Influenza-induced immune suppression to methicillin-resistant Staphylococcus aureus is mediated by TLR9.
Martínez-Colón GJ, Warheit-Niemi H, Gurczynski SJ, Taylor QM, Wilke CA, Podsiad AB, Crespo J, Bhan U, Moore BB
PLoS Pathog. Jan 2019. doi: 10.1371/journal.ppat.1007560
COMMENT: This article describes one important finding that could be involved in the known fact that methicillin-resistant Staphylococcus aureus (MRSA) lung infections have increased mortality if they appeared after influenza infection. After observing that TLR9 is increased in murine lung macrophages, dendritic cells, CD8+ T cells and epithelial cells post-influenza infection and that TLR9-/- mice have improved survival in post-influenza MRSA infection the authors investigated the possible reasons and concluded that the data showed a surprising TLR9 inhibitory role in the clearance of MRSA when the infection follows a influenza infection.
These were the main experimental results:
We demonstrate that TLR9 is upregulated on macrophages even when they are not themselves infected, suggesting that TLR9 upregulation is related to soluble mediators. We rule out a role for elevations in interferon-γ (IFNγ) in mediating the beneficial MRSA clearance in TLR9-/- mice. While macrophages from WT and TLR9-/- mice show similar phagocytosis and bacterial killing to MRSA alone, following influenza infection, there is a marked upregulation of scavenger receptor A and MRSA phagocytosis as well as inducible nitric oxide synthase (Inos) and improved bacterial killing that is specific to TLR9-deficient cells. Bone marrow transplant chimera experiments and in vitro experiments using TLR9 antagonists suggest TLR9 expression on non-hematopoietic cells, rather than the macrophages themselves, is important for regulating myeloid cell function.