Limited Anti-Inflammatory Role for Interleukin-1 Receptor Like 1 (ST2) in the Host Response to Murine Postinfluenza Pneumococcal Pneumonia

Abstract

Interleukin-1 receptor like 1 (ST2) is a negative regulator of Toll-like receptor (TLR) signaling. TLRs are important for host defense during respiratory tract infections by both influenza and Streptococcus (S.) pneumoniae. Enhanced susceptibility to pneumococcal pneumonia is an important complication following influenza virus infection. We here sought to determine the role of ST2 in primary influenza A infection and secondary pneumococcal pneumonia. ST2 knockout (st2 −/−) and wild-type (WT) mice were intranasally infected with influenza A virus; in some experiments mice were infected 2 weeks later with S. pneumoniae. Both mouse strains cleared the virus similarly during the first 14 days of influenza infection and had recovered their weights equally at day 14. Overall st2−/− mice tended to have a stronger pulmonary inflammatory response upon infection with influenza; especially 14 days after infection modest but statistically significant elevations were seen in lung IL-6, IL-1β, KC, IL-10, and IL-33 concentrations and myeloperoxidase levels, indicative of enhanced neutrophil activity. Interestingly, bacterial lung loads were higher in st2−/− mice during the later stages of secondary pneumococcal pneumonia, which was associated with relatively increased lung IFN-γ levels. ST2 deficiency did not impact on gross lung pathology in either influenza or secondary S. pneumoniae pneumonia. These data show that ST2 plays a limited anti-inflammatory role during both primary influenza and postinfluenza pneumococcal pneumonia.

Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease

“…Finally, a role for type 2 innate lymphoid cells (ILC2) in superinfection has recently been demonstrated. ILC2 cells express the IL-33 receptor ST2 (interleukin-1 receptor-like 1), and ST2 Ϫ/Ϫ mice had higher S. pneumoniae burden and increased inflammation compared to WT animals during superinfection (48). These data suggest that ILC2 may play a protective role, perhaps by producing IL-13, during postinfluenza bacterial superinfection.…”

Single Immunoglobulin Interleukin-1 Receptor-Related Molecule Impairs Host Defense during Pneumonia and Sepsis Caused by <b><i>Streptococcus Pneumoniae</i></b>

“…Similarly, tlr9-/- mice displayed accelerated growth of pneumococci upon infection of the lower airways together with enhanced mortality [13], while il-1rI-/- [29] and il-18-/- [30] mice showed a more modestly impaired immune response only reflected by higher bacterial loads. To our knowledge, the role of TLR7 has not been studied in the context of pneumococcal infections, while our laboratory recently showed that ST2 does not contribute to the host defense during S. pneumoniae pneumonia [26]. Together these data suggest that SIGIRR may impair the host defense during pneumococcal pneumonia via inhibition of TLR4, TLR9, IL-1RI, and/or IL-18R.…”

“…Lung histopathology was semiquantitatively analyzed as described [7,26]. In short: the ‘lung inflammation score' was expressed as the sum of 6 parameters [graded on a scale of 0 (absent) to 4 (severe)]: pleuritis, bronchitis, edema, interstitial inflammation, percentage of pneumonia, and endothelialitis.…”

“…The entire Ly-6G-stained lung sections were digitized with a slide scanner (Olympus, Tokyo, Japan). Immunopositive (Ly-6G+) areas were analyzed with ImageJ (version 2006.02.01; National Institutes of Health, Bethesda, Md., USA) and expressed as a percentage of the total lung surface area [26,27]. Analyses were performed in a blinded manner, i.e.…”

The role of influenza in the severity and transmission of respiratory bacterial disease

“…60 Generally, a powerful and swift response to co-infection could reduce bacterial load and improve survival by preventing the need for a more aggressive, and often immunopathological response to control co-infection. 87 If, however, inflammation is insufficient for swift bacterial clearance, then the host might fare better to prioritise immune regulation over pathogen control while handing over the task of bacterial clearance to the adaptive immune response.…”