It is characterized by ischemic necrosis of the intestinal mucosa, and ensuing severe bowel and systemic inflammation that accompanies the acute intestinal injury.…”

Naturally circulating pertactin-deficient Bordetella pertussis strains induce distinct gene expression and inflammatory signatures in human dendritic cells

“…Type I IFN responses can have protective but also detrimental effects during bacterial infections [ 34 , 35 ]. Recent work in IFNAR1-SA mice revealed that increased type I IFN signaling during a B. pertussis infection leads to exacerbated lung pathology in adult mice [ 36 ]. In contrast, this same study showed significantly lower levels of lethality in infant IFNAR1-SA mice infected with B. pertussis as compared to infant wild type mice.…”