Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population

J Clin Invest. 2010 May;120(5):1674-82. doi: 10.1172/JCI40817. Epub 2010 Apr 12.

Abstract

Type I IFN has been demonstrated to have major regulatory effects on the outcome of bacterial infections. To assess the effects of exogenously induced type I IFN on the outcome of Mycobacterium tuberculosis infection, we treated pathogen-exposed mice intranasally with polyinosinic-polycytidylic acid condensed with poly-l-lysine and carboxymethylcellulose (Poly-ICLC), an agent designed to stimulate prolonged, high-level production of type I IFN. Drug-treated, M. tuberculosis-infected WT mice, but not mice lacking IFN-alphabeta receptor 1 (IFNalphabetaR; also known as IFNAR1), displayed marked elevations in lung bacillary loads, accompanied by widespread pulmonary necrosis without detectable impairment of Th1 effector function. Importantly, lungs from Poly-ICLC-treated M. tuberculosis-infected mice exhibited a striking increase in CD11b+F4/80+Gr1int cells that displayed decreased MHC II expression and enhanced bacterial levels relative to the same subset of cells purified from infected, untreated controls. Moreover, both the Poly-ICLC-triggered pulmonary recruitment of the CD11b+F4/80+Gr1int population and the accompanying exacerbation of infection correlated with type I IFN-induced upregulation of the chemokine-encoding gene Ccl2 and were dependent on host expression of the chemokine receptor CCR2. The above findings suggest that Poly-ICLC treatment can detrimentally affect the outcome of M. tuberculosis infection, by promoting the accumulation of a permissive myeloid population in the lung. In addition, these data suggest that agents that stimulate type I IFN should be used with caution in patients exposed to this pathogen.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Administration, Intranasal
  • Animals
  • CD11b Antigen / biosynthesis
  • Carboxymethylcellulose Sodium / analogs & derivatives*
  • Carboxymethylcellulose Sodium / therapeutic use
  • Dose-Response Relationship, Drug
  • Female
  • Interferon Type I / metabolism
  • Interferon-beta / metabolism
  • Lung / microbiology*
  • Macrophages / cytology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / cytology*
  • Poly I-C / therapeutic use*
  • Polylysine / analogs & derivatives*
  • Polylysine / therapeutic use
  • Receptors, CCR2 / metabolism
  • Tuberculosis / drug therapy*

Substances

  • CD11b Antigen
  • Ccr2 protein, mouse
  • Interferon Type I
  • Receptors, CCR2
  • Polylysine
  • poly ICLC
  • Interferon-beta
  • Carboxymethylcellulose Sodium
  • Poly I-C