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


METHODS
C57BL6 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).


RESULTS
PR8-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.


CONCLUSIONS
The 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.
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201, USA. wchen@medicine.umaryland.edu
Wilbur H
WH
Chen
Franklin R
FR
Toapanta
Kari Ann
KA
Shirey
Lei
L
Zhang
Angeliki
A
Giannelou
Carly
C
Page
Matthew B
MB
Frieman
Stefanie N
SN
Vogel
Alan S
AS
Cross
D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003170:Complement Pathway, Alternative; D004198:Disease Susceptibility; D005786:Gene Expression Regulation; D009980:Influenza A virus / Q000276:immunology* / Q000472:pathogenicity; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D037102:Lectins / Q000235:genetics; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000150:complications* / Q000276:immunology*; D011008:Pneumococcal Infections / Q000209:etiology / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology* / Q000472:pathogenicity; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics
D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; D037102:Lectins; C413576:Retnla protein, mouse; D015847:Interleukin-4; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases; C544448:Arg1 protein, mouse; D001119:Arginase