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

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.

• Authors: Lis R V Antonelli, Antonio Gigliotti Rothfuchs, Ricardo Gonçalves, Ester Roffê, Allen W Cheever, Andre Bafica, Andres M Salazar, Carl G Feng, Alan Sher
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 120 Issue 5 Pg. 1674-82 (May 2010) ISSN: 1558-8238 [Electronic] United States
• PMID: 20389020 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

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

Topics

• Administration, Intranasal
• Animals
• CD11b Antigen (biosynthesis)
• Carboxymethylcellulose Sodium (analogs & derivatives, 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, therapeutic use)
• Receptors, CCR2 (metabolism)
• Tuberculosis (drug therapy)