Potential role for alternatively activated macrophages in the secondary bacterial infection during recovery from influenza

PurposeSecondary bacterial infections are a common complication of influenza. Innate immune host defenses appear to be impaired following influenza, leading to susceptibility to subsequent bacterial infections. Alternatively activated macrophages (AAM) in the lungs may play a critical role in eliciting the hypersusceptibility to secondary bacterial pneumonia.MethodsC57BL6 mice were challenged with sublethal doses of the mouse-adapted A/PR/8/34 (PR8) influenza virus or saline and allowed to recover. At complete recovery (day 14), mice were re-challenged with sublethal doses of Streptococcus pneumoniae serotype 3 (Sp3).ResultsPR8-recovered mice developed a rapidly fatal pulmonary infection to a 100-fold sublethal pneumococcal challenge, whereas PR8-naive mice demonstrated no mortality or illness. The cytokines which induce AAM (IL-4 and IL-13) and the expression of genes associated with AAM (Arginase-1, FIZZ1, and YM1) were elevated after PR8 infection. Flow cytometry suggests that alveolar macrophages demonstrate the AAM-phenotype, as indicated by MGL-1 and MHCII expression, in response to PR8 infection. Recovery from PR8 was associated with blunted cytokine responses to TLR ligands.ConclusionsThe mechanisms of immune regulation during recovery from influenza are being elucidated. We provide evidence that pulmonary AAM are induced during influenza infection and may contribute to the elicitation of hypersusceptibility to a secondary bacterial infection.

► Mice that have fully recovered from a primary influenza infection are highly susceptible to a secondary bacterial infection.
► Cytokine responses to TLR stimulation are blunted, after influenza infection.
► The initial pro-inflammatory cytokine (IL-6 and TNF-α) response of an influenza infection is followed by anti-inflammatory cytokines (IL-10 and TGF-β).
► Gene expression of markers of AAM (Arg-1, FIZZ1, YM1) and the cytokines necessary to induce AAM (IL-4 and IL-13) are elevated after influenza infection.
► Alveolar macrophages which demonstrate an AAM phenotype are induced after influenza infection.