Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis
Leticia Monin, … , Edward J. Pearce, Shabaana A. Khader
Leticia Monin, … , Edward J. Pearce, Shabaana A. Khader
Published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4699-4713. https://doi.org/10.1172/JCI77378.
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Research Article Immunology

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

Abstract

Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1–expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1–expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB.

Authors

Leticia Monin, Kristin L. Griffiths, Wing Y. Lam, Radha Gopal, Dongwan D. Kang, Mushtaq Ahmed, Anuradha Rajamanickam, Alfredo Cruz-Lagunas, Joaquín Zúñiga, Subash Babu, Jay K. Kolls, Makedonka Mitreva, Bruce A. Rosa, Rosalio Ramos-Payan, Thomas E. Morrison, Peter J. Murray, Javier Rangel-Moreno, Edward J. Pearce, Shabaana A. Khader

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Figure 6

SEA treatment impairs Mtb-driven Th1 responses and increases susceptibility to Mtb infection.

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SEA treatment impairs Mtb-driven Th1 responses and increases susceptibil...
(A) Lung CD4+ cells were purified from d30 Mtb-infected mice and incubated with Schistosoma egg antigen (Mtb + SEA) or without SEA (Mtb) and APCs. Cells were restimulated with α-CD3/CD28 beads or irradiated splenocytes, and ESAT-61–20 peptide and supernatant IFN-γ levels were assessed. (B) Overall gene-expression changes induced by SEA in cell pellets from A were assessed by RNAseq. Heat-map representation of significant genes is shown. (C) CD4+ cells sorted from ESAT-6 TCR Tg mice were transferred to Cd4–/– mice, which were Mtb infected. On d30 after infection, lung CD4+ cells were sorted, treated with SEA, and restimulated with irradiated splenocytes and ESAT-61–20 peptide. Supernatant IFN-γ levels were determined. (D) In some experiments, Mtb-infected C57BL/6 mice were immunized with SEA or saline on d15 after infection. Lung IFN-γ levels from d30 were determined. (E) Mtb-infected Yeti mice were immunized with SEA on d15 after infection, and the percentage of lung CD4+CD44+YFP+ cells was determined by flow cytometry. (F) IFN-γ MFI (YFP) within CD4+CD44+ T cells was determined. (G) The number of lung ESAT-61–20–specific, IFN-γ–producing cells was determined by ELISpot. (H) Lung CD4+CD44+IFN-γ+ cell numbers following PMA/ionomycin stimulation were determined. (I) C57BL/6 mice were infected with Mtb and immunized with SEA or saline on d1, d15, or both d1 and d15 after infection, and d30 lung bacterial burden was determined. n = 3 samples (A and B) or n = 5–9 mice (C–I). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001; 1-way ANOVA with post-hoc Tukey (A, E, F, G, and I) or unpaired, 2-tailed Student’s t test (C, D, and H) were used. One experiment of 2 shown. Un, uninfected controls.