Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population
Lis R.V. Antonelli, … , Carl G. Feng, Alan Sher
Lis R.V. Antonelli, … , Carl G. Feng, Alan Sher
Published April 12, 2010
Citation Information: J Clin Invest. 2010;120(5):1674-1682. https://doi.org/10.1172/JCI40817.
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Research Article Infectious disease

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-αβ receptor 1 (IFNαβR; 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

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Figure 7

Both recruitment of CD11b+Gr1int cells and exacerbation of M. tuberculosis infection after Poly-ICLC treatment depend on CCR2 expression.

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Both recruitment of CD11b+Gr1int cells and exacerbation of M. tuberculos...
(A) Cxcl1, Cxcr2, and Ccl2 mRNA expression levels, determined by real-time PCR in the lungs of M. tuberculosis–infected animals treated with PBS (open circles) and Poly-ICLC (filled circles). The results shown represent the fold increase relative to that observed in untreated, naive mice, with circles representing individual mice. Data were pooled from 3 independent experiments with similar results. (B) Representative flow cytometry dot plots of CD11b+Gr1–, CD11b+Gr1int, and CD11b+Gr1high pulmonary leukocytes isolated from Poly-ICLC– or PBS-treated, M. tuberculosis–infected WT mice or Ccr2-deficient animals. Numbers within or beside each box refer to the frequencies of cells within each gate. (C) Pulmonary mycobacterial loads in PBS-treated (open circles) and Poly-ICLC–treated (closed circles) WT and Ccr2-deficient mice. Circles represent individual animals. The data shown are representative of 3 independent experiments. (A and C) Horizontal lines represent comparisons between Poly-ICLC– and PBS-treated, M. tuberculosis–infected mice. **P < 0.01.